Journal articles: 'Mitogen-Activated Protein Kinase 3'

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Bassi, Rekha, Joseph R. Burgoyne, Gian F. DeNicola, Olena Rudyk, Vittorio DeSantis, Rebecca L. Charles, Philip Eaton, and Michael S. Marber. "Redox-dependent dimerization of p38α mitogen-activated protein kinase with mitogen-activated protein kinase kinase 3." Journal of Biological Chemistry 292, no. 39 (July 24, 2017): 16161–73. http://dx.doi.org/10.1074/jbc.m117.785410.

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CHAN-HUI, Po-Ying, and Robert WEAVER. "Human mitogen-activated protein kinase kinase kinase mediates the stress-induced activation of mitogen-activated protein kinase cascades." Biochemical Journal 336, no. 3 (December 15, 1998): 599–609. http://dx.doi.org/10.1042/bj3360599.

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The mitogen-activated protein kinase (MAPK) cascades represent one of the important signalling mechanisms in response to environmental stimuli. We report the identification of a human MAPK kinase kinase, MAPKKK4, via sequence similarity with other MAPKKKs. When truncated MAPKKK4 (ΔMAPKKK4) was overexpressed in HEK293 cells, it was constitutively active and induced the activation of endogenous p38α, c-Jun N-terminal kinase (JNK)1/2 and extracellular signal-regulated kinase (ERK)2 in vivo. Kinase-inactive ΔMAPKKK4 partly inhibited the activation of p38α, JNK1/2 and ERK2 induced by stress, tumour necrosis factor α or epidermal growth factor, suggesting that MAPKKK4 might be physiologically involved in all three MAPK cascades. Co-expressed MAP kinase kinase (MKK)-1, MKK-4, MKK-3 and MKK-6 were activated in vivo by ΔMAPKKK4. All of the above MKKs purified from Escherichia coli were phosphorylated and activated by ΔMAPKKK4 immunoprecipitates in vitro. When expressed by lower plasmid doses, ΔMAPKKK4 preferentially activated MKK-3 and p38α in vivo. Overexpression of ΔMAPKKK4 did not activate the NF-κB pathway. Immunoprecipitation of endogenous MAPKKK4 by specific antibodies showed that MAPKKK4 was activated after the treatment of K562 cells with various stress conditions. As a broadly distributed kinase, MAPKKK4 might serve as a stress responder. MAPKKK4 is 91% identical with the recently described murine MEKK-4β and might be its human homologue. It is also identical with the recently cloned human MAP three kinase 1 except for the lack of an internal sequence homologous to the murine MEKK-4α isoform. Differences in the reported functional activities of the three kinases are discussed.

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Lim, Nicholas R., Colleen J. Thomas, Lokugan S. Silva, Yvonne Y. Yeap, Suwan Yap, James R. Bell, Lea M. D. Delbridge, et al. "Cardioprotective 3′,4′-dihydroxyflavonol attenuation of JNK and p38MAPK signalling involves CaMKII inhibition." Biochemical Journal 456, no. 2 (November 8, 2013): 149–61. http://dx.doi.org/10.1042/bj20121538.

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3′,4′-Dihydroxyflavonol, a cardioprotective compound that prevents cardiac injury and cell death, targets Ca2+/camodulin-dependent protein kinase II to inhibit the activation of the stress-activated protein kinases, c-Jun N-terminal kinase and p38 mitogen-activated protein kinase.

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Ngo, H. T. T., L. V. Pham, J. W. Kim, Y. S. Lim, and S. B. Hwang. "Modulation of Mitogen-Activated Protein Kinase-Activated Protein Kinase 3 by Hepatitis C Virus Core Protein." Journal of Virology 87, no. 10 (March 13, 2013): 5718–31. http://dx.doi.org/10.1128/jvi.03353-12.

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Moens, Ugo, and Sergiy Kostenko. "Structure and function of MK5/PRAK: the loner among the mitogen-activated protein kinase-activated protein kinases." Biological Chemistry 394, no. 9 (September 1, 2013): 1115–32. http://dx.doi.org/10.1515/hsz-2013-0149.

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Abstract Mitogen-activated protein kinase (MAPK) pathways are important signal transduction pathways that control pivotal cellular processes including proliferation, differentiation, survival, apoptosis, gene regulation, and motility. MAPK pathways consist of a relay of consecutive phosphorylation events exerted by MAPK kinase kinases, MAPK kinases, and MAPKs. Conventional MAPKs are characterized by a conserved Thr-X-Tyr motif in the activation loop of the kinase domain, while atypical MAPKs lack this motif and do not seem to be organized into the classical three-tiered kinase cascade. One functional group of conventional and atypical MAPK substrates consists of protein kinases known as MAPK-activated protein kinases. Eleven mammalian MAPK-activated protein kinases have been identified, and they are divided into five subgroups: the ribosomal-S6-kinases RSK1-4, the MAPK-interacting kinases MNK1 and 2, the mitogen- and stress-activated kinases MSK1 and 2, the MAPK-activated protein kinases MK2 and 3, and the MAPK-activated protein kinase MK5 (also referred to as PRAK). MK5/PRAK is the only MAPK-activated protein kinase that is a substrate for both conventional and atypical MAPK, while all other MAPKAPKs are exclusively phosphorylated by conventional MAPKs. This review focuses on the structure, activation, substrates, functions, and possible implications of MK5/PRAK in malignant and nonmalignant diseases.

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Barr, Alastair J., Robin Marjoram, Jing Xu, and Ralph Snyderman. "Phospholipase C-β2 interacts with mitogen-activated protein kinase kinase 3." Biochemical and Biophysical Research Communications 293, no. 1 (April 2002): 647–52. http://dx.doi.org/10.1016/s0006-291x(02)00259-0.

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Nakamura, Shingo, Mohammad Pourkheirandish, Hiromi Morishige, Yuta Kubo, Masako Nakamura, Kazuya Ichimura, Shigemi Seo, et al. "Mitogen-Activated Protein Kinase Kinase 3 Regulates Seed Dormancy in Barley." Current Biology 26, no. 6 (March 2016): 775–81. http://dx.doi.org/10.1016/j.cub.2016.01.024.

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Stokoe, D., B. Caudwell, P. T. W. Cohen, and P. Cohen. "The substrate specificity and structure of mitogen-activated protein (MAP) kinase-activated protein kinase-2." Biochemical Journal 296, no. 3 (December 15, 1993): 843–49. http://dx.doi.org/10.1042/bj2960843.

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The substrate specificity of mitogen-activated protein (MAP) kinase-activated protein kinase-2 (MAPKAP kinase-2) was investigated by using synthetic peptides related to the N-terminus of glycogen synthase. The minimum sequence required for efficient phosphorylation was found to be Xaa-Xaa-Hyd-Xaa-Arg-Xaa-Xaa-Ser-Xaa-Xaa, where Hyd is a bulky hydrophobic residue (Phe > Leu > Val >> Ala), and the peptide Lys-Lys-Phe-Asn-Arg-Thr-Leu-Ser-Val-Ala was phosphorylated with a Km of 9.3 microM and Vmax. of 10 mumol/min per mg. MAPKAP kinase-1 (a homologue of ribosomal protein S6 kinase) also requires an arginine three residues N-terminal to the serine (position n-3), but not a hydrophobic residue at position n-5. Neither MAPKAP kinase-1 nor MAPKAP kinase-2 could tolerate a proline residue at position n + 1, indicating that their specificities do not overlap with that of MAP kinase. The specificity of calmodulin-dependent protein kinase-II resembled that of MAPKAP kinase-2, except that it could tolerate replacement of the arginine by a lysine and the phosphorylation-site serine by a threonine residue. Partial cDNAs encoding MAPKAP kinase-2 were isolated from rabbit and human skeletal muscle and human teratocarcinoma libraries, and Northern-blotting experiments revealed a single 3.3 kb mRNA transcript present at similar levels in six human tissues examined. The catalytic domain was most similar (35-40% identity) to calmodulin-dependent protein kinases II and IV, phosphorylase kinase, putative serine kinase H1 and the C-terminal domain of MAPKAP kinase-1, which form one branch of the protein kinase phylogenetic tree. The sequence N-terminal to the catalytic domain is proline-rich and contains two putative SH3-binding sites. The threonine residue phosphorylated by MAP kinase lies immediately C-terminal to the catalytic domain and is followed by a nuclear localization signal, Lys-Lys-(Xaa)10-Lys-Arg-Arg-Lys-Lys, near the C-terminus.

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Wang, Y., J. Pouysségur, and M. J. Dunn. "Endothelin stimulates mitogen-activated protein kinase activity in mesangial cells through ETA." Journal of the American Society of Nephrology 5, no. 4 (October 1994): 1074–80. http://dx.doi.org/10.1681/asn.v541074.

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Accumulating evidence suggests that endothelin (ET) contributes to the pathophysiology of such disorders as acute renal failure, cyclosporine-mediated renal and vascular toxicity, and perhaps even glomerular inflammation. The postreceptor signaling pathways that mediate the actions of ET in these pathophysiologic conditions may include activation of kinase cascades. Thus, the effects of ET isopeptides on p42 and p44 mitogen-activated protein (MAP) kinase activity in rat glomerular mesangial cells were examined. ET-1 activated both p42 and p44 MAP kinases with similar dose responses and different kinetics. The threshold for kinase activation was 10(-9) M ET-1. ET-1 stimulated p42 and p44 MAP kinases with similar rapid (5 min) but different sustained activation of p42 (3 to 6 h) and p44 (1 to 2 h). Endothelin-3 (ET-3) also activated both isoforms of MAP kinase but with a threshold at 10(-7) M. Compared with ET-1, ET-3 stimulated only a rapid increase of p42 MAP kinase activity. We further investigated which ET receptors are coupled to MAP kinase activation. BQ-123, an ETA blocker, completely blocked the responsiveness of the MAP kinase to either ET-1 or ET-3. In Chinese hamster lung fibroblasts transfected with ETA or ETB cDNA, both receptors showed a rapid stimulation of MAP kinase in response to ET-1. These results suggest that ET can activate MAP kinases through both ET receptors but act exclusively through ETA in glomerular mesangial cells.

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Ehlting, Christian, Natalia Ronkina, Oliver Böhmer, Ute Albrecht, Konrad A. Bode, Karl S. Lang, Alexey Kotlyarov, et al. "Distinct Functions of the Mitogen-activated Protein Kinase-activated Protein (MAPKAP) Kinases MK2 and MK3." Journal of Biological Chemistry 286, no. 27 (May 17, 2011): 24113–24. http://dx.doi.org/10.1074/jbc.m111.235275.

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In LPS-treated macrophages, activation of STAT3 is considered to be crucial for terminating the production of inflammatory cytokines. By analyzing the role of MAPK-activated protein kinase (MK) 2 and MK3 for LPS-induced STAT3 activation in macrophages, the present study provides evidence that MK2 is crucial for STAT3 activation in response to LPS because it prevents MK3 from impeding IFNβ gene expression. Accordingly, LPS-induced IFNβ gene expression is down-regulated in MK2-deficient macrophages and can be reconstituted by additional ablation of the MK3 gene in MK2/3−/− macrophages. This is in contrast to LPS-induced IL-10 expression, which essentially requires the presence of MK2. Further analysis of downstream signaling events involved in the transcriptional regulation of IFNβ gene expression suggests that, in the absence of MK2, MK3 impairs interferon regulatory factor 3 protein expression and activation and inhibits nuclear translocation of p65. This inhibition of p65 nuclear translocation coincides with enhanced expression and delayed degradation of IκBβ, whereas expression of IκBα mRNA and protein is impaired in the absence of MK2. The observation that siRNA directed against IκBβ is able to reconstitute IκBα expression in MK2−/− macrophages suggests that enhanced expression and delayed degradation of IκBβ and impaired NFκB-dependent IκBα expression are functionally linked. In summary, evidence is provided that MK2 regulates LPS-induced IFNβ expression and downstream STAT3 activation as it restrains MK3 from mediating negative regulatory effects on NFκB- and interferon regulatory factor 3-dependent LPS signaling.

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Adams, P. D., and P. J. Parker. "Activation of mitogen-activated protein (MAP) kinase by a MAP kinase-kinase." Journal of Biological Chemistry 267, no. 19 (July 1992): 13135–37. http://dx.doi.org/10.1016/s0021-9258(18)42181-3.

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SALVATIERRA, CRISTIANA S. B., SÍLVIA R. L. REIS, ANA F. M. PESSOA, LETÍCIA M. I. DE SOUZA, LUIZ F. STOPPIGLIA, ROBERTO V. VELOSO, MARISE A. B. REIS, et al. "Short-term low-protein diet during pregnancy alters islet area and protein content of phosphatidylinositol 3-kinase pathway in rats." Anais da Academia Brasileira de Ciências 87, no. 2 (April 3, 2015): 1007–18. http://dx.doi.org/10.1590/0001-3765201520140251.

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The phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways mediate β cell growth, proliferation, survival and death. We investigated whether protein restriction during pregnancy alters islet morphometry or the expression and phosphorylation of several proteins involved in the phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways. As controls, adult pregnant and non-pregnant rats were fed a normal-protein diet (17%). Pregnant and non-pregnant rats in the experimental groups were fed a low-protein diet (6%) for 15 days. Low protein diet during pregnancy increased serum prolactin level, reduced serum corticosterone concentration and the expression of both protein kinase B/AKT1 (AKT1) and p70 ribosomal protein S6 kinase (p70S6K), as well as the islets area, but did not alter the insulin content of pancreatic islets. Pregnancy increased the expression of the Src homology/collagen (SHC) protein and the extracellular signal-regulated kinases 1/2 (ERK1/2) independent of diet. ERK1/2 phosphorylation (pERK1/2) was similar in islets from pregnant and non-pregnant rats fed a low-protein diet, and was higher in islets from pregnant rats than in islets from non-pregnant rats fed a normal-protein diet. Thus, a short-term, low-protein diet during pregnancy was sufficient to reduce the levels of proteins in the phosphatidylinositol 3-kinase pathway and affect islet morphometry.

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KIM, Sung-Jin, and Ronald C. KAHN. "Insulin regulation of mitogen-activated protein kinase kinase (MEK), mitogen-activated protein kinase and casein kinase in the cell nucleus: a possible role in the regulation of gene expression." Biochemical Journal 323, no. 3 (May 1, 1997): 621–27. http://dx.doi.org/10.1042/bj3230621.

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After insulin receptor activation, many cytoplasmic enzymes, including mitogen-activated protein (MAP) kinase, MAP kinase kinase (MEK) and casein kinase II (CKII) are activated, but exactly how insulin signalling progresses to the nucleus remains poorly understood. In Chinese hamster ovary cells overexpressing human insulin receptors [CHO(Hirc)], MEK, CKII and the MAP kinases ERK I and ERK II can be detected by immunoblotting in the nucleus, as well as in the cytoplasm, in the unstimulated state. Nuclear localization of MAP kinase is also observed in 3T3-F442A adipocytes, NIH-3T3 cells and Fao hepatoma cells, whereas MEK is found in the nucleus only in Fao and CHO cells. Insulin treatment for 5–30 min induces a translocation of MEK from the cytoplasm to the nucleus, whereas the MAP kinases and CKII are not translocated into the nucleus in response to insulin during this period. However, nuclear MAP kinase and CKII activities increase by 2–3-fold within 1–10 min after stimulation with insulin. By using gel-shift assays, it has been shown that insulin also stimulates nuclear protein binding to an AP-1 site with kinetics similar to MEK translocation and MAP kinase and CKII activation. Treatment of the extracts in vitro with protein phosphatase 2A or treatment of the intact cells with 5,6-dichloro-1-β-d-ribofuranosylbenzimidazole, a cell-permeable inhibitor of CKII, almost completely blocks the insulin-induced DNA-binding activity, whereas incubation of cells with a MEK inhibitor produces only a slight decrease. These results suggest that insulin signalling results in the activation of serine kinases in the nucleus via two pathways: (1) insulin stimulates the nuclear translocation of some kinases, such as MEK, which might directly phosphorylate nuclear protein substrates or activate other nuclear kinases, and (2) insulin activates nuclear kinases without translocation. The latter is true of CKII, which seems to regulate the binding of nuclear proteins to the AP-1 site, possibly by phosphorylation of AP-1 transcription factors.

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McLaughlin, Megan M., Sanjay Kumar, Peter C. McDonnell, Stephanie Van Horn, John C. Lee, George P. Livi, and Peter R. Young. "Identification of Mitogen-activated Protein (MAP) Kinase-activated Protein Kinase-3, a Novel Substrate of CSBP p38 MAP Kinase." Journal of Biological Chemistry 271, no. 14 (April 5, 1996): 8488–92. http://dx.doi.org/10.1074/jbc.271.14.8488.

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Minutoli, Letteria, Pietro Antonuccio, Carmelo Romeo, Piero Antonio Nicòtina, Alessandra Bitto, Salvatore Arena, Francesca Polito, et al. "Evidence for a Role of Mitogen-Activated Protein Kinase 3/Mitogen-Activated Protein Kinase in the Development of Testicular Ischemia-Reperfusion Injury." Biology of Reproduction 73, no. 4 (October 1, 2005): 730–36. http://dx.doi.org/10.1095/biolreprod.105.040741.

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Щепеткин, И. А., О. П. Буданова, И. Ю. Малышев, and Д. Н. Аточин. "Molecular mechanisms of neutrophil apoptosis (review)." Nauchno-prakticheskii zhurnal «Patogenez», no. 4() (December 11, 2018): 5–18. http://dx.doi.org/10.25557/2310-0435.2018.04.5-18.

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В обзоре представлены современные данные о механизмах инициации, регуляции и выполнении процесса апоптоза нейтрофилов с участием «рецепторов смерти», митохондрий, белков семейства Bcl-2, PI3-K (phosphatidylinositol 3-kinase), протеинкиназных каскадов p38 MAPK (mitogen-activated protein kinase), ERK (extracellular signal regulated kinase) и JNK (c-Jun N-terminal kinase), протеинкиназ А, В и С, сAMP, белков теплового шока, NF-kB (nuclear factor-kB), кальпаинов, каспаз и их ингибиторов, активных форм кислорода и других факторов. Предложена гипотетическая модель вовлечения апоптотических процессов в регуляцию дифференцировки и реактивности нейтрофилов. This review presented recent data on initiation, regulation, and execution of neutrophil apoptosis with participation of «death receptors», mitochondria, Bcl-2 family proteins, PI3-K (phosphatidylinositol 3-kinase), p38 MAPK (mitogen-activated protein kinase), ERK (extracellular signal regulated kinase) and JNK (c-Jun N-terminal kinase) cascades, protein kinases A, B and C, сAMP, heat shock proteins, NF-kB (nuclear factor-kB), calpains, caspases and theirs inhibitors, reactive oxygen species, and other factors. A speculative model of the apoptotic processes involvement in the regulation of neutrophil differentiation and reactivity was proposed.

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Yamboliev, Ilia A., Kevin M. Wiesmann, Cherie A. Singer, Jason C. Hedges, and William T. Gerthoffer. "Phosphatidylinositol 3-kinases regulate ERK and p38 MAP kinases in canine colonic smooth muscle." American Journal of Physiology-Cell Physiology 279, no. 2 (August 1, 2000): C352—C360. http://dx.doi.org/10.1152/ajpcell.2000.279.2.c352.

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In canine colon, M2/M3 muscarinic receptors are coupled to extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein (MAP) kinases. We tested the hypothesis that this coupling is mediated by enzymes of the phosphatidylinositol (PI) 3-kinase family. RT-PCR and Western blotting demonstrated expression of two isoforms, PI 3-kinase-α and PI 3-kinase-γ. Muscarinic stimulation of intact muscle strips (10 μM ACh) activated PI 3-kinase-γ, ERK and p38 MAP kinases, and MAP kinase-activated protein kinase-2, whereas PI 3-kinase-α activation was not detected. Wortmannin (25 μM) abolished the activation of PI 3-kinase-γ, ERK, and p38 MAP kinases. MAP kinase inhibition was a PI 3-kinase-γ-specific effect, since wortmannin did not inhibit recombinant activated murine ERK2 MAP kinase, protein kinase C, Raf-1, or MAP kinase kinase. In cultured muscle cells, newborn calf serum (3%) activated PI 3-kinase-α and PI 3-kinase-γ isoforms, ERK and p38 MAP kinases, and stimulated chemotactic cell migration. Using wortmannin and LY-294002 to inhibit PI 3-kinase activity and PD-098059 and SB-203580 to inhibit ERK and p38 MAP kinases, we established that these enzymes are functionally important for regulation of chemotactic migration of colonic myocytes.

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Beppu, Satoru, Yasufumi Nakajima, Masayuki Shibasaki, Kyoko Kageyama, Toshiki Mizobe, Nobuaki Shime, and Naoyuki Matsuda. "Phosphodiesterase 3 Inhibition Reduces Platelet Activation and Monocyte Tissue Factor Expression in Knee Arthroplasty Patients." Anesthesiology 111, no. 6 (December 1, 2009): 1227–37. http://dx.doi.org/10.1097/aln.0b013e3181c155ce.

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Background Tissue damage during surgery activates platelets and provokes a prothrombic state. The current study attempted to determine the impact of phosphodiesterase 3 inhibitors on platelet activation, platelet-leukocyte aggregate formation, and monocyte tissue factor expression during and after total knee arthroplasty. Methods Thirty-four patients undergoing scheduled total knee arthroplasty were randomly assigned to receive either the phosphodiesterase 3 inhibitor milrinone or the same amount of saline perioperatively. The effects of milrinone on platelet and leukocyte function in vitro were then assessed in healthy volunteers. Results Perioperative infusion of milrinone significantly attenuated platelet activation; phosphorylation of intraplatelet p38 mitogen-activated protein kinase, extracellular signal-regulated kinase 1/2, and Akt; and platelet-leukocyte aggregation. Furthermore, perioperative tissue factor expression on monocytes and fibrin monomer complex production were reduced by milrinone infusion in patients undergoing total knee arthroplasty. In vitro studies using adenosine diphosphate- and collagen-stimulated blood samples from healthy volunteers confirmed the antiplatelet effects and reduced monocyte tissue factor expression by milrinone. These studies further showed that platelet aggregation and integrin alpha(IIb)beta(3) activation were modified by intraplatelet phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase/extracellular signal-regulated kinase pathways, and that P-selectin expression on platelets and platelet-leukocyte aggregation were modulated by intraplatelet p38 mitogen-activated protein kinase pathway. Conclusion Continuous milrinone infusion has the potential to reduce platelet activation and monocyte tissue factor expression during the perioperative period in total knee arthroplasty. These events may be mediated in part by the ability of milrinone to reduce activation of intraplatelet mitogen-activated protein kinases and phosphatidylinositol 3-kinase. The clinical impact of phosphodiesterase 3 inhibition on perioperative hemostasis remains to be elucidated.

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Stambolic, V., and J. R. Woodgett. "Mitogen inactivation of glycogen synthase kinase-3β in intact cells via serine 9 phosphorylation." Biochemical Journal 303, no. 3 (November 1, 1994): 701–4. http://dx.doi.org/10.1042/bj3030701.

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Glycogen synthase kinase-3 (GSK-3), a protein-serine kinase implicated in cell-fate determination and differentiation, phosphorylates several regulatory proteins that are activated by dephosphorylation in response to hormones or growth factors. GSK-3 beta is phosphorylated in vitro at serine 9 by p70 S6 kinase and p90rsk-1, resulting in its inhibition [Sutherland, Leighton, and Cohen (1993) Biochem. J. 296, 15-19]. Using HeLa cells expressing GSK-3 beta or a mutant containing alanine at residue 9, we demonstrate that serine 9 is modified in intact cells and is targeted specifically by p90rsk-1, and that phosphorylation leads to loss of activity. Since p90rsk-1 is directly activated by mitogen-activated protein kinases, agonists of this pathway, such as insulin, repress GSK-3 function.

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Ellinger-Ziegelbauer, Heidrun, Kathleen Kelly, and Ulrich Siebenlist. "Cell Cycle Arrest and Reversion of Ras-Induced Transformation by a Conditionally Activated Form of Mitogen-Activated Protein Kinase Kinase Kinase 3." Molecular and Cellular Biology 19, no. 5 (May 1, 1999): 3857–68. http://dx.doi.org/10.1128/mcb.19.5.3857.

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ABSTRACT Signal-induced proliferation, differentiation, or stress responses of cells depend on mitogen-activated protein kinase (MAPK) cascades, the core modules of which consist of members of three successively acting kinase families (MAPK kinase kinase [MAP3K], MAPK kinase, and MAPK). It is demonstrated here that the MEKK3 kinase inhibits cell proliferation, a biologic response not commonly associated with members of the MAP3K family of kinases. A conditionally activated form of MEKK3 stably expressed in fibroblasts arrests these cells in early G1. MEKK3 critically blocks mitogen-driven expression of cyclin D1, a cyclin which is essential for progression of fibroblasts through G1. The MEKK3-induced block of cyclin D1 expression and of cell cycle progression may be mediated via p38 MAPK, a downstream effector of MEKK3. The MEKK3-mediated block of proliferation also reverses Ras-induced cellular transformation, suggesting possible tumor-suppressing functions for this kinase. Together, these results suggest an involvement of the MEKK3 kinase in negative regulation of cell cycle progression, and they provide the first insights into biologic activities of this kinase.

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Goldberg, Yaron, Gerhild Taimor, Hans Michael Piper, and Klaus-Dieter Schlüter. "Intracellular signaling leads to the hypertrophic effect of neuropeptide Y." American Journal of Physiology-Cell Physiology 275, no. 5 (November 1, 1998): C1207—C1215. http://dx.doi.org/10.1152/ajpcell.1998.275.5.c1207.

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Signal transduction pathways involved in the hypertrophic effect of neuropeptide Y (NPY) were investigated in adult cardiomyocytes. Reduction of transforming growth factor-β activity in serum-supplemented media abolished the induction of hypertrophic responsiveness to NPY. In responsive cells, NPY (100 nM) increased protein synthesis, determined as incorporation of [14C]phenylalanine, by 35 ± 15% ( P < 0.05, n = 16 cultures). In these cells, NPY activated pertussis toxin (PTx)-sensitive G proteins and phosphatidylinositol (PI) 3-kinase. PTx and inhibition of PI 3-kinase abolished the hypertrophic effect of NPY. NPY also activated protein kinase C (PKC) and mitogen-activated protein (MAP) kinase. Inhibition of these two kinases attenuated the induction of creatine kinase (CK)-BB but not the growth response to NPY. In conclusion, NPY stimulates protein synthesis in adult cardiomyocytes via activation of PTx-sensitive G proteins and PI 3-kinase and it induces the fetal-type CK-BB via activation of PKC and MAP kinase.

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Blank, Jonathan L., Pär Gerwins, Elicia M. Elliott, Susan Sather, and Gary L. Johnson. "Molecular Cloning of Mitogen-activated Protein/ERK Kinase Kinases (MEKK) 2 and 3." Journal of Biological Chemistry 271, no. 10 (March 8, 1996): 5361–68. http://dx.doi.org/10.1074/jbc.271.10.5361.

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Clark, J. E., R. A. Flavell, M. E. Faircloth, R. J. Davis, and M. S. Marber. "Post-infarction remodeling is independent of mitogen-activated protein kinase kinase 3 (MKK3)." Journal of Molecular and Cellular Cardiology 42, no. 6 (June 2007): S52—S53. http://dx.doi.org/10.1016/j.yjmcc.2007.03.149.

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Chun, Yoon Keun, Jayoung Kim, Sijoong Kwon, Soon Hee Choi, Feng Hong, Kuen-ai Moon, Joung Mok Kim, et al. "Phosphatidylinositol 3-Kinase Stimulates Muscle Differentiation by Activating p38 Mitogen-Activated Protein Kinase." Biochemical and Biophysical Research Communications 276, no. 2 (September 2000): 502–7. http://dx.doi.org/10.1006/bbrc.2000.3486.

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CLARK, J., R. FLAVELL, M. FAIRCLOTH, R. DAVIS, R. HEADS, and M. MARBER. "Post-infarction remodeling is independent of mitogen-activated protein kinase kinase 3 (MKK3)." Cardiovascular Research 74, no. 3 (June 1, 2007): 466–70. http://dx.doi.org/10.1016/j.cardiores.2007.02.027.

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Ming, Xiu-Fen, Georg Stoecklin, Min Lu, Renate Looser, and Christoph Moroni. "Parallel and Independent Regulation of Interleukin-3 mRNA Turnover by Phosphatidylinositol 3-Kinase and p38 Mitogen-Activated Protein Kinase." Molecular and Cellular Biology 21, no. 17 (September 1, 2001): 5778–89. http://dx.doi.org/10.1128/mcb.21.17.5778-5789.2001.

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ABSTRACT AU-rich elements (ARE) present in the 3′ untranslated regions of many cytokines and immediate-early genes are responsible for targeting the transcripts for rapid decay. We present evidence from cotransfection experiments in NIH 3T3 cells that two signaling pathways, one involving phosphatidylinositol 3-kinase (PI3-K), and one involving the p38 mitogen-activated protein kinase (MAPK), lead to stabilization of interleukin-3 mRNA in parallel. Stabilization mediated by either of the two pathways was antagonized by tristetraprolin (TTP), an AU-binding protein known to promote constitutive decay of ARE-containing transcripts. Remarkably, the stabilizing AU-binding protein HuR, in collaboration with p38 MAPK but not with PI3-K, could overcome the destabilizing effect of TTP. These data argue that the stabilizing kinases PI3-K and p38 MAPK do not act through direct inactivation of TTP but via activating pathway-specific stabilizing AU-binding proteins. Our data suggest an integrated model of mRNA turnover control, where stabilizing (HuR) and destabilizing (TTP) AU-binding proteins compete and where the former are under the positive control of independent phosphokinase signaling pathways.

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Suhasini, Modem, Hien Li, Suzanne M. Lohmann, Gerry R. Boss, and Renate B. Pilz. "Cyclic-GMP-Dependent Protein Kinase Inhibits the Ras/Mitogen-Activated Protein Kinase Pathway." Molecular and Cellular Biology 18, no. 12 (December 1, 1998): 6983–94. http://dx.doi.org/10.1128/mcb.18.12.6983.

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ABSTRACT Agents which increase the intracellular cyclic GMP (cGMP) concentration and cGMP analogs inhibit cell growth in several different cell types, but it is not known which of the intracellular target proteins of cGMP is (are) responsible for the growth-suppressive effects of cGMP. Using baby hamster kidney (BHK) cells, which are deficient in cGMP-dependent protein kinase (G-kinase), we show that 8-(4-chlorophenylthio)guanosine-3′,5′-cyclic monophosphate and 8-bromoguanosine-3′,5′-cyclic monophosphate inhibit cell growth in cells stably transfected with a G-kinase Iβ expression vector but not in untransfected cells or in cells transfected with a catalytically inactive G-kinase. We found that the cGMP analogs inhibited epidermal growth factor (EGF)-induced activation of mitogen-activated protein (MAP) kinase and nuclear translocation of MAP kinase in G-kinase-expressing cells but not in G-kinase-deficient cells. Ras activation by EGF was not impaired in G-kinase-expressing cells treated with cGMP analogs. We show that activation of G-kinase inhibited c-Raf kinase activation and that G-kinase phosphorylated c-Raf kinase on Ser43, both in vitro and in vivo; phosphorylation of c-Raf kinase on Ser43 uncouples the Ras-Raf kinase interaction. A mutant c-Raf kinase with an Ala substitution for Ser43 was insensitive to inhibition by cGMP and G-kinase, and expression of this mutant kinase protected cells from inhibition of EGF-induced MAP kinase activity by cGMP and G-kinase, suggesting that Ser43 in c-Raf is the major target for regulation by G-kinase. Similarly, B-Raf kinase was not inhibited by G-kinase; the Ser43phosphorylation site of c-Raf is not conserved in B-Raf. Activation of G-kinase induced MAP kinase phosphatase 1 expression, but this occurred later than the inhibition of MAP kinase activation. Thus, in BHK cells, inhibition of cell growth by cGMP analogs is strictly dependent on G-kinase and G-kinase activation inhibits the Ras/MAP kinase pathway (i) by phosphorylating c-Raf kinase on Ser43 and thereby inhibiting its activation and (ii) by inducing MAP kinase phosphatase 1 expression.

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Kyosseva, Svetlana V., Alan D. Elbein, W. Sue T. Griffin, Robert E. Mrak, Melvin Lyon, and Craig N. Karson. "Mitogen-activated protein kinases in schizophrenia." Biological Psychiatry 46, no. 5 (September 1999): 689–96. http://dx.doi.org/10.1016/s0006-3223(99)00104-3.

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Zhou, Bo, and Zhong-Yin Zhang. "Mechanism of Mitogen-activated Protein Kinase Phosphatase-3 Activation by ERK2." Journal of Biological Chemistry 274, no. 50 (December 10, 1999): 35526–34. http://dx.doi.org/10.1074/jbc.274.50.35526.

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Zubkov, Alexander Y., K. Shadon Rollins, and John H. Zhang. "KCl activates mitogen-activated protein kinase in rabbit bailar artery." Biochemical and Biophysical Research Communications 293, no. 1 (April 2002): 660–64. http://dx.doi.org/10.1016/s0006-291x(02)00241-3.

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Garrington, Timothy P., and Gary L. Johnson. "Organization and regulation of mitogen-activated protein kinase signaling pathways." Current Opinion in Cell Biology 11, no. 2 (April 1999): 211–18. http://dx.doi.org/10.1016/s0955-0674(99)80028-3.

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Sirkar, Madhumita, and Subrata Majumdar. "Lipoarabinomannan-Induced Cell Signaling Involves Ceramide and Mitogen-Activated Protein Kinase." Clinical and Vaccine Immunology 9, no. 6 (November 2002): 1175–82. http://dx.doi.org/10.1128/cdli.9.6.1175-1182.2002.

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ABSTRACT Lipoarabinomannan (LAM) is a major cell wall-associated lipoglycan, produced in large amounts (15 mg/g of bacteria) in different species of mycobacteria. Our laboratory has previously reported that LAM from Mycobacterium smegmatis exerts its cytotoxic activity via inhibition of protein kinase C, a key signaling molecule inside the mononuclear cells (S. Ghosh, S. Pal, S. Das, S. K. Dasgupta, and S. Majumdar, FEMS Immunol. Med. Microbiol. 21:181-188, 1998). In this study we report that LAM from Mycobacterium tuberculosis induces a signal transduction pathway in favor of survivability of the host cells via the generation of ceramide, a novel second messenger. The endogenous ceramide level in mononuclear cells was found to be enhanced during LAM treatment. The effects of LAM on protein tyrosine phosphorylation in human peripheral blood mononuclear cells were examined. LAM enhanced the tyrosine phosphorylation of p42 mitogen-activated protein kinase and phosphoinositol 3-kinase (PI3 kinase) and dephosphorylation of stress-activated protein kinase. LAM-induced phosphorylation of p42 (extracellular signal-regulated kinase 2) was further enhanced by wortmannin, a PI3 kinase inhibitor. To examine whether these effects are due to elevation of endogenous ceramide, we exposed the cells to cell-permeative C2-ceramide exogenously and studied the activities of different protein kinases. Fluorescence-activated cell sorter analysis and morphological studies showed that LAM induces cell survival. Therefore, these results suggest the ability of LAM to induce ceramide in the altered signaling pathway and help in cell survival.

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Dietel, Eric, Alexander Brobeil, Stefan Gattenlöhner, and Monika Wimmer. "The Importance of the Right Framework: Mitogen-Activated Protein Kinase Pathway and the Scaffolding Protein PTPIP51." International Journal of Molecular Sciences 19, no. 10 (October 22, 2018): 3282. http://dx.doi.org/10.3390/ijms19103282.

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The protein tyrosine phosphatase interacting protein 51 (PTPIP51) regulates and interconnects signaling pathways, such as the mitogen-activated protein kinase (MAPK) pathway and an abundance of different others, e.g., Akt signaling, NF-κB signaling, and the communication between different cell organelles. PTPIP51 acts as a scaffold protein for signaling proteins, e.g., Raf-1, epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (Her2), as well as for other scaffold proteins, e.g., 14-3-3 proteins. These interactions are governed by the phosphorylation of serine and tyrosine residues of PTPIP51. The phosphorylation status is finely tuned by receptor tyrosine kinases (EGFR, Her2), non-receptor tyrosine kinases (c-Src) and the phosphatase protein tyrosine phosphatase 1B (PTP1B). This review addresses various diseases which display at least one alteration in these enzymes regulating PTPIP51-interactions. The objective of this review is to summarize the knowledge of the MAPK-related interactome of PTPIP51 for several tumor entities and metabolic disorders.

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Minutoli, Letteria, Pietro Antonuccio, Francesca Polito, Alessandra Bitto, Francesco Squadrito, Vincenzo Di Stefano, Piero Antonio Nicotina, et al. "Mitogen-activated protein kinase 3/mitogen-activated protein kinase 1 activates apoptosis during testicular ischemia–reperfusion injury in a nuclear factor-κB-independent manner." European Journal of Pharmacology 604, no. 1-3 (February 2009): 27–35. http://dx.doi.org/10.1016/j.ejphar.2008.12.028.

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Court, Naomi W., Cristobal G. dos Remedios, Jacky Cordell, and Marie A. Bogoyevitch. "Cardiac Expression and Subcellular Localization of the p38 Mitogen-activated Protein Kinase Member, Stress-activated Protein Kinase-3 (SAPK3)." Journal of Molecular and Cellular Cardiology 34, no. 4 (April 2002): 413–26. http://dx.doi.org/10.1006/jmcc.2001.1523.

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TANG, Tong, K. S. Srinivasa PRASAD, Mark J. KOURY, and Stephen J. BRANDT. "Mitogen-activated protein kinase mediates erythropoietin-induced phosphorylation of the TAL1/SCL transcription factor in murine proerythroblasts." Biochemical Journal 343, no. 3 (October 25, 1999): 615–20. http://dx.doi.org/10.1042/bj3430615.

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Ectopic expression of the basic helix-loop-helix transcription factor TAL1 (or SCL) is the most frequent gain-of-function mutation in T-cell acute lymphoblastic leukaemia. Gene-knockout studies in mice have demonstrated that TAL1 is required for embryonic and adult haematopoiesis, and considerable evidence suggests it also has important functions in terminal erythroid differentiation. We reported previously that TAL1 phosphorylation is stimulated by erythropoietin in splenic proerythroblasts isolated from mice infected with the anaemia-inducing strain of Friend virus and show here the signalling pathway responsible. Erythropoietin was found to stimulate nuclear mitogen-activated protein kinase activity in addition to TAL1 protein phosphorylation, both of which were quantitatively inhibited by the mitogen-activated protein kinase kinase inhibitor PD 098059 and the phosphatidylinositol 3-kinase inhibitor wortmannin. Tryptic phosphopeptide analysis of radiolabelled TAL1 immunoprecipitated from nuclear extracts of Friend virus-induced proerythroblasts revealed that phosphorylation of Ser122, shown previously to be a substrate for the mitogen-activated protein kinase ERK1 (extracellular signal-regulated protein kinase) in vitro, was specifically, although not exclusively, increased by erythropoietin and inhibited by wortmannin and PD 098059. These results are consistent with an erythropoietin-stimulated signalling pathway in which there is direct activation of a mitogen-activated protein kinase kinase by phosphatidylinositol 3-kinase and identify TAL1 as one of its nuclear targets. These data suggest, in addition, a specific mechanism by which the principal regulator of erythroid differentiation could enhance TAL1 function, in addition to increasing its expression.

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Wingate, Andrew D., David G. Campbell, Mark Peggie, and J. Simon C. Arthur. "Nur77 is phosphorylated in cells by RSK in response to mitogenic stimulation." Biochemical Journal 393, no. 3 (January 13, 2006): 715–24. http://dx.doi.org/10.1042/bj20050967.

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Nur77 is a nuclear orphan receptor that is able to activate transcription independently of exogenous ligand, and has also been shown to promote apoptosis on its localization to mitochondria. Phosphorylation of Nur77 on Ser354 has been suggested to reduce ability of Nur77 to bind DNA; however, the kinase responsible for this phosphorylation in cells has not been clearly established. In the present study, we show that Nur77 is phosphorylated on this site by RSK (ribosomal S6 kinase) and MSK (mitogen- and stress-activated kinase), but not by PKB (protein kinase B) or PKA (protein kinase A), in vitro. In cells, phosphorylation of Nur77 in vivo is catalysed by RSK, which is activated downstream of the classical MAPK (mitogen-activated protein kinase) cascade. Phosphorylation of Nur77 by RSK is able to promote the binding of Nur77 to 14-3-3 proteins in vitro, however, no evidence could be seen for this interaction in cells. We have established that two related proteins, Nurr1 and Nor1, are also phosphorylated on the equivalent site by RSK in cells in response to mitogenic stimulation.

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Lee, Horim. "Mitogen-Activated Protein Kinase Kinase 3 Is Required for Regulation during Dark-Light Transition." Molecules and Cells 38, no. 7 (June 17, 2015): 651–56. http://dx.doi.org/10.14348/molcells.2015.0055.

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Kanda, Tatsuo, Reina Sasaki-Tanaka, Ryota Masuzaki, Naoki Matsumoto, Hiroaki Okamoto, and Mitsuhiko Moriyama. "Knockdown of Mitogen-Activated Protein Kinase Kinase 3 Negatively Regulates Hepatitis A Virus Replication." International Journal of Molecular Sciences 22, no. 14 (July 10, 2021): 7420. http://dx.doi.org/10.3390/ijms22147420.

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Zinc chloride is known to be effective in combatting hepatitis A virus (HAV) infection, and zinc ions seem to be especially involved in Toll-like receptor (TLR) signaling pathways. In the present study, we examined this involvement in human hepatoma cell lines using a human TLR signaling target RT-PCR array. We also observed that zinc chloride inhibited mitogen-activated protein kinase kinase 3 (MAP2K3) expression, which could downregulate HAV replication in human hepatocytes. It is possible that zinc chloride may inhibit HAV replication in association with its inhibition of MAP2K3. In that regard, this study set out to determine whether MAP2K3 could be considered a modulating factor in the development of the HAV pathogen-associated molecular pattern (PAMP) and its triggering of interferon-β production. Because MAP2K3 seems to play a role in antiviral immunity against HAV infection, it is a promising target for drug development. The inhibition of MAP2K3 may also prevent HAV patients from developing a severe hepatitis A infection.

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Caboche, Jocelyne, Emmanuel Valjent, and Peter Vanhoutte. "Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Induced Gene Regulation in Brain." Molecular Neurobiology 23, no. 2-3 (2001): 083–100. http://dx.doi.org/10.1385/mn:23:2-3:083.

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SHAW, Morag, Philip COHEN, and Dario R. ALESSI. "The activation of protein kinase B by H2O2 or heat shock is mediated by phosphoinositide 3-kinase and not by mitogen-activated protein kinase-activated protein kinase-2." Biochemical Journal 336, no. 1 (November 15, 1998): 241–46. http://dx.doi.org/10.1042/bj3360241.

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Protein kinase B (PKB) isoforms became activated [and glycogen synthase kinase-3 (GSK3) became inhibited] when mouse Swiss 3T3 fibroblasts were exposed to oxidative stress (H2O2) or heat shock, but not when they were exposed to osmotic shock (0.5 M sorbitol or 0.7 M NaCl), chemical stress (sodium arsenite), the protein-synthesis inhibitor anisomycin, or UV radiation. In contrast, all seven stimuli activated mitogen-activated protein kinase-activated protein kinase-2 (MAPKAP-K2). The activation of MAPKAP-K2 was suppressed by the drug SB 203580, but not by inhibitors of phosphoinositide (phosphatidylinositide, PI) 3-kinase. In contrast, the activation of PKB isoforms and the inhibition of GSK3 by oxidative stress or heat shock were prevented by inhibitors of PI 3-kinase, but not by SB 203580. Thus the activation of PKB by oxidative stress or heat shock is mediated by PI 3-kinase and not by MAPKAP-K2. PKBα and PKBγ were also activated by heat shock and oxidative stress in human embryonic kidney 293 cells and PKBγ was activated by heat shock in NIH 3T3 cells; in each case activation was suppressed by inhibitors of PI 3-kinase. The activation of PKB isoforms by H2O2 may underlie some of the insulin-mimetic effects of this compound.

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Capano, Michela, and Martin Crompton. "Bax translocates to mitochondria of heart cells during simulated ischaemia: involvement of AMP-activated and p38 mitogen-activated protein kinases." Biochemical Journal 395, no. 1 (March 15, 2006): 57–64. http://dx.doi.org/10.1042/bj20051654.

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The cytosolic protein Bax plays a key role in apoptosis by migrating to mitochondria and releasing proapoptotic proteins from the mitochondrial intermembrane space. The present study investigates the movement of Bax in isolated rat neonatal cardiomyocytes subjected to simulated ischaemia (minus glucose, plus cyanide), using green fluorescent protein-tagged Bax as a means of imaging Bax movements. Simulated ischaemia induced Bax translocation from the cytosol to mitochondria, commencing within 20 min of simulated ischaemia and progressing for several hours. Under the same conditions, there was an increase in the active, phosphorylated forms of p38 MAPK (mitogen-activated protein kinase) and AMPK (AMP-activated protein kinase). The AMPK activators AICAR (5-aminoimidazole-4-carboxamide ribonucleoside) and metformin also stimulated Bax translocation. Inhibition of p38 MAPK with SB203580 attenuated the phosphorylation of the downstream substrates, MAPK-activated protein kinases 2 and 3, but not that of the upstream MAPK kinase 3, nor of AMPK. Under all conditions (ischaemia, AICAR and metformin), SB203580 blocked Bax translocation completely. It is concluded that Bax translocation to mitochondria is an early step in ischaemia and that it occurs in response to activation of p38 MAPK downstream of AMPK.

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Kulkarni, Vishwesh V., Aditya Paranjape, Khem Raj Ghusinga, and Naira Hovakimyan. "Synthesis of robust tunable oscillators using mitogen activated protein kinase cascades." Systems and Synthetic Biology 4, no. 4 (December 2010): 331–41. http://dx.doi.org/10.1007/s11693-011-9078-3.

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King, W. G., M. D. Mattaliano, T. O. Chan, P. N. Tsichlis, and J. S. Brugge. "Phosphatidylinositol 3-kinase is required for integrin-stimulated AKT and Raf-1/mitogen-activated protein kinase pathway activation." Molecular and Cellular Biology 17, no. 8 (August 1997): 4406–18. http://dx.doi.org/10.1128/mcb.17.8.4406.

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Cell attachment to fibronectin stimulates the integrin-dependent interaction of p85-associated phosphatidylinositol (PI) 3-kinase with integrin-dependent focal adhesion kinase (FAK) as well as activation of the Ras/mitogen-activated protein (MAP) kinase pathway. However, it is not known if this PI 3-kinase-FAK interaction increases the synthesis of the 3-phosphorylated phosphoinositides (3-PPIs) or what role, if any, is played by activated PI 3-kinase in integrin signaling. We demonstrate here the integrin-dependent accumulation of the PI 3-kinase products, PI 3,4-bisphosphate [PI(3,4)P2] and PI(3,4,5)P3, as well as activation of AKT kinase, a serine/threonine kinase that can be stimulated by binding of PI(3,4)P2. The PI 3-kinase inhibitors wortmannin and LY294002 significantly decreased the integrin-induced accumulation of the 3-PPIs and activation of AKT kinase, without having significant effects on the levels of PI(4,5)P2 or tyrosine phosphorylation of paxillin. These inhibitors also reduced cell adhesion/spreading onto fibronectin but had no effect on attachment to polylysine. Interestingly, integrin-mediated Erk-2, Mek-1, and Raf-1 activation, but not Ras-GTP loading, was inhibited at least 80% by wortmannin and LY294002. In support of the pharmacologic results, fibronectin activation of Erk-2 and AKT kinases was completely inhibited by overexpression of a dominant interfering p85 subunit of PI 3-kinase. We conclude that integrin-mediated adhesion to fibronectin results in the accumulation of the PI 3-kinase products PI(3,4)P2 and PI(3,4,5)P3 as well as the PI 3-kinase-dependent activation of the kinases Raf-1, Mek-1, Erk-2, and AKT and that PI 3-kinase may function upstream of Raf-1 but downstream of Ras in integrin activation of Erk-2 MAP and AKT kinases.

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Russell, M., S. Winitz, and G. L. Johnson. "Acetylcholine muscarinic m1 receptor regulation of cyclic AMP synthesis controls growth factor stimulation of Raf activity." Molecular and Cellular Biology 14, no. 4 (April 1994): 2343–51. http://dx.doi.org/10.1128/mcb.14.4.2343.

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Acetylcholine muscarinic m2 receptors (m2R) couple to heterotrimeric Gi proteins and activate the Ras/Raf/mitogen-activated protein kinase pathway and phosphatidylinositol 3-kinase in Rat 1a cells. In contrast to the m2R, stimulation of the acetylcholine muscarinic m1 receptor (m1R) does not activate the Ras/Raf/mitogen-activated protein kinase regulatory pathway in Rat 1a cells but rather causes a pronounced inhibition of epidermal growth factor and platelet-derived growth factor receptor activation of Raf. In Rat 1a cells, m1R stimulation of phospholipase C beta and the marked rise in intracellular calcium stimulated cyclic AMP (cAMP) synthesis, resulting in the activation of protein kinase A. Stimulation of protein kinase A inhibited Raf activation in response to growth factors. Platelet-derived growth factor receptor stimulation of phosphatidylinositol 3-kinase activity was not affected by either m1R stimulation or protein kinase A activation in response to forskolin-stimulated cAMP synthesis. GTP loading of Ras in response to growth factors was unaffected by protein kinase A activation but was partially inhibited by carbachol stimulation of the m1R. Therefore, protein kinase A action at the Ras/Raf activation interface selectively inhibited only one branch of the signal transduction network initiated by tyrosine kinases. Specific adenylyl cyclases responding to different signals, including calcium, with enhanced cAMP synthesis will regulate Raf activation in response to Ras.GTP. Taken together, the data indicate that G protein-coupled receptors can positively and negatively regulate the responsiveness of tyrosine kinase-stimulated mitogenic response pathways.

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Russell, M., S. Winitz, and G. L. Johnson. "Acetylcholine muscarinic m1 receptor regulation of cyclic AMP synthesis controls growth factor stimulation of Raf activity." Molecular and Cellular Biology 14, no. 4 (April 1994): 2343–51. http://dx.doi.org/10.1128/mcb.14.4.2343-2351.1994.

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Acetylcholine muscarinic m2 receptors (m2R) couple to heterotrimeric Gi proteins and activate the Ras/Raf/mitogen-activated protein kinase pathway and phosphatidylinositol 3-kinase in Rat 1a cells. In contrast to the m2R, stimulation of the acetylcholine muscarinic m1 receptor (m1R) does not activate the Ras/Raf/mitogen-activated protein kinase regulatory pathway in Rat 1a cells but rather causes a pronounced inhibition of epidermal growth factor and platelet-derived growth factor receptor activation of Raf. In Rat 1a cells, m1R stimulation of phospholipase C beta and the marked rise in intracellular calcium stimulated cyclic AMP (cAMP) synthesis, resulting in the activation of protein kinase A. Stimulation of protein kinase A inhibited Raf activation in response to growth factors. Platelet-derived growth factor receptor stimulation of phosphatidylinositol 3-kinase activity was not affected by either m1R stimulation or protein kinase A activation in response to forskolin-stimulated cAMP synthesis. GTP loading of Ras in response to growth factors was unaffected by protein kinase A activation but was partially inhibited by carbachol stimulation of the m1R. Therefore, protein kinase A action at the Ras/Raf activation interface selectively inhibited only one branch of the signal transduction network initiated by tyrosine kinases. Specific adenylyl cyclases responding to different signals, including calcium, with enhanced cAMP synthesis will regulate Raf activation in response to Ras.GTP. Taken together, the data indicate that G protein-coupled receptors can positively and negatively regulate the responsiveness of tyrosine kinase-stimulated mitogenic response pathways.

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Shafiq, Mohammad, Kumaravelu Jagavelu, Hina Iqbal, Pankaj Yadav, Debabrata Chanda, Neeraj Kumar Verma, Jimut Kanti Ghosh, Matthias Gaestel, and Kashif Hanif. "Inhibition of Mitogen-Activated Protein Kinase (MAPK)-Activated Protein Kinase 2 (MK2) is Protective in Pulmonary Hypertension." Hypertension 77, no. 4 (April 2021): 1248–59. http://dx.doi.org/10.1161/hypertensionaha.120.15229.

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Mitogen-Activated Protein Kinase (MAPK)-Activated Protein Kinase 2 (MK2), downstream to p38MAPK (p38mitogen-activated protein kinase), regulates cellular inflammation and proliferation. So far, the role of MK2 has been studied in many cardiovascular diseases, but it remains unexplored in pulmonary hypertension (PH). Therefore, to investigate the role of MK2 in the PH pathogenesis, human pulmonary artery smooth muscle cells were exposed to hypoxia (1% O 2 ) for 72 hours, and MK2 was inhibited by siRNA. We observed significantly increased MK2 expression, inflammatory cytokines, proliferation, mitochondrial dysfunction, and apoptosis resistance in hypoxic human pulmonary artery smooth muscle cells, which were reversed by treatment with MK2 siRNA. For in vivo studies, male Sprague Dawley rats were treated with monocrotaline (60 mg/kg, SC, once) to induce PH. To inhibit MK2, a peptide MMI-0100 (40 μg/kg, IP daily, 5 weeks for preventive and 3 weeks for curative study) was administered. MMI-0100 treatment decreased right ventricle pressure and hypertrophy, hallmarks of PH, in both preventive and curative study. MMI-0100-treated rats showed better cardiac functions as revealed by 2-dimensional echocardiography study. Furthermore, MMI-0100 reversed pulmonary vascular remodeling and improved pulmonary vascular relaxation in monocrotaline-treated rats. Finally, the above results were confirmed in MK2 knockout mice. MK2 knockout mice, received 600 mg/kg monocrotaline, subcutaneous weekly for 5 weeks, failed to develop PH and showed no increase in right ventricle pressure and hypertrophy. This study, therefore, proved that MK2 is involved in PH, and its inhibition may be a novel target for PH treatment.

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Mark, John K., Rémy A. Aubin, Sophie Smith, and Mary Alice Hefford. "Inhibition of Mitogen-activated Protein Kinase Phosphatase 3 Activity by Interdomain Binding." Journal of Biological Chemistry 283, no. 42 (August 11, 2008): 28574–83. http://dx.doi.org/10.1074/jbc.m801747200.

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Lemoine, Sandrine, Gallic Beauchef, Lan Zhu, Emmanuelle Renard, Olivier Lepage, Massimo Massetti, André Khayat, Philippe Galera, Jean-Louis Gérard, and Jean-Luc Hanouz. "Signaling Pathways Involved in Desflurane-induced Postconditioning in Human Atrial Myocardium In Vitro." Anesthesiology 109, no. 6 (December 1, 2008): 1036–44. http://dx.doi.org/10.1097/aln.0b013e31818d6b09.

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Background Isoflurane and sevoflurane have been shown to elicit myocardial postconditioning, but the effect of desflurane remain unknown. The authors studied the mechanisms involved in desflurane-induced myocardial postconditioning. Methods Contracting isolated human right atrial trabeculae (34 degrees C, stimulation frequency 1 Hz) were exposed to 30-min hypoxia followed by 60-min reoxygenation. Desflurane at 3%, 6%, and 9% was administered during the first 5-min of reoxygenation. Postconditioning with 6% desflurane was studied in the presence of 1 microM calphostin C, a protein kinase C inhibitor; 800 mm 5-hydroxydecanoate, a mitochondrial adenosine triphosphate-sensitive potassium channels antagonist; 1 microM Akt inhibitor; 20 microM PD89058, an extracellular-regulated kinase 1/2 inhibitor; and 1 microM SB 202190, a p38 mitogen-activated protein kinase inhibitor. The force of contraction at the end of the 60-min reoxygenation period was compared (mean +/- SD). The p38 mitogen-activated protein kinase phosphorylation was studied using Western blotting. Results Desflurane at 3% (77 +/- 10% of baseline), 6% (90 +/- 14% of baseline), and 9% (86 +/- 11% of baseline) enhanced the recovery of force after 60 min of reoxygenation as compared with the control group (51 +/- 9% of baseline; P < 0.001). Calphostin C (55 +/- 3% of baseline), 5-hydroxydecanoate (53 +/- 3% of baseline), Akt inhibitor (57 +/- 8% of baseline), PD89058 (64 +/- 6% of baseline), and SB 202190 (61 +/- 3% of baseline) abolished desflurane-induced postconditioning. Western blot analysis showed that 6% desflurane increased p38 mitogen-activated protein kinase phosphorylation. Conclusions In vitro, desflurane postconditioned human atrial myocardium through protein kinase C activation, opening of mitochondrial adenosine triphosphate-sensitive potassium channels, Akt and extracellular-regulated kinase 1/2 activation, and p38 mitogen-activated protein kinase phosphorylation.

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Hsu, Shu-Ching, Chia-Cheng Wu, Jiahuai Han, and Ming-Zong Lai. "Involvement of p38 mitogen–activated protein kinase in different stages of thymocyte development." Blood 101, no. 3 (February 1, 2003): 970–76. http://dx.doi.org/10.1182/blood-2002-03-0744.

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Abstract Positive selection of thymocytes during T-cell development is mediated by T-cell receptor (TCR)–activated signals. For different mitogen-activated protein kinases (MAPKs) activated by TCR complex, a selective involvement of extracellular signal–regulated kinase, but not p38 MAPK, in positive selection has been suggested. Using transgenic mice with dominant-negative mutation of both MAP kinase kinase 3 (MMK3) and MKK6, we obtained mice with different extents of inhibition of p38 MAPK activation. Partial inhibition of p38 MAPK impaired CD4−CD8− thymocyte development and T-cell proliferation, but not positive selection. Interference with thymocyte positive selection was observed in mice with effective suppression of p38 MAPK. Our results suggest that, in addition to early thymocyte development, p38 is involved in positive selection.

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Journal articles on the topic 'Mitogen-Activated Protein Kinase 3'

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