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1
Qu, Changxiu, Ji Young Park, Min Woo Yun, Qing-tao He, Fan Yang, Kiae Kim, Donghee Ham, et al. "Scaffolding mechanism of arrestin-2 in the cRaf/MEK1/ERK signaling cascade." Proceedings of the National Academy of Sciences 118, no. 37 (September 10, 2021): e2026491118. http://dx.doi.org/10.1073/pnas.2026491118.
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Arrestins were initially identified for their role in homologous desensitization and internalization of G protein–coupled receptors. Receptor-bound arrestins also initiate signaling by interacting with other signaling proteins. Arrestins scaffold MAPK signaling cascades, MAPK kinase kinase (MAP3K), MAPK kinase (MAP2K), and MAPK. In particular, arrestins facilitate ERK1/2 activation by scaffolding ERK1/2 (MAPK), MEK1 (MAP2K), and Raf (MAPK3). However, the structural mechanism underlying this scaffolding remains unknown. Here, we investigated the mechanism of arrestin-2 scaffolding of cRaf, MEK1, and ERK2 using hydrogen/deuterium exchange–mass spectrometry, tryptophan-induced bimane fluorescence quenching, and NMR. We found that basal and active arrestin-2 interacted with cRaf, while only active arrestin-2 interacted with MEK1 and ERK2. The ATP binding status of MEK1 or ERK2 affected arrestin-2 binding; ATP-bound MEK1 interacted with arrestin-2, whereas only empty ERK2 bound arrestin-2. Analysis of the binding interfaces suggested that the relative positions of cRaf, MEK1, and ERK2 on arrestin-2 likely facilitate sequential phosphorylation in the signal transduction cascade.
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Ghanaatgar-Kasbi, Sadaf, Majid Khazaei, Azam Rastgar-Moghadam, Gordon A. Ferns, Seyed Mahdi Hassanian, and Amir Avan. "The Therapeutic Potential of MEK1/2 Inhibitors in the Treatment of Gynecological Cancers: Rational Strategies and Recent Progress." Current Cancer Drug Targets 20, no. 6 (July 7, 2020): 417–28. http://dx.doi.org/10.2174/1568009620666200424144303.
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The mitogen-activated protein kinase (MAPK) pathway is among the key factors in numerous cellular processes involved in tumorigenesis, suggesting it as a potential therapeutic target in gynecological cancer. MAPKs connect gene expression pathways and external stimulations. They include a network consisting of Ras, Raf or MAP3K, MEK or MAP2K, ERK or MAPK. Among these, MEK is an attractive molecular target of novel cancer therapeutics as it joints upstream activators and their corresponding downstream targets. MEK inhibitors were among the first inhibitors of the MAPK pathway entering into clinical trials. Several drugs have recently been developed as MEK inhibitors. MEK1/2 inhibitors demonstrate promising efficacy and anticancer activity to treat this malignancy and captured much attention in the past decade. Here, we summarize the role of MAPK/MEK/ERK pathway in the pathogenesis of gynecological cancer, with particular emphasis on MEK inhibitors in clinical settings, including PD-0325901, Selumetinib, Cobimetinib, Refametinib, Trametinib, Pimasertib, MEK162 and WX-554 in gynecologic cancers.
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Hiratsuka, Toru, Ignacio Bordeu, Gunnar Pruessner, and Fiona M. Watt. "Regulation of ERK basal and pulsatile activity control proliferation and exit from the stem cell compartment in mammalian epidermis." Proceedings of the National Academy of Sciences 117, no. 30 (July 10, 2020): 17796–807. http://dx.doi.org/10.1073/pnas.2006965117.
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Fluctuation in signal transduction pathways is frequently observed during mammalian development. However, its role in regulating stem cells has not been explored. Here we tracked spatiotemporal ERK MAPK dynamics in human epidermal stem cells. While stem cells and differentiated cells were distinguished by high and low stable basal ERK activity, respectively, we also found cells with pulsatile ERK activity. Transitions from Basalhi-Pulselo(stem) to Basalhi-Pulsehi, Basalmid-Pulsehi, and Basallo-Pulselo(differentiated) cells occurred in expanding keratinocyte colonies and in response to differentiation stimuli. Pharmacological inhibition of ERK induced differentiation only when cells were in the Basalmid-Pulsehistate. Basal ERK activity and pulses were differentially regulated by DUSP10 and DUSP6, leading us to speculate that DUSP6-mediated ERK pulse down-regulation promotes initiation of differentiation, whereas DUSP10-mediated down-regulation of mean ERK activity promotes and stabilizes postcommitment differentiation. Levels of MAPK1/MAPK3 transcripts correlated with DUSP6 and DUSP10 transcripts in individual cells, suggesting that ERK activity is negatively regulated by transcriptional and posttranslational mechanisms. When cells were cultured on a topography that mimics the epidermal−dermal interface, spatial segregation of mean ERK activity and pulses was observed. In vivo imaging of mouse epidermis revealed a patterned distribution of basal cells with pulsatile ERK activity, and down-regulation was linked to the onset of differentiation. Our findings demonstrate that ERK MAPK signal fluctuations link kinase activity to stem cell dynamics.
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Usta, Diren, Romain Sigaud, Juliane L. Buhl, Florian Selt, Viktoria Marquardt, David Pauck, Stefan Pusch, et al. "LGG-17. SYNERGISTIC ACTIVITY OF MAPK INHIBITOR CLASSES REVEALED BY A NOVEL CELL-BASED MAPK ACTIVITY PEDIATRIC LOW-GRADE GLIOMA ASSAY." Neuro-Oncology 22, Supplement_3 (December 1, 2020): iii369. http://dx.doi.org/10.1093/neuonc/noaa222.399.
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Abstract Pilocytic astrocytomas (PAs) and other pediatric low-grade gliomas (pLGGs) exhibit aberrant activation of the MAPK signaling pathway caused by genetic alterations, most commonly KIAA1549:BRAF fusions, BRAF V600E and NF1 mutations. In such a single-pathway disease, novel drugs targeting the MAPK pathway (MAPKi) are prime candidates for treatment. We developed an assay suitable for pre-clinical testing of MAPKi in pLGGs, aiming at the identification of novel MAPK pathway suppressing synergistic drug combinations. We generated a reporter plasmid (pDIPZ) expressing destabilized firefly luciferase driven by a MAPK-responsive ELK-1-binding element, packaged in a lentiviral vector system. We stably transfected pediatric glioma cell lines with a BRAF fusion (DKFZ-BT66) and a BRAFV600E mutation (BT-40) background, respectively. Measurement of MAPK pathway activity was performed using the luciferase reporter. pERK protein levels were detected for validation. We performed a screen of a MAPKi library and calculated Combination Indices of selected combinations. The MAPKi library screen revealed MEK inhibitors as the class inhibiting the pathway with the lowest IC50s, followed by ERK and second generation RAF inhibitors. Synergistic effects in both BRAF-fusion and BRAFV600E mutation backgrounds were observed following combination treatments with different MAPKi classes (RAFi/MEKi, > RAFi/ERKi > MEKi/ERKi). We have generated a novel reporter assay for medium- to high-throughput pre-clinical drug testing of MAPKi in pLGG cell lines. MEK, ERK and next-generation RAF inhibitors were confirmed as potential treatment approaches for KIAA1549:BRAF and BRAFV600E mutated pLGGs. Synergistic suppression of MAPK pathway activity upon combination treatments was revealed using our assay in addition.
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Wei, Xiumei, Yu Zhang, Cheng Li, Kete Ai, Kang Li, Huiying Li, and Jialong Yang. "The evolutionarily conserved MAPK/Erk signaling promotes ancestral T-cell immunity in fish via c-Myc–mediated glycolysis." Journal of Biological Chemistry 295, no. 10 (January 29, 2020): 3000–3016. http://dx.doi.org/10.1074/jbc.ra119.012231.
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The mitogen-activated protein kinase (MAPK) cascade is an ancient and evolutionarily conserved signaling pathway involved in numerous physiological processes. Despite great advances in understanding MAPK-mediated regulation of adaptive immune responses in mammals, its contribution to T-cell immunity in early vertebrates remains unclear. Herein, we used Nile tilapia (Oreochromis niloticus) to investigate the regulatory roles of MAPK/extracellular signal–regulated kinase (Erk) signaling in ancestral T-cell immunity of jawed fish. We found that Nile tilapia possesses an evolutionarily conserved MAPK/Erk axis that is activated through a classical three-tier kinase cascade, involving sequential phosphorylation of RAF proto-oncogene serine/threonine-protein kinase (Raf), MAPK/Erk kinase 1/2 (Mek1/2), and Erk1/2. In Nile tilapia, MAPK/Erk signaling participates in adaptive immune responses during bacterial infection. Upon T-cell activation, the MAPK/Erk axis is robustly activated, and MAPK/Erk blockade by specific inhibitors severely impairs T-cell activation. Furthermore, signals from MAPK/Erk were indispensable for primordial T cells to proliferate and exert their effector functions. Mechanistically, activation of the MAPK/Erk axis promoted glycolysis via induction of the transcriptional regulator proto-oncogene c-Myc (c-Myc), to ensure the proper activation and proliferation of fish T cells. Our results reveal the regulatory mechanisms of MAPK/Erk signaling in T-cell immunity in fish and highlight a close link between immune signals and metabolic programs. We propose that regulation of T-cell immunity by MAPK/Erk is a basic and sophisticated strategy that evolved before the emergence of the tetrapod lineage. These findings shed light on the evolution of the adaptive immune system.
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Liu, Qinghang, and Polly A. Hofmann. "Protein phosphatase 2A-mediated cross-talk between p38 MAPK and ERK in apoptosis of cardiac myocytes." American Journal of Physiology-Heart and Circulatory Physiology 286, no. 6 (June 2004): H2204—H2212. http://dx.doi.org/10.1152/ajpheart.01050.2003.
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Mitogen-activated protein kinases (MAPKs) play different regulatory roles in signaling oxidative stress-induced apoptosis in cardiac ventricular myocytes. The regulation and functional role of cross-talk between p38 MAPK and extracellular signal-regulated kinase (ERK) pathways were investigated in cardiac ventricular myocytes in the present study. We demonstrated that inhibition of p38 MAPK with SB-203580 and SB-239063 enhanced H2O2-stimulated ERK phosphorylation, whereas preactivation of p38 MAPK with sodium arsenite reduced H2O2-stimulated ERK phosphorylation. In addition, pretreatment of cells with the protein phosphatase 2A (PP2A) inhibitors okadaic acid and fostriecin increased basal and H2O2-stimulated ERK phosphorylation. We also found that PP2A coimmunoprecipitated with ERK and MAPK/ERK (MEK) in cardiac ventricular myocytes, and H2O2increased the ERK-associated PP2A activity that was blocked by inhibition of p38 MAPK. Finally, H2O2-induced apoptosis was attenuated by p38 MAPK or PP2A inhibition, whereas it was enhanced by MEK inhibition. Thus the present study demonstrated that p38 MAPK activation decreases H2O2-induced ERK activation through a PP2A-dependent mechanism in cardiac ventricular myocytes. This represents a novel cellular mechanism that allows for interaction of two opposing MAPK pathways and fine modulation of apoptosis during oxidative stress.
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Zhong, Bin, Kun Jiang, Danielle L. Gilvary, Pearlie K. Epling-Burnette, Connie Ritchey, Jinhong Liu, Rosalind J. Jackson, Elizabeth Hong-Geller, and Sheng Wei. "Human neutrophils utilize a Rac/Cdc42-dependent MAPK pathway to direct intracellular granule mobilization toward ingested microbial pathogens." Blood 101, no. 8 (April 15, 2003): 3240–48. http://dx.doi.org/10.1182/blood-2001-12-0180.
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AbstractElevated levels of mitogen-activated protein kinase/extracellular regulatory kinase (MAPK/ERK) activity are frequently found in some cancer cells. In efforts to reduce tumor growth, attempts have been made to develop cancer therapeutic agents targeting the MAPK. Here, by use of biologic, biochemical, and gene manipulation methods in human polymorphonuclear neutrophils (PMNs), we have identified a key pathway important in normal cell function involving MAPK/ERK in PMNs for growth inhibition of Candida albicans. Contact withC albicans triggered MAPK/ERK activation in PMNs within 5 minutes, and blocking of MAPK/ERK activation, either by the pharmacologic reagent PD098059 or by dominant-negative MAPK kinase (MEK) expression via vaccinia viral delivery, suppressed antimicrobial activity. Rac and Cdc42, but not Ras or Rho, were responsible for this MAPK/ERK activation. Expression of dominant-negative Rac (N17Rac) or Cdc42 (N17Cdc42) eliminated not only C albicans– mediated ERK phosphorylation but also phagocytosis and granule migration toward the ingested microbes, whereas dominant-negative Ras (N17Ras) and Rho (N19Rho) did not. PAK1 (p21-activated kinase 1) activation is induced by C albicans, suggesting that PAK1 may also be involved in the Rac1 activation of MAPK/ERK. We conclude from these data that Rac/Cdc42-dependent activation of MAPK/ERK is a critical event in the immediate phagocytic response of PMNs to microbial challenge. Therefore, use of MAPK pharmacologic inhibitors for the treatment of cancer may result in the interruption of normal neutrophil function. A balance between therapeutic outcome and undesirable side effects must be attained to achieve successful and safe anticancer therapy.
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Šrámek, Jan, Vlasta Němcová-Fürstová, Kamila Balušíková, Petr Daniel, Michael Jelínek, and Jan Kovář. "Role of p38 MAPK pathway in apoptosis induction by saturated fatty acid in human pancreatic β-cells." Problems of Endocrinology 62, no. 5 (September 22, 2016): 13–14. http://dx.doi.org/10.14341/probl201662513-14.
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Background. Pancreatic β-cells failure and apoptosis in response to chronically elevated concentrations of saturated fatty acids in blood was considered as one of the main causes of type 2 diabetes mellitus development. Although precise molecular mechanisms of this process are still unclear, there are some indications that the p38 MAPK signaling pathway could be involved.Aim, materials and methods. Therefore, we tested the role of p38 MAPK signaling pathway activation in apoptosis induction by SA in human pancreatic β-cells NES2Y. Crosstalk between p38 MAPK pathway activation and accompanying ERK pathway inhibition after SA application was also tested.Results. We have found that saturated SA at apoptosis-inducing concentration (1 mM) activated the p38 MAPK signaling pathway MKK3/6→p38 MAPK→MAPKAPK-2 and inhibited the ERK signaling pathway c-Raf→MEK1/2→ERK1/2. The inhibition of p38 MAPK expression by siRNA silencing had no significant effect on cell viability or the level of phosphorylated ERK pathway members after SA administration. The inhibition of p38 MAPK activity by the specific inhibitor SB202190 resulted in noticeable activation of ERK pathway members after SA treatment but in no significant effect on cell viability. p38 MAPK overexpression by plasmid transfection produced no significant influence on cell viability or ERK pathway activation after SA exposure. The activation of p38 MAPK by the specific activator anisomycin led to apoptosis induction similar to application of SA (PARP cleavage and caspase-7, -8, and -9 activation) and in inhibition of ERK pathway members.Conclusions. We demonstrated that apoptosis-inducing concentrations of SA activate the p38 MAPK signaling pathway and that this activation could be involved in apoptosis induction by SA in the human pancreatic β-cells NES2Y. However, this involvement does not seem to play a key role. Crosstalk between p38 MAPK pathway activation and ERK pathway inhibition in NES2Y cells seems likely. Thus, the ERK pathway inhibition by p38 MAPK activation does not also seem to be essential for SA-induced apoptosis.
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Bell-Horner, Cathy L., Akiko Dohi, Quynh Nguyen, Glenn H. Dillon, and Meharvan Singh. "ERK/MAPK pathway regulates GABAA receptors." Journal of Neurobiology 66, no. 13 (2006): 1467–74. http://dx.doi.org/10.1002/neu.20327.
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Vališ, Karel, and Petr Novák. "Targeting ERK-Hippo Interplay in Cancer Therapy." International Journal of Molecular Sciences 21, no. 9 (May 3, 2020): 3236. http://dx.doi.org/10.3390/ijms21093236.
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Extracellular signal-regulated kinase (ERK) is a part of the mitogen-activated protein kinase (MAPK) signaling pathway which allows the transduction of various cellular signals to final effectors and regulation of elementary cellular processes. Deregulation of the MAPK signaling occurs under many pathological conditions including neurodegenerative disorders, metabolic syndromes and cancers. Targeted inhibition of individual kinases of the MAPK signaling pathway using synthetic compounds represents a promising way to effective anti-cancer therapy. Cross-talk of the MAPK signaling pathway with other proteins and signaling pathways have a crucial impact on clinical outcomes of targeted therapies and plays important role during development of drug resistance in cancers. We discuss cross-talk of the MAPK/ERK signaling pathway with other signaling pathways, in particular interplay with the Hippo/MST pathway. We demonstrate the mechanism of cell death induction shared between MAPK/ERK and Hippo/MST signaling pathways and discuss the potential of combination targeting of these pathways in the development of more effective anti-cancer therapies.
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DuShane, Jeanne K., and Melissa S. Maginnis. "Human DNA Virus Exploitation of the MAPK-ERK Cascade." International Journal of Molecular Sciences 20, no. 14 (July 12, 2019): 3427. http://dx.doi.org/10.3390/ijms20143427.
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The extracellular signal-regulated kinases (ERKs) comprise a particular branch of the mitogen-activated protein kinase cascades (MAPK) that transmits extracellular signals into the intracellular environment to trigger cellular growth responses. Similar to other MAPK cascades, the MAPK-ERK pathway signals through three core kinases—Raf, MAPK/ERK kinase (MEK), and ERK—which drive the signaling mechanisms responsible for the induction of cellular responses from extracellular stimuli including differentiation, proliferation, and cellular survival. However, pathogens like DNA viruses alter MAPK-ERK signaling in order to access DNA replication machineries, induce a proliferative state in the cell, or even prevent cell death mechanisms in response to pathogen recognition. Differential utilization of this pathway by multiple DNA viruses highlights the dynamic nature of the MAPK-ERK pathway within the cell and the importance of its function in regulating a wide variety of cellular fates that ultimately influence viral infection and, in some cases, result in tumorigenesis.
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DuShane, Jeanne K., Colleen L. Mayberry, Michael P. Wilczek, Sarah L. Nichols, and Melissa S. Maginnis. "JCPyV-Induced MAPK Signaling Activates Transcription Factors during Infection." International Journal of Molecular Sciences 20, no. 19 (September 26, 2019): 4779. http://dx.doi.org/10.3390/ijms20194779.
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JC polyomavirus (JCPyV), a ubiquitous human pathogen, is the etiological agent of the fatal neurodegenerative disease progressive multifocal leukoencephalopathy (PML). Like most viruses, JCPyV infection requires the activation of host-cell signaling pathways in order to promote viral replication processes. Previous works have established the necessity of the extracellular signal-regulated kinase (ERK), the terminal core kinase of the mitogen-activated protein kinase (MAPK) cascade (MAPK-ERK) for facilitating transcription of the JCPyV genome. However, the underlying mechanisms by which the MAPK-ERK pathway becomes activated and induces viral transcription are poorly understood. Treatment of cells with siRNAs specific for Raf and MAP kinase kinase (MEK) targets proteins in the MAPK-ERK cascade, significantly reducing JCPyV infection. MEK, the dual-specificity kinase responsible for the phosphorylation of ERK, is phosphorylated at times congruent with early events in the virus infectious cycle. Moreover, a MAPK-specific signaling array revealed that transcription factors downstream of the MAPK cascade, including cMyc and SMAD4, are upregulated within infected cells. Confocal microscopy analysis demonstrated that cMyc and SMAD4 shuttle to the nucleus during infection, and nuclear localization is reduced when ERK is inhibited. These findings suggest that JCPyV induction of the MAPK-ERK pathway is mediated by Raf and MEK and leads to the activation of downstream transcription factors during infection. This study further defines the role of the MAPK cascade during JCPyV infection and the downstream signaling consequences, illuminating kinases as potential therapeutic targets for viral infection.
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Suzuki, Kenichi, Masayuki Hino, Fumihiko Hato, Noriyuki Tatsumi, and Seiichi Kitagawa. "Cytokine-Specific Activation of Distinct Mitogen-Activated Protein Kinase Subtype Cascades in Human Neutrophils Stimulated by Granulocyte Colony-Stimulating Factor, Granulocyte-Macrophage Colony-Stimulating Factor, and Tumor Necrosis Factor-." Blood 93, no. 1 (January 1, 1999): 341–49. http://dx.doi.org/10.1182/blood.v93.1.341.
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Abstract To clarify the differences of the signaling pathways used by granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor- (TNF), we investigated activation of mitogen-activated protein kinase (MAPK) subtype cascades in human neutrophils stimulated by these cytokines. G-CSF exclusively tyrosine-phosphorylated extracellular signal-regulated kinase (ERK). GM-CSF tyrosine-phosphorylated ERK strongly and p38 MAPK weakly, whereas TNF tyrosine-phosphorylated p38 MAPK strongly and ERK weakly. Consistent with these findings, MEK, an upstream kinase of ERK, was phosphorylated by G-CSF, GM-CSF, and TNF, whereas MKK3/MKK6, an upstream kinase of p38 MAPK, was phosphorylated by GM-CSF and TNF, but not by G-CSF. The potency of these cytokines to phosphorylate ERK and MEK was GM-CSF > G-CSF > TNF, whereas that to phosphorylate p38 MAPK and MKK3/MKK6 was TNF > GM-CSF. C-Jun amino-terminal kinase (JNK) was not tyrosine-phosphorylated by any cytokine despite the existence of JNK proteins in human neutrophils, whereas it was tyrosine-phosphorylated by TNF in undifferentiated and all-trans retinoic acid-differentiated HL-60 cells. Increased phosphorylation of ERK or p38 MAPK was detected within 1 to 5 minutes after stimulation with each cytokine and was dependent on the concentrations of cytokines used. MEK inhibitor (PD98059) reduced tyrosine phosphorylation of ERK, but not p38 MAPK, induced by G-CSF, GM-CSF, or TNF. GM-CSF– or TNF-induced superoxide (O2−) release was inhibited by p38 MAPK inhibitor (SB203580) in a dose-dependent manner, suggesting the possible involvement of p38 MAPK in GM-CSF– or TNF-induced O2− release. The results indicate that G-CSF, GM-CSF, and TNF activate the overlapping but distinct MAPK subtype cascades in human neutrophils and suggest that the differential activation of ERK and p38 MAPK cascades may explain the differences of the effects of these cytokines on human neutrophil functions.
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Suzuki, Kenichi, Masayuki Hino, Fumihiko Hato, Noriyuki Tatsumi, and Seiichi Kitagawa. "Cytokine-Specific Activation of Distinct Mitogen-Activated Protein Kinase Subtype Cascades in Human Neutrophils Stimulated by Granulocyte Colony-Stimulating Factor, Granulocyte-Macrophage Colony-Stimulating Factor, and Tumor Necrosis Factor-." Blood 93, no. 1 (January 1, 1999): 341–49. http://dx.doi.org/10.1182/blood.v93.1.341.401k09_341_349.
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To clarify the differences of the signaling pathways used by granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor- (TNF), we investigated activation of mitogen-activated protein kinase (MAPK) subtype cascades in human neutrophils stimulated by these cytokines. G-CSF exclusively tyrosine-phosphorylated extracellular signal-regulated kinase (ERK). GM-CSF tyrosine-phosphorylated ERK strongly and p38 MAPK weakly, whereas TNF tyrosine-phosphorylated p38 MAPK strongly and ERK weakly. Consistent with these findings, MEK, an upstream kinase of ERK, was phosphorylated by G-CSF, GM-CSF, and TNF, whereas MKK3/MKK6, an upstream kinase of p38 MAPK, was phosphorylated by GM-CSF and TNF, but not by G-CSF. The potency of these cytokines to phosphorylate ERK and MEK was GM-CSF > G-CSF > TNF, whereas that to phosphorylate p38 MAPK and MKK3/MKK6 was TNF > GM-CSF. C-Jun amino-terminal kinase (JNK) was not tyrosine-phosphorylated by any cytokine despite the existence of JNK proteins in human neutrophils, whereas it was tyrosine-phosphorylated by TNF in undifferentiated and all-trans retinoic acid-differentiated HL-60 cells. Increased phosphorylation of ERK or p38 MAPK was detected within 1 to 5 minutes after stimulation with each cytokine and was dependent on the concentrations of cytokines used. MEK inhibitor (PD98059) reduced tyrosine phosphorylation of ERK, but not p38 MAPK, induced by G-CSF, GM-CSF, or TNF. GM-CSF– or TNF-induced superoxide (O2−) release was inhibited by p38 MAPK inhibitor (SB203580) in a dose-dependent manner, suggesting the possible involvement of p38 MAPK in GM-CSF– or TNF-induced O2− release. The results indicate that G-CSF, GM-CSF, and TNF activate the overlapping but distinct MAPK subtype cascades in human neutrophils and suggest that the differential activation of ERK and p38 MAPK cascades may explain the differences of the effects of these cytokines on human neutrophil functions.
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Vanhoutte, Peter, Jean-Vianney Barnier, Bernard Guibert, Christiane Pagès, Marie-Jo Besson, Robert A. Hipskind, and Jocelyne Caboche. "Glutamate Induces Phosphorylation of Elk-1 and CREB, Along with c-fos Activation, via an Extracellular Signal-Regulated Kinase-Dependent Pathway in Brain Slices." Molecular and Cellular Biology 19, no. 1 (January 1, 1999): 136–46. http://dx.doi.org/10.1128/mcb.19.1.136.
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ABSTRACT In cell culture systems, the TCF Elk-1 represents a convergence point for extracellular signal-related kinase (ERK) and c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) subclasses of mitogen-activated protein kinase (MAPK) cascades. Its phosphorylation strongly potentiates its ability to activate transcription of the c-fos promoter through a ternary complex assembled on the c-fos serum response element. In rat brain postmitotic neurons, Elk-1 is strongly expressed (V. Sgambato, P. Vanhoutte, C. Pagès, M. Rogard, R. A. Hipskind, M. J. Besson, and J. Caboche, J. Neurosci. 18:214–226, 1998). However, its physiological role in these postmitotic neurons remains to be established. To investigate biochemically the signaling pathways targeting Elk-1 and c-fos in mature neurons, we used a semi-in vivo system composed of brain slices stimulated with the excitatory neurotransmitter glutamate. Glutamate treatment leads to a robust, progressive activation of the ERK and JNK/SAPK MAPK cascades. This corresponds kinetically to a significant increase in Ser383-phosphorylated Elk-1 and the appearance of c-fos mRNA. Glutamate also causes increased levels of Ser133-phosphorylated cyclic AMP-responsive element-binding protein (CREB) but only transiently relative to Elk-1 and c-fos. ERK and Elk-1 phosphorylation are blocked by the MAPK kinase inhibitor PD98059, indicating the primary role of the ERK cascade in mediating glutamate signaling to Elk-1 in the rat striatum in vivo. Glutamate-mediated CREB phosphorylation is also inhibited by PD98059 treatment. Interestingly, KN62, which interferes with calcium-calmodulin kinase (CaM-K) activity, leads to a reduction of glutamate-induced ERK activation and of CREB phosphorylation. These data indicate that ERK functions as a common component in two signaling pathways (ERK/Elk-1 and ERK/?/CREB) converging on the c-fospromoter in postmitotic neuronal cells and that CaM-Ks act as positive regulators of these pathways.
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Armstead, William M., Douglas B. Cines, Khalil H. Bdeir, Yasmina Bdeir, Sherman C. Stein, and Abd Al-Roof Higazi. "uPA Modulates the Age-Dependent Effect of Brain Injury on Cerebral Hemodynamics through LRP and ERK MAPK." Journal of Cerebral Blood Flow & Metabolism 29, no. 3 (December 3, 2008): 524–33. http://dx.doi.org/10.1038/jcbfm.2008.142.
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We hypothesized that urokinase plasminogen activator (uPA) contributes to age-dependent early hyperemia after fluid percussion brain injury (FPI) by activating extracellular signal-related kinase (ERK) mitogen-activated protein kinase (MAPK), leading to histopathologic changes in the underlying cortex. Both cerebrospinal fluid (CSF) uPA and phosphorylation of CSF ERK MAPK was increased at 1 min after FPI in newborn pigs, but was unchanged in juvenile pigs. uPA and phosphorylated ERK MAPK, detectable in sham piglet brain by immunohistochemistry, was markedly elevated and associated with histopathology 4 h after FPI in the newborn but there was minimal staining and histopathology in the juvenile. EEIIMD, a peptide derived from PA inhibitor-1 that does not affect proteolysis, blunted FPI-induced phosphorylation of ERK MAPK. FPI produced pial artery dilation and increased cerebral blood flow at 1 min after insult in the newborn, but not in the juvenile. Antilipoprotein-related protein (LRP) antibody, EEIIMD, a soluble uPA antagonist, and the ERK MAPK antagonist U 0126 inhibited FPI-associated hyperemia. These data indicate that uPA is upregulated after FPI and produces an age-dependent early hyperemia followed by histopathology through an LRP- and ERK MAPK-dependent pathway.
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Dawson, Christopher W., Louise Laverick, Mhairi A. Morris, Giorgos Tramoutanis, and Lawrence S. Young. "Epstein-Barr Virus-Encoded LMP1 Regulates Epithelial Cell Motility and Invasion via the ERK-MAPK Pathway." Journal of Virology 82, no. 7 (January 16, 2008): 3654–64. http://dx.doi.org/10.1128/jvi.01888-07.
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ABSTRACT The Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) is an oncogenic protein which has previously been shown to engage the NF-κB, stress-activated MAP kinase, phosphatidylinositol 3-kinase (PI 3-kinase), and extracellular-regulated kinase (ERK)-MAPK pathways. In this study, we demonstrate that LMP1 activates ERK-MAPK in epithelial cells via the canonical Raf-MEK-ERK-MAPK pathway but in a Ras-independent manner. In agreement with the results of a previous study (B. A. Mainou, D. N. Everly, Jr., and N. Raab-Traub, J. Virol. 81:9680-9692, 2007), we show that the ability of LMP1 to activate ERK-MAPK mapped to its CTAR1 domain, the TRAF binding domain previously implicated in PI 3-kinase activation. A role for ERK-MAPK in LMP1-induced epithelial cell motility was identified, as LMP1-expressing cells displayed increased rates of haptotactic migration compared to those of LMP1-negative cells. These data implicate the ERK-MAPK pathway in LMP1-induced effects associated with transformation, suggesting that this pathway may contribute to the oncogenicity of LMP1 through its ability to promote cell motility and to enhance the invasive properties of epithelial cells.
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Hoang, Van T., Katherine Nyswaner, Pedro Torres-Ayuso, and John Brognard. "The protein kinase MAP3K19 phosphorylates MAP2Ks and thereby activates ERK and JNK kinases and increases viability of KRAS-mutant lung cancer cells." Journal of Biological Chemistry 295, no. 25 (April 30, 2020): 8470–79. http://dx.doi.org/10.1074/jbc.ra119.012365.
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Identifying additional mitogen-activated protein kinase (MAPK) pathway regulators is invaluable in aiding our understanding of the complex signaling networks that regulate cellular processes, including cell proliferation and survival. Here, using in vitro kinase assays and by expressing WT or kinase-dead MAPK kinase kinase 19 (MAP3K19) in the HEK293T cell line and assessing activation of the extracellular signal–regulated kinase (ERK) and JUN N-terminal kinase (JNK) signaling pathways, we defined MAP3K19 as a novel regulator of MAPK signaling. We also observed that overexpression of WT MAP3K19 activates both the ERK and JNK pathways in a panel of cancer cell lines. Furthermore, MAP3K19 sustained ERK pathway activation in the presence of inhibitors targeting the RAF proto-oncogene Ser/Thr protein kinase (RAF) and MAPK/ERK kinase, indicating that MAP3K19 activates ERK via a RAF-independent mechanism. Findings from in vitro and in-cell kinase assays demonstrate that MAP3K19 is a kinase that directly phosphorylates both MAPK/ERK kinase (MEK) and MAPK kinase 7 (MKK7). Results from an short-hairpin RNA screen indicated that MAP3K19 is essential for maintaining survival in KRAS-mutant cancers; therefore, we depleted or inhibited MAP3K19 in KRAS-mutant cancer cell lines and observed that this reduces viability and decreases ERK and JNK pathway activation. In summary, our results reveal that MAP3K19 directly activates the ERK and JNK cascades and highlight a role for this kinase in maintaining survival of KRAS-mutant lung cancer cells.
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Moon, Hyuk, and Simon Weonsang Ro. "MAPK/ERK Signaling Pathway in Hepatocellular Carcinoma." Cancers 13, no. 12 (June 17, 2021): 3026. http://dx.doi.org/10.3390/cancers13123026.
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Hepatocellular carcinoma (HCC) is a major health concern worldwide, and its incidence is increasing steadily. Recently, the MAPK/ERK signaling pathway in HCC has gained renewed attention from basic and clinical researchers. The MAPK/ERK signaling pathway is activated in more than 50% of human HCC cases; however, activating mutations in RAS and RAF genes are rarely found in HCC, which are major genetic events leading to the activation of the MAPK/ERK signaling pathway in other cancers. This suggests that there is an alternative mechanism behind the activation of the signaling pathway in HCC. Here, we will review recent advances in understanding the cellular and molecular mechanisms involved in the activation of the MAPK/ERK signaling pathway and discuss potential therapeutic strategies targeting the signaling pathway in the context of HCC.
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Wang, Ke, and Yuekun Zhu. "Dexmedetomidine protects against oxygen-glucose deprivation/reoxygenation injury-induced apoptosis via the p38 MAPK/ERK signalling pathway." Journal of International Medical Research 46, no. 2 (December 6, 2017): 675–86. http://dx.doi.org/10.1177/0300060517734460.
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Objective To investigate the protective effects of dexmedetomidine (DEX) in oxygen-glucose deprivation/reoxygenation (OGD/R) injury, which is involved in a number of ischaemic diseases. Methods An in vitro OGD/R injury model was generated using mouse Neuro 2A neuroblastoma (N2A) cells. Different concentrations of DEX were administrated to OGD/R cells. CV-65 was used to inhibit p38 microtubule associated protein kinase/extracellular signal-regulated kinases (MAPK/ERK) signalling. Cell proliferation, cell cycle, apoptosis, and the levels of proteins related to p38 MAPK/ERK signalling and apoptosis were evaluated using Cell Counting Kit-8, flow cytometry, TdT-UTP nick end labelling and Western blot analysis, respectively. Results DEX treatment of OGD/R cells promoted cell survival and attenuated OGD/R-induced cell apoptosis. It also activated the p38 MAPK/ERK signalling pathway, increased the levels of Bcl-2, and decreased the levels of Bax and cleaved caspase-3. Treatment with the p38 MAPK/ERK inhibitor CV-65 inhibited the activation of p38 MAPK/ERK and abrogated the DEX-induced effects on cell survival and apoptosis. Conclusions DEX protects N2A cells from OGD/R-induced apoptosis via the activation of the p38 MAPK/ERK signalling pathway. DEX might be an effective agent for the treatment of ischaemic diseases.
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Brock, Ethan J., Ryan M. Jackson, Julie L. Boerner, Quanwen Li, Meredith A. Tennis, Bonnie F. Sloane, and Raymond R. Mattingly. "Sprouty4 negatively regulates ERK/MAPK signaling and the transition from in situ to invasive breast ductal carcinoma." PLOS ONE 16, no. 5 (May 28, 2021): e0252314. http://dx.doi.org/10.1371/journal.pone.0252314.
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Breast ductal carcinoma in situ (DCIS) is a non-obligate precursor of invasive ductal carcinoma (IDC). It is still unclear which DCIS will become invasive and which will remain indolent. Patients often receive surgery and radiotherapy, but this early intervention has not produced substantial decreases in late-stage disease. Sprouty proteins are important regulators of ERK/MAPK signaling and have been studied in various cancers. We hypothesized that Sprouty4 is an endogenous inhibitor of ERK/MAPK signaling and that its loss/reduced expression is a mechanism by which DCIS lesions progress toward IDC, including triple-negative disease. Using immunohistochemistry, we found reduced Sprouty4 expression in IDC patient samples compared to DCIS, and that ERK/MAPK phosphorylation had an inverse relationship to Sprouty4 expression. These observations were reproduced using a 3D culture model of disease progression. Knockdown of Sprouty4 in MCF10.DCIS cells increased ERK/MAPK phosphorylation as well as their invasive capability, while overexpression of Sprouty4 in MCF10.CA1d IDC cells reduced ERK/MAPK phosphorylation, invasion, and the aggressive phenotype exhibited by these cells. Immunofluorescence experiments revealed reorganization of the actin cytoskeleton and relocation of E-cadherin back to the cell surface, consistent with the restoration of adherens junctions. To determine whether these effects were due to changes in ERK/MAPK signaling, MEK1/2 was pharmacologically inhibited in IDC cells. Nanomolar concentrations of MEK162/binimetinib restored an epithelial-like phenotype and reduced pericellular proteolysis, similar to Sprouty4 overexpression. From these data we conclude that Sprouty4 acts to control ERK/MAPK signaling in DCIS, thus limiting the progression of these premalignant breast lesions.
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Chakraborty, Rikhia, Oliver A. Hampton, Xiaoyun Shen, Stephen J. Simko, Albert Shih, Harshal Abhyankar, Karen Phaik Har Lim, et al. "Mutually exclusive recurrent somatic mutations in MAP2K1 and BRAF support a central role for ERK activation in LCH pathogenesis." Blood 124, no. 19 (November 6, 2014): 3007–15. http://dx.doi.org/10.1182/blood-2014-05-577825.
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Key Points Recurrent somatic mutations in MAP2K1 were identified in 33% of LCH lesions with wild-type BRAF. The mutant MAPK kinase 1 proteins activate ERK. The ability of MAPK pathway inhibitors to suppress MAPK kinase and ERK phosphorylation in vitro was dependent on the specific LCH mutation.
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PARRA-PALAU, Josep L., Gert C. SCHEPER, Daniel E. HARPER, and Christopher G. PROUD. "The Drosophila protein kinase LK6 is regulated by ERK and phosphorylates the eukaryotic initiation factor eIF4E in vivo." Biochemical Journal 385, no. 3 (January 24, 2005): 695–702. http://dx.doi.org/10.1042/bj20040769.
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In Drosophila cells, phosphorylation of eIF4E (eukaryotic initiation factor 4E) is required for growth and development. In Drosophila melanogaster, LK6 is the closest homologue of mammalian Mnk1 and Mnk2 [MAPK (mitogen-activated protein kinase) signal-integrating kinases 1 and 2 respectively] that phosphorylate mammalian eIF4E. Mnk1 is activated by both mitogen- and stress-activated signalling pathways [ERK (extracellular-signal-regulated kinase) and p38 MAPK], whereas Mnk2 contains a MAPK-binding motif that is selective for ERKs. LK6 possesses a binding motif similar to that in Mnk2. In the present study, we show that LK6 can phosphorylate eIF4E at the physiological site. LK6 activity is increased by the ERK signalling pathway and not by the stress-activated p38 MAPK signalling pathway. Consistent with this, LK6 binds ERK in mammalian cells, and this requires an intact binding motif. LK6 can bind to eIF4G in mammalian cells, and expression of LK6 increases the phosphorylation of the endogenous eIF4E. In Drosophila S2 Schneider cells, LK6 binds the ERK homologue Rolled, but not the p38 MAPK homologue. LK6 phosphorylates Drosophila eIF4E in vitro. The phosphorylation of endogenous eIF4E in Drosophila cells is increased by activation of the ERK pathway but not by arsenite, an activator of p38 MAPK. RNA interference directed against LK6 significantly decreases eIF4E phosphorylation in Drosophila cells. These results show that LK6 binds to ERK and is activated by ERK signalling and it is responsible for phosphorylating eIF4E in Drosophila.
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Barber, Sheila A., Linda Bruett, Brian R. Douglass, David S. Herbst, M. Christine Zink, and Janice E. Clements. "Visna Virus-Induced Activation of MAPK Is Required for Virus Replication and Correlates with Virus-Induced Neuropathology." Journal of Virology 76, no. 2 (January 15, 2002): 817–28. http://dx.doi.org/10.1128/jvi.76.2.817-828.2002.
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ABSTRACT It is well accepted that viruses require access to specific intracellular environments in order to proliferate or, minimally, to secure future proliferative potential as latent reservoirs. Hence, identification of essential virus-cell interactions should both refine current models of virus replication and proffer alternative targets for therapeutic intervention. In the present study, we examined the activation states of mitogen-activated protein kinases (MAPKs), ERK-1/2, in primary cells susceptible to visna virus and report that virus infection induces and sustains activation of the ERK/MAPK pathway. Treatment of infected cells with PD98059, a specific inhibitor of the ERK/MAPK pathway, abolishes visna virus replication, as evidenced by extremely low levels of Gag protein expression and reverse transcriptase activity in culture supernatants. In addition, although visna virus-induced activation of MAPK is detectable within 15 min, early events of viral replication (i.e., reverse transcription, integration, and transcription) are largely unaffected by PD98059. Interestingly, further examination demonstrated that treatment with PD98059 results in decreased cytoplasmic expression of gag and env, but not rev, mRNA, highly suggestive of an ERK/MAPK-dependent defect in Rev function. In vivo analysis of ERK-1/2 activation in brains derived from visna virus-infected sheep demonstrates a strong correlation between ERK/MAPK activation and virus-associated encephalitis. Moreover, double-labeling experiments revealed that activation of MAPK occurs not only in cells classically infected by visna virus (i.e., macrophages and microglia), but also in astrocytes, cells not considered to be major targets of visna virus replication, suggesting that activation of the ERK/MAPK pathway may contribute to the virus-induced processes leading to neurodegenerative pathology.
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Butcher, Greg Q., Boyoung Lee, and Karl Obrietan. "Temporal Regulation of Light-Induced Extracellular Signal-Regulated Kinase Activation in the Suprachiasmatic Nucleus." Journal of Neurophysiology 90, no. 6 (December 2003): 3854–63. http://dx.doi.org/10.1152/jn.00524.2003.
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Signaling via the p42/p44 mitogen activated protein kinase (MAPK) pathway has been implicated as an intermediate event coupling light to entrainment of the mammalian circadian clock located in the suprachiasmatic nucleus (SCN). To examine how photic input dynamically regulates the activation state of the MAPK pathway, we monitored extracellular signal-regulated kinase (ERK) activation using different light stimulus paradigms. Compared with control animals not exposed to light, a 15 min light exposure during the early night triggered a marked increase in ERK activation and the translocation of ERK from the cytosol to the nucleus. ERK activation peaked 15 min after light onset, then returned to near basal levels within ∼45 min. The MAPK pathway could be reactivated multiple times by light pulses spaced 45 min apart, indicating that the MAPK cascade rapidly resets and resolves individual light pulses into discrete signaling events. Under conditions of constant light (120 min), the time course for ERK activation, nuclear translocation, and inactivation was similar to the time course observed after a 15-min light treatment. The parallels between the ERK inactivation profiles elicited by a 15 and a 120 min light exposure suggest that SCN cells contain a MAPK pathway signal-termination mechanism that limits the duration of pathway activation. This concept was supported by the observation that the small G protein Ras, a regulator of the MAPK pathway, remained in the active, GTP-bound, state under conditions of constant light (120-min duration), indicating that photic information was relayed to the SCN and that SCN cells maintained their responsiveness for the duration of the light treatment. The SCN expressed both nuclear MAPK phosphatases (MKP-1 and MKP-2) and the cytosolic MAPK phosphatase Mkp-3, thus providing mechanisms by which light-induced ERK activation is terminated. Collectively, these observations provide important new information regarding the regulation of the MAPK cascade, a signaling intermediate that couples light to resetting of the SCN clock.
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Ellington, John K., Adam Elhofy, Kenneth L. Bost, and Michael C. Hudson. "Involvement of Mitogen-Activated Protein Kinase Pathways in Staphylococcus aureus Invasion of Normal Osteoblasts." Infection and Immunity 69, no. 9 (September 1, 2001): 5235–42. http://dx.doi.org/10.1128/iai.69.9.5235-5242.2001.
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ABSTRACT Staphylococcus aureus invades osteoblasts and can persist in the intracellular environment. The present study examined the role of osteoblast mitogen-activated protein kinase (MAPK) pathways in bacterial invasion. S. aureus infection of normal human and mouse osteoblasts resulted in an increase in the phosphorylation of the extracellular signal-regulated protein kinases (ERK 1 and 2). This stimulation of ERK 1 and 2 correlated with the time course of S. aureus invasion, and bacterial adherence induced the MAPK pathway. ERK 1 and 2 phosphorylation was time and dose dependent and required active S. aureus gene expression for maximal induction. The nonpathogenic Staphylococcus carnosus was also able to induce ERK 1 and 2 phosphorylation, albeit at lower levels than S. aureus. Phosphorylation of the stress-activated protein kinases was increased in both infected human and mouse osteoblasts; however, the p38 MAPK pathway was not activated in response to S. aureus. Finally, the transcription factor c-Jun, but not Elk-1 or ATF-2, was phosphorylated in response to S. aureus infection.
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Поварнина, Полина Ю. "Нейропротекторная активность дипептидных миметиков BDNF, по-разному активирующих сопряженные с TRKB пути трансдукции сигнала, в условиях экспериментального ишемического инсульта." Экспериментальная и клиническая фармакология 83, no. 12 (January 5, 2021): 8–12. http://dx.doi.org/10.30906/0869-2092-2020-83-12-8-12.
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На модели ишемического инсульта, вызванного транзиторной окклюзией средней мозговой артерии у крыс, изучена нейропротекторная активность димерных дипептидных миметиков BDNF, отличающихся по активации PI3K/AKT и MAPK/ERK сигнальных путей. Обнаружены наиболее выраженные нейропротекторные свойства у дипептидного миметика 4 петли BDNF, активирующего PI3K/AKT и MAPK/ERK (снижение объема ишемического повреждения на 66 %). Миметик 1 петли BDNF, активирующий PI3K/AKT, также обладает нейропротекторной активностью, но менее выраженной (снижение объема повреждения на 28 %). Миметик 2 петли BDNF, активирующий MAPK/ERK, не оказывал нейропротекторного эффекта.
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Hindley, Christopher J., Lynsey Fazal, Joanne M. Munck, Vanessa Martins, Alpesh D. Shah, Nicola E. Wilsher, Nicola G. Wallis, Harold N. Keer, and John F. Lyons. "Anti-Tumor Activity of ASTX029, a Dual Mechanism Inhibitor of ERK1/2, in Preclinical AML Models." Blood 136, Supplement 1 (November 5, 2020): 7–8. http://dx.doi.org/10.1182/blood-2020-139175.
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Oncogenic mutations in genes such as the RAS family (KRAS, NRAS or HRAS) or receptor tyrosine kinases (RTKs) drive tumor growth through aberrant activation of the mitogen activated protein kinase (MAPK) signaling pathway. Acute myeloid leukemia (AML) patients frequently exhibit activating mutations in MAPK pathway members, such as NRAS and KRAS, suggesting that these malignancies may be driven by aberrant activation of the MAPK pathway. Targeting of the MAPK pathway has been clinically validated in solid tumors, with agents targeting BRAF and MEK approved for the treatment of BRAF-mutant melanoma. However, there is currently no approved therapy directly targeting activated RAS family members and resistance to MAPK pathway inhibitors is frequently associated with reactivation of MAPK signaling. ERK1/2 (ERK) is a downstream node in the MAPK pathway and therefore represents an attractive therapeutic target for inhibition of MAPK signaling in these settings. We have recently described in vivo anti-tumor activity in MAPK-activated solid tumor models following treatment with ASTX029, a highly potent ERK inhibitor developed using fragment-based drug design. ASTX029 has a distinctive ERK binding mode which confers dual mechanism inhibition of ERK, inhibiting both the catalytic activity of ERK and its phosphorylation by MEK. Here, we demonstrate that ASTX029 is also active in AML models and potently inhibits in vitro and in vivo MAPK signaling and growth in these models. Using a panel of 15 AML cell lines, we investigated sensitivity to ASTX029 in vitro. We observed that 8 cell lines bearing mutations leading to increased MAPK pathway signaling were sensitive to treatment with ASTX029 with an average IC50 value of 47 nM, in contrast to an average IC50 value of 1800 nM for cell lines without activating mutations. The phosphorylation of RSK, a direct substrate of ERK, was suppressed for up to 24 h following treatment with ASTX029 in vitro. We have previously demonstrated good oral bioavailability for ASTX029 and once daily dosing resulted in significant tumor growth inhibition in AML cell line xenograft models. To confirm target engagement in vivo, we examined MAPK signaling in xenograft tissue and observed inhibition of the phosphorylation of RSK and of ERK itself, consistent with the dual mechanism of action proposed for ASTX029. In summary, the ERK inhibitor, ASTX029, has potent activity against MAPK-activated tumor models, including AML models, and is now being tested in a Phase 1/2 clinical trial in advanced solid tumors (NCT03520075). These data highlight its therapeutic potential for the treatment of AML in patients with mutations leading to MAPK pathway activation and support further investigation in these patient populations. Disclosures Hindley: Astex Pharmaceuticals: Current Employment. Fazal:Astex Pharmaceuticals: Current Employment. Munck:Astex Pharmaceuticals: Current Employment. Martins:Astex Pharmaceuticals: Current Employment. Shah:Astex Pharmaceuticals: Current Employment. Wilsher:Astex Pharmaceuticals: Current Employment. Wallis:Astex Pharmaceuticals: Current Employment. Keer:Astex Pharmaceuticals, Inc.: Current Employment. Lyons:Astex Pharmaceuticals: Current Employment.
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Yang, Shen-Hsi, and Andrew D. Sharrocks. "Convergence of the SUMO and MAPK pathways on the ETS-domain transcription factor Elk-1." Biochemical Society Symposia 73 (January 1, 2006): 121–29. http://dx.doi.org/10.1042/bss0730121.
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The ETS-domain transcription factor Elk-1 is regulated by phosphorylation in response to activation of the MAPK (mitogen-activated protein kinase) pathways. This phosphorylation triggers a series of molecular events that convert Elk-1 from a transcriptionally silent state into a highly active state and then back to a basal level. At the same time, activation of the ERK (extracellular-signal-regulated kinase) MAPK pathway leads to loss of modification of Elk-1 by SUMO (small ubiquitin-related modifier). As SUMO imparts repressive properties on Elk-1, ERK-mediated SUMO loss leads to de-repression at the same time as the ERK pathway promotes activation of Elk-1. Thus a two-step mechanism is employed to convert Elk-1 into its fully activated state. Here, the molecular events underlying these changes in Elk-1 status, and the role of PIASxα [protein inhibitor of activated STAT (signal transducer and activator of transcription) xα] as a co-activator that facilitates this process, are discussed.
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Wihastyoko, Herman Yosef Limpat, and Erdo Puncak Sidarta. "The Expression of TGF-b1, p38 MAPK, and ERK-1 Protein in Cleft Affected Tissue of the Lip: An Observational Study." Molecular and Cellular Biomedical Sciences 5, no. 2 (July 6, 2021): 82. http://dx.doi.org/10.21705/mcbs.v5i2.195.
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Background: Cleft lip is a congenital birth defect caused by many proteins. Transforming growth factor (TGF)-β1, p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated protein kinase (ERK)-1 are proteins which regulate proliferation and apoptosis role during intrauterine period. This study aimed to observe the expression of these proteins in cleft affected tissue of the lip.Materials and Methods: A descriptive study by examining the TGF-β1, p38 MAPK, and ERK-1 immunohistochemical expression of cleft affected tissue of the lip was conducted. Subjects were patients that were participating for the social event held by Plastic Surgery Department, Faculty of Medicine, Univesitas Brawijaya, on December 3-12, 2012 in Nusa Tenggara Timur. Excess lip mucosa (waste tissue) during the operation were stored in 10% formalin then stained by immunohistochemistry for TGF-β1, p38 MAPK, and ERK-1. We counted the average protein expression under the light microscope with 1000x magnification for 20 different fields of view, randomly.Results: Paraffin blocks from 30 subjects were selected. The mean p38 MAPK expression was found to be highest, with the average of 8 per field of view; followed by the mean TGF-β1 expression, with the average of 5 per field of view; and the mean ERK-1 expression was found to be the lowest, with the average of 2 per field of view. Conclusion: Expression of p38 MAPK and TGF-β1 are higher than ERK-1, suggesting that p38 MAPK is in the same signalling pathway as TGF-β1, while ERK-1 is lower, as its role as anti-apoptotic. This is consistent with several previous studies showing that all proteins took part in the development of cleft lip or craniofacial development. Further study needs to be conducted to determine which protein plays the bigger role.Keywords: cleft lip, TGF-β1, p38 MAPK, ERK-1
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Yao, Zhong, and Rony Seger. "The Molecular Mechanism of MAPK / ERK Inactivation." Current Genomics 5, no. 4 (May 1, 2004): 385–93. http://dx.doi.org/10.2174/1389202043349309.
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McKay, M. M., and D. K. Morrison. "Integrating signals from RTKs to ERK/MAPK." Oncogene 26, no. 22 (May 2007): 3113–21. http://dx.doi.org/10.1038/sj.onc.1210394.
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Keifer, Joyce, Zhao-Qing Zheng, and Dantong Zhu. "MAPK Signaling Pathways Mediate AMPA Receptor Trafficking in an In Vitro Model of Classical Conditioning." Journal of Neurophysiology 97, no. 3 (March 2007): 2067–74. http://dx.doi.org/10.1152/jn.01154.2006.
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The mitogen-activated protein kinase (MAPK) signal transduction pathways have been implicated in underlying mechanisms of synaptic plasticity and learning. However, the differential roles of the MAPK family members extracellular signal-regulated kinase (ERK) and p38 in learning remain to be clarified. Here, an in vitro model of classical conditioning was examined to assess the roles of ERK and p38 MAPK in this form of learning. Previous studies showed that NMDA-mediated trafficking of synaptic glutamate receptor 4 (GluR4)–containing AMPA receptors (AMPARs) underlies conditioning in this preparation and that this is accomplished through GluR4 interactions with the immediate-early gene protein Arc and the actin cytoskeleton. Here, it is shown that attenuation of conditioned responses (CRs) by ERK and p38 MAPK antagonists is associated with significantly reduced synaptic localization of GluR4 subunits. Western blotting reveals that p38 MAPK significantly increases its activation levels during late stages of conditioning during CR expression. In contrast, ERK MAPK activation is enhanced in early conditioning during CR acquisition. The results suggest that MAPKs have a central role in the synaptic delivery of GluR4-containing AMPARs during in vitro classical conditioning.
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Booth, Allyson, Tammy Trudeau, Crystal Gomez, M. Scott Lucia, and Arthur Gutierrez-Hartmann. "Persistent ERK/MAPK Activation Promotes Lactotrope Differentiation and Diminishes Tumorigenic Phenotype." Molecular Endocrinology 28, no. 12 (December 1, 2014): 1999–2011. http://dx.doi.org/10.1210/me.2014-1168.
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The signaling pathways that govern the lactotrope-specific differentiated phenotype, and those that control lactotrope proliferation in both physiological and pathological lactotrope expansion, are poorly understood. Moreover, the specific role of MAPK signaling in lactotrope proliferation vs differentiation, whether activated phosphorylated MAPK is sufficient for prolactinoma tumor formation remain unknown. Given that oncogenic Ras mutations and persistently activated phosphorylated MAPK are found in human tumors, including prolactinomas and other pituitary tumors, a better understanding of the role of MAPK in lactotrope biology is required. Here we directly examined the role of persistent Ras/MAPK signaling in differentiation, proliferation, and tumorigenesis of rat pituitary somatolactotrope GH4 cells. We stimulated Ras/MAPK signaling in a persistent, long-term manner (over 6 d) in GH4 cells using two distinct approaches: 1) a doxycycline-inducible, oncogenic V12Ras expression system; and 2) continuous addition of exogenous epidermal growth factor. We find that long-term activation of the Ras/MAPK pathway over 6 days promotes differentiation of the bihormonal somatolactotrope GH4 precursor cell into a prolactin-secreting, lactotrope cell phenotype in vitro and in vivo with GH4 cell xenograft tumors. Furthermore, we show that persistent activation of the Ras/MAPK pathway not only fails to promote cell proliferation, but also diminishes tumorigenic characteristics in GH4 cells in vitro and in vivo. These data demonstrate that activated MAPK promotes differentiation and is not sufficient to drive tumorigenesis, suggesting that pituitary lactotrope tumor cells have the ability to evade the tumorigenic fate that is often associated with Ras/MAPK activation.
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Shiratsuchi, Hiroe, and Marc D. Basson. "Activation of p38 MAPKα by extracellular pressure mediates the stimulation of macrophage phagocytosis by pressure." American Journal of Physiology-Cell Physiology 288, no. 5 (May 2005): C1083—C1093. http://dx.doi.org/10.1152/ajpcell.00543.2004.
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We have previously demonstrated that constant 20 mmHg extracellular pressure increases serum-opsonized latex bead phagocytosis by phorbol 12-myristate 13-acetate (PMA)- differentiated THP-1 macrophages in part by inhibiting focal adhesion kinase (FAK) and extracellular signal-regulated kinase (ERK). Because p38 MAPK is activated by physical forces in other cells, we hypothesized that modulation of p38 MAPK might also contribute to the stimulation of macrophage phagocytosis by pressure. We studied phagocytosis in PMA-differentiated THP-1 macrophages, primary human monocytes, and human monocyte-derived macrophages (MDM). p38 MAPK activation was inhibited using SB-203580 or by p38 MAPKα small interfering RNA (siRNA). Pressure increased phagocytosis in primary monocytes and MDM as in THP-1 cells. Increased extracellular pressure for 30 min increased phosphorylated p38 MAPK by 46.4 ± 20.5% in DMSO-treated THP-1 macrophages and by 20.9 ± 9% in primary monocytes ( P < 0.05 each). SB-203580 (20 μM) reduced basal p38 MAPK phosphorylation by 34.7 ± 2.1% in THP-1 macrophages and prevented pressure activation of p38. p38 MAPKα siRNA reduced total p38 MAPK protein by 50–60%. Neither SB-203580 in THP-1 cells and peripheral monocytes nor p38 MAPK siRNA in THP-1 cells affected basal phagocytosis, but each abolished pressure-stimulated phagocytosis. SB-203580 did not affect basal or pressure-reduced FAK activation in THP-1 macrophages, but significantly attenuated the reduction in ERK phosphorylation associated with pressure. p38 MAPKα siRNA reduced total FAK protein by 40–50%, and total ERK by 10–15%, but increased phosphorylated ERK 1.4 ± 0.1-fold. p38 MAPKα siRNA transfection did not affect the inhibition of FAK-Y397 phosphorylation by pressure but prevented inhibition of ERK phosphorylation. Changes in extracellular pressure during infection or inflammation regulate macrophage phagocytosis by a FAK-dependent inverse effect on p38 MAPKα that might subsequently downregulate ERK.
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Lin, Edwin, Andrew W. Hahn, Guru Sonpavde, Michael B. Lilly, Roberto Nussenzveig, Elisa Ledet, Sumanta K. Pal, et al. "Profiling of genomic alterations in MAPK/ERK signaling in a large cohort of metastatic prostate cancer (mPC) patients." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 5032. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.5032.
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5032 Background: All mPC patients eventually progress on current treatments and prognosis remains poor. In vitro models and small patient cohorts have shown that mPC progression is associated with increased MAPK/ERK signaling. However, in clinical mPC, the genomic alterations that cause aberrant MAPK/ERK signaling and their frequency are poorly defined. We hypothesize that profiling of genomic alterations in MAPK/ERK in a large cohort of heavily pretreated progressive mPC patients will provide a robust measure of importance, and reveal recurrent patterns of alteration. Given the large number of drugs that target MAPK/ERK, these may be incorporated into novel combinatorial treatments for mPC. Methods: 2,679 plasma samples from 2,309 men with mPC were assessed by a validated ctDNA NGS panel that sequences 73 clinically relevant cancer genes (Guardant360, Redwood City, CA) and profiles indels, amplifications, and fusions with high sensitivity and specificity. Genes were assigned to gene sets corresponding to biological pathways and molecular functional classes using the REACTOME database, followed by calculation of summary statistics. Interdependencies between genetic alterations at inter- and intra-gene set levels were discovered by a Bayesian network approach. Results: 56% of mPC samples harbored alterations in MAPK/ERK signaling genes. These included receptor tyrosine kinases (RTKs), MAP kinase cascade, and cell cycle control genes. Gene amplifications were the most frequent alterations in RTK, RAF, and cell cycle control genes, a novel finding. Bayesian network analysis revealed positive interdependencies between all MAPK/ERK genes. In RTK genes, co-amplifications were especially frequent between MET & EGFR and PDGFRA & KIT. Conclusions: In a large cohort of mPC patients, we show that MAPK/ERK gene alterations are present in over half of mPC patients. RTKs, BRAF, and CDK4/6 amplifications are among the most frequent events, display recurrent patterns of co-alteration, and are targetable by existing drugs. Future work to assess the biological and clinical significance of these recurrent patterns of alteration will pave the way for novel combinatorial treatments.
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Lemire, Bruno B., Richard Debigaré, Annie Dubé, Marie-Eve Thériault, Claude H. Côté, and François Maltais. "MAPK signaling in the quadriceps of patients with chronic obstructive pulmonary disease." Journal of Applied Physiology 113, no. 1 (July 1, 2012): 159–66. http://dx.doi.org/10.1152/japplphysiol.01518.2011.
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Muscle atrophy in chronic obstructive pulmonary disease (COPD) is associated with reduced exercise tolerance, muscle strength, and survival. The molecular mechanisms leading to muscle atrophy in COPD remain elusive. The mitogen-activated protein kinases (MAPKs) such as p38 MAPK and ERK 1/2 can increase levels of MAFbx/Atrogin and MuRF1, which are specifically involved in muscle protein degradation and atrophy. Our aim was to investigate the level of activation of p38 MAPK, ERK 1/2, and JNK in the quadriceps of patients with COPD. A biopsy of the quadriceps was obtained in 18 patients with COPD as well as in 9 healthy controls. We evaluated the phosphorylated as well as total protein levels of p38 MAPK, ERK 1/2, and JNK as well as MAFbx/Atrogin and MuRF1 in these muscle samples. The corresponding mRNA expression was also assessed by RT-PCR. Ratios of phosphorylated to total level of p38 MAPK ( P = 0.02) and ERK 1/2 ( P = 0.01) were significantly elevated in patients with COPD compared with controls. Moreover, protein levels of MAFbx/Atrogin showed a tendency to be greater in patients with COPD ( P = 0.08). mRNA expression of p38 MAPK ( P = 0.03), ERK 1/2 ( P = 0.02), and MAFbx/Atrogin ( P = 0.04) were significantly elevated in patients with COPD. In addition, phosphorylated-to-total p38 MAPK ratio (Pearson's r = −0.45; P < 0.05) and phosphorylated-to-total ERK 1/2 ratio (Pearson's r = −0.47; P < 0.05) were negatively associated with the mid-thigh muscle cross-sectional area. These data support the hypothesis that the MAPKs might play a role in the development of muscle atrophy in COPD.
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Taha, C., T. Tsakiridis, A. McCall, and A. Klip. "Glucose transporter expression in L6 muscle cells: regulation through insulin- and stress-activated pathways." American Journal of Physiology-Endocrinology and Metabolism 273, no. 1 (July 1, 1997): E68—E76. http://dx.doi.org/10.1152/ajpendo.1997.273.1.e68.
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We addressed the effect of long-term treatment with insulin, 2,4-dinitrophenol (DNP; an uncoupler of oxidative phosphorylation that increases energy demand) and 300 mM mannitol (hyperosmolarity) on glucose transporter (GLUT) expression in L6 muscle cells and the signaling pathways involved. We found the following. 1) The insulin-mediated increase in GLUT-1 is 70-kDa ribosomal protein S6 kinase (p70 S6 kinase) and p38 mitogen-activated protein kinase (MAPK) dependent but extracellular signal-regulated protein kinase (ERK) and MAPK/ERK kinase (MEK) independent. The hypertonicity-stimulated elevation in GLUT-1 is p70 S6 kinase, p38 MAPK, and MEK dependent yet ERK independent. DNP also increased GLUT-1 protein but did not depend on any of the above pathways, 2) Insulin increased GLUT-3 protein in a p70 S6 kinase-independent but MEK/ERK-dependent fashion. Inhibition of p38 MAPK potentiated the effect of insulin on GLUT-3. Hypertonicity increased GLUT-3 via p70 S6 kinase- and p38 MAPK-dependent pathways. In conclusion, we have dissected the molecular mechanisms used by insulin and hypertonicity that culminate in the induction of GLUT-1 and GLUT-3. The mechanism(s) used by DNP remains unknown.
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Frank, Matthew J., David W. Dawson, Steven J. Bensinger, Jason S. Hong, Wendy M. Knosp, Lizhong Xu, Cynthia E. Balatoni, et al. "Expression of sprouty2 inhibits B-cell proliferation and is epigenetically silenced in mouse and human B-cell lymphomas." Blood 113, no. 11 (March 12, 2009): 2478–87. http://dx.doi.org/10.1182/blood-2008-05-156943.
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B-cell lymphoma is the most common immune system malignancy. TCL1 transgenic mice (TCL1-tg), in which TCL1 is ectopically expressed in mature lymphocytes, develop multiple B- and T-cell leukemia and lymphoma subtypes, supporting an oncogenic role for TCL1 that probably involves AKT and MAPK-ERK signaling pathway augmentation. Additional, largely unknown genetic and epigenetic alterations cooperate with TCL1 during lymphoma progression. We examined DNA methylation patterns in TCL1-tg B-cell tumors to discover tumor-associated epigenetic changes, and identified hypermethylation of sprouty2 (Spry2). Sprouty proteins are context-dependent negative or positive regulators of MAPK-ERK pathway signaling, but their role(s) in B-cell physiology or pathology are unknown. Here we show that repression of Spry2 expression in TCL1-tg mouse and human B-cell lymphomas and cell lines is associated with dense DNA hypermethylation and was reversed by inhibition of DNA methylation. Spry2 expression was induced in normal splenic B cells by CD40/B-cell receptor costimulation and regulated a negative feedback loop that repressed MAPK-ERK signaling and decreased B-cell viability. Conversely, loss of Spry2 function hyperactivated MAPK-ERK signaling and caused increased B-cell proliferation. Combined, these results implicate epigenetic silencing of Spry2 expression in B lymphoma progression and suggest it as a companion lesion to ectopic TCL1 expression in enhancing MAPK-ERK pathway signaling.
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Gu, Xiaoxiao, and Kristyn S. Masters. "Role of the MAPK/ERK pathway in valvular interstitial cell calcification." American Journal of Physiology-Heart and Circulatory Physiology 296, no. 6 (June 2009): H1748—H1757. http://dx.doi.org/10.1152/ajpheart.00099.2009.
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Much remains to be discovered about the etiology of heart valve disease and the molecular level mechanisms that drive it. The MAPK/ERK pathway influences calcification in many cell types and has been linked to the expression of a contractile phenotype in valvular interstitial cells (VICs). However, a direct correlation between MAPK/ERK pathway activity and VIC calcification has not been previously described. Thus the role of the MAPK pathway in the calcification of VIC cultures was investigated by measuring ERK activation in both calcifying and noncalcifying VIC environments and then, conversely, analyzing the effects of ERK pathway inhibition on VIC calcification and phenotype. Prolonged elevation of phosphorylated ERK-1/2 was found in calcifying VIC cultures, whereas directly blocking phosphorylation of ERK-1/2 resulted in a dramatic decrease in nodule number, nodule size, and total calcified area. Application of the ERK pathway inhibitor was also associated with a dramatic decrease in apoptosis, which may have contributed to the decreased nodule formation obtained via ERK inhibition. Real-time PCR analysis revealed that calcified samples exhibited significantly elevated expression of several myofibroblastic and osteoblastic markers, while ERK inhibition substantially reduced the expression of these markers, often to levels comparable to the noncalcifying control. These data suggest that the MAPK pathway plays an important role in regulating the phenotype and calcification of VICs, wherein sustained pathway activation is associated with increased VIC calcification. These findings may be used to further elucidate the mechanisms of valvular disease and identify potential treatment targets.
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Ngan, Hoi-Lam, Yuchen Liu, Andrew Yuon Fong, Peony Hiu Yan Poon, Chun Kit Yeung, Sharon Suet Man Chan, Alexandria Lau, et al. "MAPK pathway mutations in head and neck cancer affect immune microenvironments and ErbB3 signaling." Life Science Alliance 3, no. 6 (May 7, 2020): e201900545. http://dx.doi.org/10.26508/lsa.201900545.
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MAPK pathway mutations affect one-fifth of head and neck squamous cell carcinoma (HNSCC). Unexpectedly, MAPK pathway aberrations are associated with remarkably long patient survival, even among patients with TP53 mutations (median ∼14 yr). We explored underlying outcome-favoring mechanisms with omics followed by preclinical models. Strikingly, multiple hotspot and non-hotspot MAPK mutations (A/BRAF, HRAS, MAPK1, and MAP2K1/2) all abrogated ErbB3 activation, a well-established HNSCC progression signal. Inhibitor studies functionally defined ERK activity negatively regulating phospho-ErbB3 in MAPK-mutants. Furthermore, pan-pathway immunoprofiling investigations identified MAPK-mutant tumors as the only “CD8+ T-cell–inflamed” tumors inherently bearing high-immunoreactive, constitutive cytolytic tumor microenvironments. Immunocompetent MAPK-mutant HNSCC models displayed active cell death and massive CD8+ T-cell recruitment in situ. Consistent with CD8+ T-inflamed phenotypes, MAPK-mutant HNSCC patients, independent of tumor-mutational burden, survived 3.3–4 times longer than WT patients with anti-PD1/PD-L1 immunotherapies. Similar prognosticity was noted in pan-cancers. We uncovered clinical, signaling, and immunological uniqueness of MAPK-mutant HNSCC with potential biomarker utilities predicting favorable patient survival.
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Schrader, Laura A., Shari G. Birnbaum, Brian M. Nadin, Yajun Ren, Duy Bui, Anne E. Anderson, and J. David Sweatt. "ERK/MAPK regulates the Kv4.2 potassium channel by direct phosphorylation of the pore-forming subunit." American Journal of Physiology-Cell Physiology 290, no. 3 (March 2006): C852—C861. http://dx.doi.org/10.1152/ajpcell.00358.2005.
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Kv4.2 is the primary pore-forming subunit encoding A-type currents in many neurons throughout the nervous system, and it also contributes to the transient outward currents of cardiac myocytes. A-type currents in the dendrites of hippocampal CA1 pyramidal neurons are regulated by activation of ERK/MAPK, and Kv4.2 is the likely pore-forming subunit of that current. We showed previously that Kv4.2 is directly phosphorylated at three sites by ERK/MAPK (T602, T607, and S616). In this study we determined whether direct phosphorylation of Kv4.2 by ERK/MAPK is responsible for the regulation of the A-type current observed in neurons. We made site-directed mutants, changing the phosphosite serine (S) or threonine (T) to aspartate (D) to mimic phosphorylation. We found that the T607D mutation mimicked the electrophysiological changes elicited by ERK/MAPK activation in neurons: a rightward shift of the activation curve and an overall reduction in current compared with wild type (WT). Surprisingly, the S616D mutation caused the opposite effect, a leftward shift in the activation voltage. K+ channel-interacting protein (KChIP)3 ancillary subunit coexpression with Kv4.2 was necessary for the T607D effect, as the T607D mutant when expressed in the absence of KChIP3 was not different from WT Kv4.2. These data suggest that direct phosphorylation of Kv4.2 at T607 is involved in the dynamic regulation of the channel function by ERK/MAPK and an interaction of the primary subunit with KChIP is also necessary for this effect. Overall these studies provide new insights into the structure-function relationships for MAPK regulation of membrane ion channels.
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Klomp, Jennifer E., Jeff A. Klomp, and Channing J. Der. "The ERK mitogen-activated protein kinase signaling network: the final frontier in RAS signal transduction." Biochemical Society Transactions 49, no. 1 (February 5, 2021): 253–67. http://dx.doi.org/10.1042/bst20200507.
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The RAF–MEK–ERK mitogen-activated protein kinase (MAPK) cascade is aberrantly activated in a diverse set of human cancers and the RASopathy group of genetic developmental disorders. This protein kinase cascade is one of the most intensely studied cellular signaling networks and has been frequently targeted by the pharmaceutical industry, with more than 30 inhibitors either approved or under clinical evaluation. The ERK–MAPK cascade was originally depicted as a serial and linear, unidirectional pathway that relays extracellular signals, such as mitogenic stimuli, through the cytoplasm to the nucleus. However, we now appreciate that this three-tiered protein kinase cascade is a central core of a complex network with dynamic signaling inputs and outputs and autoregulatory loops. Despite our considerable advances in understanding the ERK–MAPK network, the ability of cancer cells to adapt to the inhibition of key nodes reveals a level of complexity that remains to be fully understood. In this review, we summarize important developments in our understanding of the ERK–MAPK network and identify unresolved issues for ongoing and future study.
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Zhang, Zheng, and David M. Cohen. "Urea activates ribosomal S6 kinase (RSK) in a MEK-dependent fashion in renal mIMCD3 cells." American Journal of Physiology-Renal Physiology 274, no. 1 (January 1, 1998): F73—F78. http://dx.doi.org/10.1152/ajprenal.1998.274.1.f73.
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Urea activates a characteristic subset of signaling pathways in a tissue-specific fashion, including transcription of immediate early genes through activation of the mitogen-activated protein kinase (MAPK), ERK (extracellular signal-regulated kinase), and activation of its transcription factor substrate, Elk-1. The ability of urea to activate the ERK effector and pivotal regulatory kinase, ribosomal S6 kinase (RSK), was investigated in mIMCD3 renal inner medullary collecting duct cells. Urea upregulated RSK activity in a time-dependent fashion in serum-deprived mIMCD3 cells; the effect was maximal at 5 min. Activation by hypertonic NaCl, in contrast, was negligible at 5 min and peaked at 15 min. Both stimuli induced the nuclear translocation of cytosolic RSK, as determined via immunofluorescence. Importantly, activation of RSK by both solutes was MAPK/ERK kinase (MEK) dependent, as determined by the ability of the specific MEK inhibitor, PD-98059, to abrogate the response. Taken together, these data indicate that urea activates the ERK effector, RSK, in cells of the renal medulla in an ERK-dependent fashion, further emphasizing the functional significance of urea signaling through ERK activation in renal medullary cells.
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Guerrero, Carmen, Liuska Pesce, Emilia Lecuona, Karen M. Ridge, and Jacob I. Sznajder. "Dopamine activates ERKs in alveolar epithelial cells via Ras-PKC-dependent and Grb2/Sos-independent mechanisms." American Journal of Physiology-Lung Cellular and Molecular Physiology 282, no. 5 (May 1, 2002): L1099—L1107. http://dx.doi.org/10.1152/ajplung.00178.2001.
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Recently it has been described that dopamine (DA), via dopaminergic type 2 receptors (D2R), activates the mitogen-activated protein kinase extracellular signal-regulated kinase (MAPK/ERK) proteins in alveolar epithelial cells (AEC), which results in the upregulation of Na+-K+-ATPase. In the present report, we used AEC to investigate the signaling pathway that links DA with ERK activation. Incubation of AEC with DA resulted in rapid and transient stimulation of ERK activity, which was mediated by Ras proteins and the serine/threonine kinase Raf-1. Pretreatment of AEC with Src homology 3 binding peptide, which blocks the interaction between Grb2 and Sos, did not prevent DA activation of ERK. Diacylglycerol (DAG)-dependent protein kinase C (PKC) isoenzymes, involved in the DA-mediated activation of ERK proteins as pretreatment with either bisindolylmaleimide or Ro-31-8220, prevented the phosphorylation of Elk-1, and quinpirole, a D2R activator, stimulates the translocation of PKCε. Together, the data suggest that DA activated MAPK/ERK via Ras, Raf-1 kinase, and DAG-dependent PKC isoenzymes, but, importantly and contrary to the classical model, this pathway did not involve the Grb2-Sos complex formation.
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Kurtzeborn, Kwon, and Kuure. "MAPK/ERK Signaling in Regulation of Renal Differentiation." International Journal of Molecular Sciences 20, no. 7 (April 10, 2019): 1779. http://dx.doi.org/10.3390/ijms20071779.
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Congenital anomalies of the kidney and urinary tract (CAKUT) are common birth defects derived from abnormalities in renal differentiation during embryogenesis. CAKUT is the major cause of end-stage renal disease and chronic kidney diseases in children, but its genetic causes remain largely unresolved. Here we discuss advances in the understanding of how mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) activity contributes to the regulation of ureteric bud branching morphogenesis, which dictates the final size, shape, and nephron number of the kidney. Recent studies also demonstrate that the MAPK/ERK pathway is directly involved in nephrogenesis, regulating both the maintenance and differentiation of the nephrogenic mesenchyme. Interestingly, aberrant MAPK/ERK signaling is linked to many cancers, and recent studies suggest it also plays a role in the most common pediatric renal cancer, Wilms’ tumor.
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Kubin, Thomas, Ayse Cetinkaya, Natalia Kubin, Peter Bramlage, Bedriye Sen-Hild, Praveen Gajawada, Hakan Akintürk, et al. "The MEK/ERK Module Is Reprogrammed in Remodeling Adult Cardiomyocytes." International Journal of Molecular Sciences 21, no. 17 (September 1, 2020): 6348. http://dx.doi.org/10.3390/ijms21176348.
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Fetal and hypertrophic remodeling are hallmarks of cardiac restructuring leading chronically to heart failure. Since the Ras/Raf/MEK/ERK cascade (MAPK) is involved in the development of heart failure, we hypothesized, first, that fetal remodeling is different from hypertrophy and, second, that remodeling of the MAPK occurs. To test our hypothesis, we analyzed models of cultured adult rat cardiomyocytes as well as investigated myocytes in the failing human myocardium by western blot and confocal microscopy. Fetal remodeling was induced through endothelial morphogens and monitored by the reexpression of Acta2, Actn1, and Actb. Serum-induced hypertrophy was determined by increased surface size and protein content of cardiomyocytes. Serum and morphogens caused reprogramming of Ras/Raf/MEK/ERK. In both models H-Ras, N-Ras, Rap2, B- and C-Raf, MEK1/2 as well as ERK1/2 increased while K-Ras was downregulated. Atrophy, MAPK-dependent ischemic resistance, loss of A-Raf, and reexpression of Rap1 and Erk3 highlighted fetal remodeling, while A-Raf accumulation marked hypertrophy. The knock-down of B-Raf by siRNA reduced MAPK activation and fetal reprogramming. In conclusion, we demonstrate that fetal and hypertrophic remodeling are independent processes and involve reprogramming of the MAPK.
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Rubinfeld, Hadara, and Rony Seger. "The ERK Cascade: A Prototype of MAPK Signaling." Molecular Biotechnology 31, no. 2 (2005): 151–74. http://dx.doi.org/10.1385/mb:31:2:151.
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Kolch, Walter. "Coordinating ERK/MAPK signalling through scaffolds and inhibitors." Nature Reviews Molecular Cell Biology 6, no. 11 (October 14, 2005): 827–37. http://dx.doi.org/10.1038/nrm1743.
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Zeng, Wenfeng, Yan Yan, Fayun Zhang, Chunling Zhang, and Wei Liang. "Chrysin promotes osteogenic differentiation via ERK/MAPK activation." Protein & Cell 4, no. 7 (June 6, 2013): 539–47. http://dx.doi.org/10.1007/s13238-013-3003-3.
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