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1
Annunziata, Maria Carmela, Melania Parisi, Gabriella Esposito, Gabriella Fabbrocini, Rosario Ammendola, and Fabio Cattaneo. "Phosphorylation Sites in Protein Kinases and Phosphatases Regulated by Formyl Peptide Receptor 2 Signaling." International Journal of Molecular Sciences 21, no. 11 (May 27, 2020): 3818. http://dx.doi.org/10.3390/ijms21113818.
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FPR1, FPR2, and FPR3 are members of Formyl Peptides Receptors (FPRs) family belonging to the GPCR superfamily. FPR2 is a low affinity receptor for formyl peptides and it is considered the most promiscuous member of this family. Intracellular signaling cascades triggered by FPRs include the activation of different protein kinases and phosphatase, as well as tyrosine kinase receptors transactivation. Protein kinases and phosphatases act coordinately and any impairment of their activation or regulation represents one of the most common causes of several human diseases. Several phospho-sites has been identified in protein kinases and phosphatases, whose role may be to expand the repertoire of molecular mechanisms of regulation or may be necessary for fine-tuning of switch properties. We previously performed a phospho-proteomic analysis in FPR2-stimulated cells that revealed, among other things, not yet identified phospho-sites on six protein kinases and one protein phosphatase. Herein, we discuss on the selective phosphorylation of Serine/Threonine-protein kinase N2, Serine/Threonine-protein kinase PRP4 homolog, Serine/Threonine-protein kinase MARK2, Serine/Threonine-protein kinase PAK4, Serine/Threonine-protein kinase 10, Dual specificity mitogen-activated protein kinase kinase 2, and Protein phosphatase 1 regulatory subunit 14A, triggered by FPR2 stimulation. We also describe the putative FPR2-dependent signaling cascades upstream to these specific phospho-sites.
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Dara, Lily. "The Receptor Interacting Protein Kinases in the Liver." Seminars in Liver Disease 38, no. 01 (February 2018): 073–86. http://dx.doi.org/10.1055/s-0038-1629924.
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AbstractThe receptor interacting serine/threonine kinase1 and 3 (RIPK1, RIPK3) are regulators of cell death and survival. RIPK1 kinase activity is required for necroptosis and apoptosis, while its scaffolding function is necessary for survival. Although both proteins can mediate apoptosis, RIPK1 and RIPK3 are most well-known for their role in the execution of necroptosis via the mixed lineage domain like pseudokinase. Necroptosis is a caspase-independent regulated cell death program which was first described in cultured cells with unknown physiologic relevance in the liver. Many recent reports have suggested that RIPK1 and/or RIPK3 participate in liver disease pathogenesis and cell death. Notably, both proteins have been shown to mediate inflammation independent of cell death. Whether necroptosis occurs in hepatocytes, and how it is executed in the presence of an intact caspase machinery is controversial. In spite of this controversy, it is evident that RIPK1 and RIPK3 participate in many experimental liver disease models. Therefore, in addition to cell death signaling, their necroptosis-independent role warrants further examination.
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Kueng, Peter, Zariana Nikolova, Valentin Djonov, Andrew Hemphill, Valeria Rohrbach, Dominik Boehlen, Gisela Zuercher, Anne-Catherine Andres, and Andrew Ziemiecki. "A Novel Family of Serine/Threonine Kinases Participating in Spermiogenesis." Journal of Cell Biology 139, no. 7 (December 29, 1997): 1851–59. http://dx.doi.org/10.1083/jcb.139.7.1851.
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The molecular mechanisms regulating the spectacular cytodifferentiation observed during spermiogenesis are poorly understood. We have recently identified a murine testis-specific serine kinase (tssk) 1, constituting a novel subfamily of serine/threonine kinases. Using low stringency screening we have isolated and molecularly characterized a second closely related family member, tssk 2, which is probably the orthologue of the human DGS-G gene. Expression of tssk 1 and tssk 2 was limited to the testis of sexually mature males. Immunohistochemical staining localized both kinases to the cytoplasm of late spermatids and to structures resembling residual bodies. tssk 1 and tssk 2 were absent in released sperms in the lumen of the seminiferous tubules and the epididymis, demonstrating a tight window of expression restricted to the last stages of spermatid maturation. In vitro kinase assays of immunoprecipitates containing either tssk 1 or tssk 2 revealed no autophosphorylation of the kinases, however, they led to serine phosphorylation of a coprecipitating protein of ∼65 kD. A search for interacting proteins using the yeast two-hybrid system with tssk 1 and tssk 2 cDNA as baits and a prey cDNA library from mouse testis, led to the isolation of a novel cDNA, interacting specifically with both tssk 1 and tssk 2, and encoding the coprecipitated 65-kD protein phosphorylated by both kinases. Interestingly, expression of the interacting clone was also testis specific and paralleled the developmental expression observed for the kinases themselves. These results represent the first demonstration of the involvement of a distinct kinase family, the tssk serine/threonine kinases, together with a substrate in the cytodifferentiation of late spermatids to sperms.
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Leconte, I., and E. Clauser. "Two sequences flanking the major autophosphorylation site of the insulin receptor are essential for tyrosine kinase activation." Biochemical Journal 306, no. 2 (March 1, 1995): 465–72. http://dx.doi.org/10.1042/bj3060465.
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The tyrosine kinase domain of the human insulin receptor (IR) contains several short amino acid motifs which are strictly conserved in all protein kinases and two sequence motifs which are specific to the tyrosine kinases (AAR or RAA and P(I)/VK/RWT/M). In the serine/threonine kinases these motifs are replaced by the sequences KPE and GT/SXXY/PX respectively. In the present work, the tyrosine kinase-specific sequences of the IR (1134AAR1136 and 1172PVRWM1176) were replaced using site-directed mutagenesis by sequences which confer a serine kinase specificity on the receptor. Five different IR mutants were expressed in Chinese hamster ovary (CHO) or COS cells and their structural and functional properties compared with those of the wild-type recombinant human IR. These mutants are processed normally and bind insulin with normal affinities. None of the mutants containing a putative serine kinase-specific sequence display detectable autophosphorylation or tyrosine kinase activity in response to insulin, either in vitro or in vivo. These mutants were also unable to phosphorylate serine/threonine kinase substrates after insulin stimulation. Unexpectedly, they showed impaired ATP binding, as studied by an original technique consisting of cross-linking adenosine 5′-([35S]thio)triphosphate to partially purified receptors. Finally, none of the studied mutants transmit the insulin signal necessary to stimulate either DNA or glycogen synthesis. These data provide evidence for the importance of these conserved sequences in the kinase domain for both receptor activation and kinase activity. Furthermore, they demonstrate that the exchange of sequences specific to the catalytic domain of tyrosine kinases for those specific to the serine/threonine kinases is not sufficient to confer serine/threonine specificity on the insulin receptor.
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Jänne, O. A., A. M. Moilanen, H. Poukka, N. Rouleau, U. Karvonen, N. Kotaja, M. Häkli, and J. J. Palvimo. "Androgen-receptor-interacting nuclear proteins." Biochemical Society Transactions 28, no. 4 (August 1, 2000): 401–5. http://dx.doi.org/10.1042/bst0280401.
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Androgen receptor (AR) belongs to the super-family of nuclear hormone receptors that employ complex molecular mechanisms to guide the development and physiological functions of their target tissues. Our recent work has led to the identification of four novel proteins that recognize AR zinc-finger region (ZFR) both in vivo and in vitro. One is a small nuclear RING-finger protein that possesses separate interaction interfaces for AR and for other transcription activators such as Spl. The second is a nuclear serine/threonine protein kinase (androgen-receptor-interacting nuclear protein kinase; ANPK); however, the receptor itself does not seem to be a substrate for this kinase. The third one is dubbed androgen-receptor-interacting protein 3 (ARIP3) and is a novel member of the PIAS (protein inhibitor of activated STAT) protein family. The fourth protein, termed ARIP4, is a nuclear ATPase that belongs to the SNF2-like family of chromatin remodelling proteins. All four proteins exhibit a punctate nuclear pattern when expressed in cultured cells. Each protein modulates AR-dependent transactivation in co-transfection experiments; their activating functions are not restricted to AR. Current work is aimed at elucidating the biochemical and functional properties of these AR-interacting proteins and at finding the partner proteins that form complexes with them in vivo.
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Mason, Amanda R., Lisa P. Elia, and Steven Finkbeiner. "The Receptor-interacting Serine/Threonine Protein Kinase 1 (RIPK1) Regulates Progranulin Levels." Journal of Biological Chemistry 292, no. 8 (January 9, 2017): 3262–72. http://dx.doi.org/10.1074/jbc.m116.752006.
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Progranulin (PGRN), a secreted growth factor, is a key regulator of inflammation and is genetically linked to two common and devastating neurodegenerative diseases. Haploinsufficiency mutations in GRN, the gene encoding PGRN, cause frontotemporal dementia (FTD), and a GRN SNP confers significantly increased risk for Alzheimer's disease (AD). Because cellular and animal data indicate that increasing PGRN can reverse phenotypes of both FTD and AD, modulating PGRN level has been proposed as a therapeutic strategy for both diseases. However, little is known about the regulation of PGRN levels. In this study, we performed an siRNA-based screen of the kinome to identify genetic regulators of PGRN levels in a rodent cell-based model system. We found that knocking down receptor-interacting serine/threonine protein kinase 1 (Ripk1) increased both intracellular and extracellular PGRN protein levels by increasing the translation rate of PGRN without affecting mRNA levels. We observed this effect in Neuro2a cells, wild-type primary mouse neurons, and Grn-haploinsufficient primary neurons from an FTD mouse model. We found that the effect of RIPK1 on PGRN is independent of the kinase activity of RIPK1 and occurs through a novel signaling pathway. These data suggest that targeting RIPK1 may be a therapeutic strategy in both AD and FTD.
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Lamm, Marilyn L. G., Rajsree M. Rajagopalan-Gupta, and Mary Hunzicker-Dunn. "Epidermal Growth Factor-Induced Heterologous Desensitization of the Luteinizing Hormone/Choriogonadotopin Receptor in a Cell-Free Membrane Preparation Is Associated with the Tyrosine Phosphorylation of the Epidermal Growth Factor Receptor**This work was supported by USDA Grant NRICGP-9401432 (to M.H.D.)." Endocrinology 140, no. 1 (January 1, 1999): 29–36. http://dx.doi.org/10.1210/endo.140.1.6414.
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Abstract Epidermal growth factor (EGF) attenuated hCG-stimulated adenylyl cyclase activity in rat luteal and follicular membranes. H7, an equipotent serine/threonine protein kinase inhibitor of cAMP-dependent protein kinases, cGMP-dependent protein kinases, and lipid-dependent protein kinase C, did not effect the ability of EGF to decrease hCG-responsive adenylyl cyclase activity, suggesting that a serine/threonine phosphorylation event catalyzed by these kinases was not critically involved in EGF-induced desensitization. Likewise, pertussis toxin-catalyzed ADP-ribosylation of a 40-kDa luteal membrane protein, which exhibited immunoreactivity with an antibody against Giα, did not hinder the ability of EGF to attenuate hCG-stimulated adenylyl cyclase activity, indicating that Gi did not mediate EGF-induced desensitization. Rather, EGF-induced heterologous desensitization of LH/CG receptor in ovarian membranes was closely associated with the specific and prominent tyrosine phosphorylation of the 170-kDa EGF receptor. Both EGF-stimulated autophosphorylation of EGF receptor and EGF-induced LH/CG receptor desensitization were attenuated by genistein, a tyrosine kinase inhibitor. These results suggest that tyrosine phosphorylation of the 170-kDa EGF receptor is a necessary component of the signaling pathway in EGF-induced heterologous desensitization of the LH/CG receptor.
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Asamoah, K. A., P. G. P. Atkinson, W. G. Carter, and G. J. Sale. "Studies on an insulin-stimulated insulin receptor serine kinase activity: separation of the kinase activity from the insulin receptor and its reconstitution back to the insulin receptor." Biochemical Journal 308, no. 3 (June 15, 1995): 915–22. http://dx.doi.org/10.1042/bj3080915.
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In cells insulin stimulates autophosphorylation of the insulin receptor on tyrosine and its phosphorylation on serine and threonine by poorly characterized kinases. Recently we have achieved co-purification of the insulin receptor with insulin-stimulated insulin receptor serine kinase activity. We now show that the co-purified serine kinase activity can be removed by NaCl washing and reconstituted by adding back the NaCl eluate. Reconstitution enabled higher serine phosphorylation than achieved with the co-purified preparation. Myelin basic protein was discovered to be a potent substrate for insulin-stimulated serine phosphorylation by the co-purified preparation, with the activity responsible having similar properties to the serine kinase activity towards the receptor. Myelin basic protein was also phosphorylated on serine by the NaCl eluate. Myelin basic protein phosphorylated by the co-purified preparation or the NaCl eluate gave the same set of phosphoserine peptides. The major myelin basic protein serine kinase activity in the NaCl eluate co-purified exactly on Mono Q with the activity that restored insulin-stimulated insulin receptor serine phosphorylation. These results provide strong evidence for the true separation of the serine kinase from the insulin receptor and the distinctiveness of the serine kinase activity from the insulin receptor tyrosine kinase and mitogen-activated protein kinases. The procedures developed for the isolation of the serine kinase and the establishment of an effective in vitro substrate should allow purification of the kinase. The protocols also provide flexible systems for identifying the functions of the insulin-stimulated serine phosphorylations and the respective kinase(s).
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Knape, Matthias J., Maximilian Wallbott, Nicole C. G. Burghardt, Daniela Bertinetti, Jan Hornung, Sven H. Schmidt, Robin Lorenz, and Friedrich W. Herberg. "Molecular Basis for Ser/Thr Specificity in PKA Signaling." Cells 9, no. 6 (June 25, 2020): 1548. http://dx.doi.org/10.3390/cells9061548.
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cAMP-dependent protein kinase (PKA) is the major receptor of the second messenger cAMP and a prototype for Ser/Thr-specific protein kinases. Although PKA strongly prefers serine over threonine substrates, little is known about the molecular basis of this substrate specificity. We employ classical enzyme kinetics and a surface plasmon resonance (SPR)-based method to analyze each step of the kinase reaction. In the absence of divalent metal ions and nucleotides, PKA binds serine (PKS) and threonine (PKT) substrates, derived from the heat-stable protein kinase inhibitor (PKI), with similar affinities. However, in the presence of metal ions and adenine nucleotides, the Michaelis complex for PKT is unstable. PKA phosphorylates PKT with a higher turnover due to a faster dissociation of the product complex. Thus, threonine substrates are not necessarily poor substrates of PKA. Mutation of the DFG+1 phenylalanine to β-branched amino acids increases the catalytic efficiency of PKA for a threonine peptide substrate up to 200-fold. The PKA Cα mutant F187V forms a stable Michaelis complex with PKT and shows no preference for serine versus threonine substrates. Disease-associated mutations of the DFG+1 position in other protein kinases underline the importance of substrate specificity for keeping signaling pathways segregated and precisely regulated.
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Verma, Anita, and Anthony T. Maurelli. "Identification of Two Eukaryote-Like Serine/Threonine Kinases Encoded by Chlamydia trachomatis Serovar L2 and Characterization of Interacting Partners of Pkn1." Infection and Immunity 71, no. 10 (October 2003): 5772–84. http://dx.doi.org/10.1128/iai.71.10.5772-5784.2003.
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ABSTRACT Genome sequencing of C. trachomatis serovar D revealed the presence of three putative open reading frames (ORFs), CT145 (Pkn1), CT673 (Pkn5), and CT301 (PknD), encoding eukaryote-like serine/threonine kinases (Ser/Thr kinases). Two of these putative kinase genes, CT145 and CT301, were PCR amplified from serovar L2, cloned, and sequenced. Predicted translation products of the ORFs showed the presence of conserved kinase motifs at the N terminus of the proteins. CT145 and CT301 (encoding Pkn1 and PknD, respectively) were expressed in Escherichia coli as GST fusion proteins. In vitro kinase assays with Escherichia coli-derived glutathione S-transferase fusion proteins showed autophosphorylation of Pkn1 and PknD, indicating that they are functional kinases. Gene expression analysis of these kinase genes in Chlamydia by reverse transcriptase PCR indicated expression of these kinases at the early mid phase of the developmental cycle. Immunoprecipitated native chlamydial Pkn1 and PknD proteins also showed autophosphorylation in an in vitro kinase assay. Phosphoamino acid analysis by thin-layer chromatography confirmed that Pkn1 and PknD are phosphorylated on both serine and threonine residues. Interaction of Pkn1 and PknD with each other as well as interaction of Pkn1 with inclusion membrane protein G (IncG) was demonstrated by using a bacterial two-hybrid system. These interactions were further suggested by phosphorylation of the proteins in in vitro kinase assays. This report is the first description of the existence of functional Ser/Thr kinases in Chlamydia. The results of these findings should lead to a better understanding of how Chlamydia interact and interfere with host signaling pathways, since kinases represent potential mediators of the intimate host-pathogen interactions that are essential to the intracellular life cycle of Chlamydia.
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Khoza, Thembisile, Ian Dubery, and Lizelle Piater. "Identification of Candidate Ergosterol-Responsive Proteins Associated with the Plasma Membrane of Arabidopsis thaliana." International Journal of Molecular Sciences 20, no. 6 (March 14, 2019): 1302. http://dx.doi.org/10.3390/ijms20061302.
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The impact of fungal diseases on crop production negatively reflects on sustainable food production and overall economic health. Ergosterol is the major sterol component in fungal membranes and regarded as a general elicitor or microbe-associated molecular pattern (MAMP) molecule. Although plant responses to ergosterol have been reported, the perception mechanism is still unknown. Here, Arabidopsis thaliana protein fractions were used to identify those differentially regulated following ergosterol treatment; additionally, they were subjected to affinity-based chromatography enrichment strategies to capture and categorize ergosterol-interacting candidate proteins using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). Mature plants were treated with 250 nM ergosterol over a 24 h period, and plasma membrane-associated fractions were isolated. In addition, ergosterol was immobilized on two different affinity-based systems to capture interacting proteins/complexes. This resulted in the identification of defense-related proteins such as chitin elicitor receptor kinase (CERK), non-race specific disease resistance/harpin-induced (NDR1/HIN1)-like protein, Ras-related proteins, aquaporins, remorin protein, leucine-rich repeat (LRR)- receptor like kinases (RLKs), G-type lectin S-receptor-like serine/threonine-protein kinase (GsSRK), and glycosylphosphatidylinositol (GPI)-anchored protein. Furthermore, the results elucidated unknown signaling responses to this MAMP, including endocytosis, and other similarities to those previously reported for bacterial flagellin, lipopolysaccharides, and fungal chitin.
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McQuade, Thomas, YoungSik Cho, and Francis Ka-Ming Chan. "Positive and negative phosphorylation regulates RIP1- and RIP3-induced programmed necrosis." Biochemical Journal 456, no. 3 (November 22, 2013): 409–15. http://dx.doi.org/10.1042/bj20130860.
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The present study shows that RIP1 (receptor-interacting serine/threonine protein kinase 1) is regulated by positive as well as inhibitory phosphorylation. It also shows that gain-of-function RIP3 mutant can partially bypass the requirement of RIP1 in TNF-induced programmed necrosis.
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Schmitz, Michael Lienhard, Alfonso Rodriguez-Gil, and Juliane Hornung. "Integration of stress signals by homeodomain interacting protein kinases." Biological Chemistry 395, no. 4 (April 1, 2014): 375–86. http://dx.doi.org/10.1515/hsz-2013-0264.
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Abstract The family of homeodomain interacting protein kinases (HIPKs) consists of four related kinases, HIPK1 to HIPK4. These serine/threonine kinases are evolutionary conserved and derive from the yeast kinase Yak1. The largest group of HIPK phosphorylation substrates is represented by transcription factors and chromatin-associated regulators of gene expression, thus transferring HIPK-derived signals into changes of gene expression programs. The HIPKs mainly function as regulators of developmental processes and as integrators of a wide variety of stress signals. A number of conditions representing precarious situations, such as DNA damage, hypoxia, reactive oxygen intermediates and metabolic stress affect the function of HIPKs. The kinases function as integrators for these stress signals and feed them into many different downstream effector pathways that serve to cope with these precarious situations. HIPKs do not function as essential core components in the different stress signaling pathways, but rather serve as modulators of signal output and as connectors of different stress signaling pathways. Their central role as signaling hubs with the ability to shape many downstream effector pathways frequently implies them in proliferative diseases such as cancer or fibrosis.
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Zheng, Yanbin, Wenshuo Zhang, Elisha Pendleton, Sanhua Leng, Jiong Wu, Ridong Chen, and Xiao Jian Sun. "Improved insulin sensitivity by calorie restriction is associated with reduction of ERK and p70S6K activities in the liver of obese Zucker rats." Journal of Endocrinology 203, no. 3 (October 2, 2009): 337–47. http://dx.doi.org/10.1677/joe-09-0181.
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Calorie restriction (CR) improves obesity-related insulin resistance through undefined molecular mechanisms. Insulin receptor substrate (IRS)-1 serine/threonine kinases have been proposed to modulate insulin sensitivity through phosphorylation of IRS proteins. The aim of this study is to test the hypothesis that changes in the activity of IRS1 serine/threonine kinases may underlie the molecular mechanism of CR in improving insulin sensitivity. Obese and lean Zucker rats were subjected to 40% CR or allowed to feed ad libitum (AL) for 20 weeks; body weight and insulin sensitivity were monitored throughout this period. The activity of IRS1 serine/threonine kinases – including JNK, ERK, MTOR/p70S6K (RPS6KB1 as listed in the MGI Database), glycogen synthase kinase 3β (GSK3B), AMPK (PRKAA1 as listed in the MGI Database), and protein kinase Cθ (PRKCQ) in liver tissue extracts was measured by an in vitro kinase assay using various glutathione-S-transferase (GST)–IRS1 fragments as substrates, while phosphorylation of IRS1 and serine kinases was determined by western blotting using phosphospecific antibodies. CR in obese rats significantly reduced body weight and increased insulin sensitivity compared to AL controls. Serine kinase activity toward IRS1S612 (corresponding to S616 in human IRS1) and IRS1S632/635 (corresponding to S636/639 in human IRS1) was increased in obese rats compared to lean littermates, and was markedly decreased following CR. Concomitantly, obesity increased and CR decreased the activity of hepatic ERK and p70S6K against IRS1. The close association between the activity of hepatic ERK and p70S6K with insulin resistance suggests an important role for ERK and p70S6K in the development of insulin resistance, presumably via phosphorylation of IRS proteins.
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LANG, Mark L., Yih-Wen CHEN, Li SHEN, Hong GAO, Gillian A. LANG, Terri K. WADE, and William F. WADE. "IgA Fc receptor (FcαR) cross-linking recruits tyrosine kinases, phosphoinositide kinases and serine/threonine kinases to glycolipid rafts." Biochemical Journal 364, no. 2 (June 1, 2002): 517–25. http://dx.doi.org/10.1042/bj20011696.
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The human IgA Fc receptor (FcαR, CD89) triggers several important physiological functions, including phagocytosis, NADPH oxidase activation and antigen presentation. Efforts are underway to delineate FcαR signal-transduction pathways that control these functions. In a previous study, we demonstrated that cross-linking of FcαR increased its partitioning into membrane glycolipid rafts and was accompanied by γ-chain-dependent recruitment and phosphorylation of the tyrosine kinases Lck/Yes-related novel protein tyrosine kinase (Lyn) and Bruton's tyrosine kinase (Btk). Here we have performed a more extensive characterization of signalling effectors recruited to rafts on FcαR cross-linking. We demonstrate that in addition to tyrosine kinases Lyn and Btk, FcαR cross-linking also recruits B-lymphocyte kinase (Blk) and spleen tyrosine kinase (Syk) to rafts. We show recruitment of phosphoinositide kinases, including 3-phosphoinositide 3-kinase and phospholipase Cγ2, and serine/threonine kinases such as protein kinase C (PKC) α, PKC∊, and protein kinase B (PKB) α. This suggests that lipid rafts serve as sites for FcαR-triggered recruitment of multiple classes of signalling effectors. We further demonstrate that tyrosine kinases and PKCα have a sustained association with rafts, whereas phosphoinositide 3-kinase and its downstream effectors have a transient association with rafts. This is consistent with temporally regulated divergence of FcαR signalling pathways in rafts. Furthermore, we suggest the spatial separation of signalling effectors by transport of phosphoinositide 3-kinase, phosphoinositide-dependent kinase 1, PKBα and PKC∊ to endocytic compartments containing internalized FcαR.
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XU, Xiulong, and Anita S. F. CHONG. "Vav in natural killer cells is tyrosine phosphorylated upon cross-linking of Fcγ RIIIA and is constitutively associated with a serine/threonine kinase." Biochemical Journal 318, no. 2 (September 1, 1996): 527–32. http://dx.doi.org/10.1042/bj3180527.
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Cross-linking of FcγRIIIA (CD16) receptor on natural killer (NK) cells induces receptor-associated tyrosine kinase activation and tyrosine phosphorylation of numerous intracellular proteins, including phospholipase C (PLC)-γ1, PLC-γ2 and the associated ζ chain. Here we report that Vav, a proto-oncogene, also became tyrosine phosphorylated upon stimulation of CD16 in interleukin 2-activated NK cells (LAK-NK) as well as in an NK cell line, NK3.3. In addition, we observed that in LAK-NK cells, Vav was associated with a 70 kDa protein that also became tyrosine phosphorylated upon CD16 cross-linking. The association of this 70 kDa protein with Vav was disrupted by ionic detergent treatment. Tyrosine phosphorylation of Vav was inhibited by herbimycin A, a specific tyrosine kinase inhibitor. In vitro kinase assays with Vav immunoprecipitates derived from NK3.3 cells or LAK-NK cells resulted in the appearance of a phosphorylated 58 kDa protein, suggesting the presence of a kinase within the Vav immunoprecipitates. Cross-linking of CD16 did not enhance this Vav-associated kinase activity. Phosphoamino acid analysis of the 58 kDa protein revealed that it was phosphorylated only on serine and threonine residues, indicating that an unidentified serine/threonine kinase is constitutively associated with Vav. These observations suggest that the downstream signalling events regulated by Vav and its associated proteins are complex involving both tyrosine kinases as well as the yet unidentified serine/threonine kinase in NK cells.
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Basu, Sunanda, Barbara Graham-Evans, and Hal E. Broxmeyer. "Protein Phosphatase2A Regulates Stromal Cell- Derived Factor-1 Mediated Responses of CD34+ Cord Blood Cells." Blood 106, no. 11 (November 16, 2005): 2279. http://dx.doi.org/10.1182/blood.v106.11.2279.2279.
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Abstract The chemokine stromal cell- derived factor-1(SDF-1) and its receptor, CXCR4, play a major role in migration, retention, and development of hematopoietic progenitors in the bone marrow. During steady-state hematopoiesis, CXCR4/SDF-1 interaction restricts hematopoietic stem progenitor cells in marrow and disruption of the SDF-1/CXCR4 axis leads to their egress into circulation. However, biological responses to SDF-1 are rapidly attenuated by overlapping mechanisms that include peptide degradation by cell surface proteases, receptor uncoupling from heterotrimeric G-proteins and receptor endocytosis. It is known that phosphorylation of G-protein coupled receptors (GPCRs) by several protein kinases including serine-threonine kinase, protein kinase C (PKC), can result in receptor desensitization. This prompted us to investigate whether the role of serine- threonine phosphatase in the regulation of SDF-1 induced responses of CD34+ cord blood (CB) cells. To investigate the role of serine- threonine phosphatase we evaluated the effect of okadaic acid, a specific serine-threonine phosphatase inhibitor, on SDF-1 induced chemotaxis and adhesion of CD34+ cells from cord blood. Pre-incubation of CD34+ CB cells with okadaic acid (100–1000nM) significantly reduced SDF-1 directed chemotaxis and adhesion of CD34+ CB cells. This correlated with an increase in PKC phosphorylation. Although primary SDF-1 induced calcium flux in CD34+CB cells was unaffected by okadaic acid, if the cells were pretreated with SDF-1 and then stimulated with SDF-1, calcium flux was significantly less in CD34+CB cells pretreated with okadaic acid compared to untreated cells. Further, confocal microscopy was used to demonstrate the co-localization of serine threonine phosphatase and PKC. Using antibodies specific to PP2A catalytic subunit (PP2Ac) and various classes of PKC super family, it was observed in unstimulated CD34+ CB cells PP2Ac was mainly localized in nucleus and some phosphor-PKC-delta was detected in the cytoplasm. However, upon SDF-1 stimulation, co-localization of PP2Ac and phospho-PKC-delta was observed on the membrane of CD34+CB cells. These results indicate that serine-threonine phosphatase regulate SDF-1 mediated responses in CD34+CB cells and may play an important role in the ability of hematopoietic stem progenitor cells to continually respond to SDF-1.
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Karschin, Andreas. "G Protein Regulation of Inwardly Rectifying K+ Channels." Physiology 14, no. 5 (October 1999): 215–20. http://dx.doi.org/10.1152/physiologyonline.1999.14.5.215.
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Inwardly rectifying K+ (Kir) channels respond to receptor-stimulated signaling cascades that involve G proteins and other cytosolic messengers. Channel activity is controlled both by direct coupling of G protein subunits and by phosphorylation via protein serine/threonine and tyrosine kinases. The coincidence of both forms of Kir channel signaling may give rise to complex cellular responses.
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Tsuchida, K., L. S. Mathews, and W. W. Vale. "Cloning and characterization of a transmembrane serine kinase that acts as an activin type I receptor." Proceedings of the National Academy of Sciences 90, no. 23 (December 1, 1993): 11242–46. http://dx.doi.org/10.1073/pnas.90.23.11242.
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Activin type II receptors are transmembrane protein-serine/threonine kinases. By using a reverse-transcription PCR assay to screen for protein kinase sequences, we isolated a cDNA clone, activin X1 receptor, from rat brain that encodes a 55-kDa transmembrane protein-serine kinase which is structurally related to other receptors in this kinase subfamily. The predicted protein consists of 509 amino acids, and the kinase domain shows 40% and 37% identity to the activin and transforming growth factor beta type II receptors, respectively. No activin-binding was observed when activin X1 receptor was expressed alone in COS-M6 cells; however, coexpression with type II activin receptors gave rise to a 68-kDa affinity-labeled complex in addition to the 85-kDa type II receptor complex. The size of this cross-linked band is consistent with the size of the type I activin receptor; furthermore, activin X1 receptor associated with type II receptors, as judged by coimmunoprecipitation with type II receptor antibodies. These data suggest that activin X1 receptor can serve as an activin type I receptor and that the diverse biological effects of activins may be mediated by a complex formed by the interaction of two transmembrane protein-serine kinases.
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Dong, Lily Q., and Feng Liu. "PDK2: the missing piece in the receptor tyrosine kinase signaling pathway puzzle." American Journal of Physiology-Endocrinology and Metabolism 289, no. 2 (August 2005): E187—E196. http://dx.doi.org/10.1152/ajpendo.00011.2005.
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Activation of members of the protein kinase AGC (cAMP dependent, cGMP dependent, and protein kinase C) family is regulated primarily by phosphorylation at two sites: a conserved threonine residue in the activation loop and a serine/threonine residue in a hydrophobic motif (HM) near the COOH terminus. Although phosphorylation of these kinases in the activation loop has been found to be mediated by phosphoinositide-dependent protein kinase-1 (PDK1), the kinase(s) that catalyzes AGC kinase phosphorylation in the HM remains uncharacterized. So far, at least 10 kinases have been suggested to function as an HM kinase or the so-called “PDK2,” including mitogen-activated protein (MAP) kinase-activated protein kinase-2 (MK2), integrin-linked kinase (ILK), p38 MAP kinase, protein kinase Cα (PKCα), PKCβ, the NIMA-related kinase-6 (NEK6), the mammalian target of rapamycin (mTOR), the double-stranded DNA-dependent protein kinase (DNK-PK), and the ataxia telangiectasia mutated (ATM) gene product. However, whether any or all of these kinases act as a physiological HM kinase remains to be established. Nonetheless, available data suggest that multiple systems may be used in cells to regulate the activation of the AGC family kinases. It is possible that, unlike activation loop phosphorylation, phosphorylation of the HM site in the different AGC family kinases is mediated by distinct kinases. In addition, phosphorylation of the AGC family kinase at the HM site could be cell type, signaling pathway, and substrate specific. Identification and characterization of the bonafide HM kinase(s) will be essential to verify these hypotheses.
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Sugden, Peter H., Liam J. McGuffin, and Angela Clerk. "SOcK, MiSTs, MASK and STicKs: the GCKIII (germinal centre kinase III) kinases and their heterologous protein–protein interactions." Biochemical Journal 454, no. 1 (July 26, 2013): 13–30. http://dx.doi.org/10.1042/bj20130219.
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The GCKIII (germinal centre kinase III) subfamily of the mammalian Ste20 (sterile 20)-like group of serine/threonine protein kinases comprises SOK1 (Ste20-like/oxidant-stress-response kinase 1), MST3 (mammalian Ste20-like kinase 3) and MST4. Initially, GCKIIIs were considered in the contexts of the regulation of mitogen-activated protein kinase cascades and apoptosis. More recently, their participation in multiprotein heterocomplexes has become apparent. In the present review, we discuss the structure and phosphorylation of GCKIIIs and then focus on their interactions with other proteins. GCKIIIs possess a highly-conserved, structured catalytic domain at the N-terminus and a less-well conserved C-terminal regulatory domain. GCKIIIs are activated by tonic autophosphorylation of a T-loop threonine residue and their phosphorylation is regulated primarily through protein serine/threonine phosphatases [especially PP2A (protein phosphatase 2A)]. The GCKIII regulatory domains are highly disorganized, but can interact with more structured proteins, particularly the CCM3 (cerebral cavernous malformation 3)/PDCD10 (programmed cell death 10) protein. We explore the role(s) of GCKIIIs (and CCM3/PDCD10) in STRIPAK (striatin-interacting phosphatase and kinase) complexes and their association with the cis-Golgi protein GOLGA2 (golgin A2; GM130). Recently, an interaction of GCKIIIs with MO25 has been identified. This exhibits similarities to the STRADα (STE20-related kinase adaptor α)–MO25 interaction (as in the LKB1–STRADα–MO25 heterotrimer) and, at least for MST3, the interaction may be enhanced by cis-autophosphorylation of its regulatory domain. In these various heterocomplexes, GCKIIIs associate with the Golgi apparatus, the centrosome and the nucleus, as well as with focal adhesions and cell junctions, and are probably involved in cell migration, polarity and proliferation. Finally, we consider the association of GCKIIIs with a number of human diseases, particularly cerebral cavernous malformations.
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Rosorius, O., G. Mieskes, O. G. Issinger, C. Körner, B. Schmidt, K. von Figura, and T. Braulke. "Characterization of phosphorylation sites in the cytoplasmic domain of the 300 kDa mannose-6-phosphate receptor." Biochemical Journal 292, no. 3 (June 15, 1993): 833–38. http://dx.doi.org/10.1042/bj2920833.
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The human 300 kDa mannose-6-phosphate receptor (MPR 300) is phosphorylated in vivo at serine residues of its cytoplasmic domain. Two-dimensional separation can resolve tryptic phosphopeptides into four major species. To identify the kinases involved in MPR 300 phosphorylation and the phosphorylation sites the entire coding sequence of the cytoplasmic tail was expressed in Escherichia coli. The isolated cytoplasmic domain was used as a substrate for four purified serine/threonine kinases [casein kinase II (CK II), protein kinase A (PKA), protein kinase C and Ca2+/calmodulin kinase]. All kinases phosphorylate the cytoplasmic tail exclusively on serine residues. Inhibition studies using synthetic peptides, partial sequencing of isolated tryptic phosphopeptides and co-migration with tryptic phosphopeptides from MPR 300 labelled in vivo showed that (i) PKA phosphorylates the cytoplasmic MPR 300 domain at Ser20 and at a non-identified site, neither of which are phosphorylated in vivo, and that (ii) the two sites phosphorylated by CK II in vivo and in vitro are Ser82 and Ser157. The results indicate that the human MPR 300 is a physiological substrate of either CK II or a related kinase which may play a role in the transport function of MPR 300 and/or interaction with other proteins.
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Galisteo, M. L., J. Chernoff, Y. C. Su, E. Y. Skolnik, and J. Schlessinger. "The adaptor protein Nck links receptor tyrosine kinases with the serine-threonine kinase Pak1." Journal of Biological Chemistry 271, no. 35 (August 30, 1996): 20997–1000. http://dx.doi.org/10.1074/jbc.271.35.20997.
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Liu, Z. H., K. Tsuchida, T. Matsuzaki, Y. L. Bao, A. Kurisaki, and H. Sugino. "Characterization of isoforms of activin receptor-interacting protein 2 that augment activin signaling." Journal of Endocrinology 189, no. 2 (May 2006): 409–21. http://dx.doi.org/10.1677/joe.1.06420.
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Activin type II receptors (ActRIIs) including ActRIIA and ActRIIB are serine/threonine kinase receptors that form complexes with type I receptors to transmit intracellular signaling of activins, nodal, myostatin and a subset of bone morphogenetic proteins. ActRIIs are unique among serine/threonine kinase receptors in that they associate with proteins having PSD-95, Discs large and ZO-1 (PDZ) domains. In our previous studies, we reported specific interactions of ActRIIs with two independent PDZ proteins named activin receptor-interacting proteins 1 and 2 (ARIP1 and ARIP2). Overexpression of both ARIP1 and ARIP2 reduce activin-induced transcription. Here, we report the isolation of two isoforms of ARIP2 named ARIP2b and 2c. ARIP2, ARIP2b and ARIP2c recognize COOH-terminal residues of ActRIIA that match a PDZ-binding consensus motif. ARIP2 and its isoforms have one PDZ domain in the NH2-terminal region, and interact with ActRIIA. Although PDZ domains containing GLGF motifs of ARIP2b and 2c are identical to that of ARIP2, their COOH-terminal sequences differ from that of ARIP2. Interestingly, unlike ARIP2, overexpression of ARIP2b or 2c did not affect ActRIIA internalization. ARIP2b/2c inhibit inhibitory actions of ARIP2 on activin signaling. ARIP2 is widely distributed in mouse tissues. ARIP2b/2c is expressed in more restricted tissues such as heart, brain, kidneys and liver. Our results indicate that although both ARIP2 and ARIP2b/2c interact with activin receptors, they regulate ActRIIA function in a different manner.
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Ji, Y., L. A. Ward, and C. J. Hawkins. "Reconstitution of Human Necrosome Interactions in Saccharomyces cerevisiae." Biomolecules 11, no. 2 (January 25, 2021): 153. http://dx.doi.org/10.3390/biom11020153.
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The necrosome is a large-molecular-weight complex in which the terminal effector of the necroptotic pathway, Mixed Lineage Kinase Domain-Like protein (MLKL), is activated to induce necroptotic cell death. The precise mechanism of MLKL activation by the upstream kinase, Receptor Interacting Serine/Threonine Protein Kinase 3 (RIPK3) and the role of Receptor Interacting Serine/Threonine Protein Kinase 1 (RIPK1) in mediating MLKL activation remain incompletely understood. Here, we reconstituted human necrosome interactions in yeast by inducible expression of these necrosome effectors. Functional interactions were reflected by the detection of phosphorylated MLKL, plasma membrane permeabilization, and reduced proliferative potential. Following overexpression of human necrosome effectors in yeast, MLKL aggregated in the periphery of the cell, permeabilized the plasma membrane and compromised clonogenic potential. RIPK1 had little impact on RIPK3/MLKL-mediated yeast lethality; however, it exacerbated the toxicity provoked by co-expression of MLKL with a RIPK3 variant bearing a mutated RHIM-domain. Small molecule necroptotic inhibitors necrostatin-1 and TC13172, and viral inhibitors M45 (residues 1–90) and BAV_Rmil, abated the yeast toxicity triggered by the reconstituted necrosome. This yeast model provides a convenient tool to study necrosome protein interactions and to screen for and characterize potential necroptotic inhibitors.
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Stateva, Silviya R., and Antonio Villalobo. "O-GlcNAcylation of the human epidermal growth factor receptor." Organic & Biomolecular Chemistry 13, no. 30 (2015): 8196–204. http://dx.doi.org/10.1039/c5ob00443h.
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The cartoon represents the EGFR at the plasma membrane where serine/threonine residues could be subjected to phosphorylation/dephosphorylation events by protein kinases (PK) and phospho-protein phosphatases (PPP) and to O-GlcNAcylation/deGlcNAcylation events by O-linked β-N-acetylglucosamine transferase (OGT) and O-linked β-N-acetylglucosaminidase (OGA).
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Zhang, Qiaojian, Shengchen Wang, Shufang Zheng, Ziwei Zhang, and Shiwen Xu. "Chlorpyrifos Suppresses Neutrophil Extracellular Traps in Carp by Promoting Necroptosis and Inhibiting Respiratory Burst Caused by the PKC/MAPK Pathway." Oxidative Medicine and Cellular Longevity 2019 (February 7, 2019): 1–11. http://dx.doi.org/10.1155/2019/1763589.
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Neutrophil extracellular traps (NETs) are reticular structures formed by myeloperoxidase (MPO), histones, and neutrophil elastase (NE) that are released from neutrophils in response to pathogenic stimuli. Chlorpyrifos (CPF) is wildly used as an organophosphorus pesticide that causes a range of toxicological and environmental problems. Exposure to CPF can increase the production of neutrophils in carps, and this increase can be considered a biomarker of water pollution. To explore a relationship between NETs and CPF and its mechanism of influence, we treated neutrophils from the blood of carp with 1 μg/mL phorbol 12-myristate 13-acetate (PMA), 0.325 mg/L CPF, or 20 μM necrostatin-1 (Nec-1). The production of MPO and NETs was reduced in the CPF+PMA group compared with that in the PMA group. CPF can cause an increase in reactive oxygen species (ROS), while inhibiting respiratory burst caused by PMA stimulation. We found that the expression levels of protein-coupled receptor 84 (gpr84), dystroglycan (DAG), proto-oncogene serine/threonine kinase (RAF), protein kinase C (PKC), and mitogen-activated protein kinase 3 (MAPK3) in the CPF+PMA group were lower than those in the PMA group, indicating that the PKC-MAPK pathway was suppressed. The expression levels of cylindromatosis (CYLD), mixed lineage kinase domain-like pseudokinase (MLKL), receptor-interacting serine-threonine kinase 1 (RIP1), and receptor-interacting serine-threonine kinase 3 (RIP3) were increased, and the expression levels of caspase 8 were reduced by CPF, indicating that CPF may cause necroptosis. The addition of Nec-1 restored the number of NETs in the CPF+PMA group. The results indicate that CPF reduced the production of NETs by inhibiting respiratory burst and increasing necroptosis. The results contribute to the understanding of the immunotoxicological mechanism of CPF and provide a reference for comparative medical studies.
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Singer, A. J., A. S. Reddy, S. A. McClain, A. Abraham, S. Sandoval, and R. A. F. Clark. "Receptor-Interacting Serine/Threonine-Protein Kinase 3 (RIP-3) Expression in Normal and Burned Skin." Annals of Emergency Medicine 62, no. 4 (October 2013): S30. http://dx.doi.org/10.1016/j.annemergmed.2013.07.363.
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Jaafar, Rola F., Zeid Ibrahim, Karim Ataya, Joelle Hassanieh, Natasha Ard, and Walid Faraj. "Receptor-Interacting Serine/Threonine-Protein Kinase-2 as a Potential Prognostic Factor in Colorectal Cancer." Medicina 57, no. 7 (July 14, 2021): 709. http://dx.doi.org/10.3390/medicina57070709.
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Background and objectives: Receptor-interacting serine/threonine-protein kinase-2 (RIPK2) is an important mediator in different pathways in the immune and inflammatory response system. RIPK2 was also shown to play different roles in different cancer types; however, in colorectal cancer (CRC), its role is not well established. This study aims at identifying the role of RIPK2 in CRC progression and survival. Materials and methods: Data of patients and mRNA protein expression level of genes associated with CRC (RIPK2, tumor necrosis factor (TNF), TRAF1, TRAF7, KLF6, interlukin-6 (Il6), interlukin-8 (Il8), vascular-endothelial growth factor A (VEGFA), MKI67, TP53, nuclear factor-kappa B (NFKB), NFKB2, BCL2, XIAP, and RELA) were downloaded from the PrognoScan online public database. Patients were divided between low and high RIPK2 expression and different CRC characteristics were studied between the two groups. Survival curves were evaluated using a Kaplan–Meier estimator. The Pearson correlation was used to study the correlation between RIPK2 and the other factors. Statistical analysis was carried out using SPSS version 25.0. The Human Protein Atlas was also used for the relationship between RIPK2 expression in CRC tissues and survival. Differences were considered statistically significant at p < 0.05. Results: A total of 520 patients were downloaded from the PrognoScan database, and RIPK2 was found to correlate with MKI67, TRAF1, KLF6, TNF, Il6, Il8, VEGFA, NFKB2, BCL2, and RELA. High expression of RIPK2 was associated with high expression of VEGFA (p < 0.01) and increased mortality (p < 0.01). Conclusions: In this study, RIPK2 is shown to be a potential prognostic factor in CRC; however, more studies are needed to assess and verify its potential role as a prognostic marker and in targeted therapy.
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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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VOISIN, Laure, Louise LAROSE, and Sylvain MELOCHE. "Angiotensin II stimulates serine phosphorylation of the adaptor protein Nck: physical association with the serine/threonine kinases Pak1 and casein kinase I." Biochemical Journal 341, no. 1 (June 24, 1999): 217–23. http://dx.doi.org/10.1042/bj3410217.
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Nck is a small adaptor protein consisting exclusively of three SH3 domains and one SH2 domain. Nck is thought to have an important role in cell signalling by coupling receptor tyrosine kinases, via its SH2 domain, to downstream SH3-binding effectors. We report here that angiotensin II, working through the AT1 receptor subtype, stimulates the phosphorylation of Nck in rat aortic smooth muscle cells. Phosphopeptide mapping analysis revealed that Nck is phosphorylated on four peptides containing exclusively phosphoserine in quiescent cells. Treatment with angiotensin II resulted in increased phosphorylation of these four peptides, without the appearance of new phosphopeptides. We show that Nck, via its SH3 domains, specifically binds three major phosphoproteins of 95, 82 and 66 kDa both in vitro and in intact cells. Notably, the phosphorylation of these Nck-binding proteins was found to increase in parallel with that of Nck on stimulation by angiotensin II. One candidate for the 66 kDa phosphoprotein is the serine/threonine kinase p21-activated kinase 1 (Pak1), which was found to form a stable complex with Nck in aortic smooth muscle cells. We have also identified the γ2 isoform of casein kinase I as another protein kinase that associates with Nck in these cells. These findings indicate that Nck is a target of G-protein-coupled receptors and suggest a role for Pak1 and casein kinase I-γ2 in downstream signalling or regulation of the AT1 receptor.
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Lease, Kevin A., Nelson Y. Lau, Robert A. Schuster, Keiko U. Torii, and John C. Walker. "Receptor serine/threonine protein kinases in signalling: analysis of the erecta receptor-like kinase of Arabidopsis thaliana." New Phytologist 151, no. 1 (July 2001): 133–43. http://dx.doi.org/10.1046/j.1469-8137.2001.00150.x.
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Krstic, M. D., I. Rogatsky, K. R. Yamamoto, and M. J. Garabedian. "Mitogen-activated and cyclin-dependent protein kinases selectively and differentially modulate transcriptional enhancement by the glucocorticoid receptor." Molecular and Cellular Biology 17, no. 7 (July 1997): 3947–54. http://dx.doi.org/10.1128/mcb.17.7.3947.
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Cyclin-dependent kinase (CDK) and mitogen-activated protein kinase (MAPK) phosphorylate the rat glucocorticoid receptor in vitro at distinct sites that together correspond to the major phosphorylated receptor residues observed in vivo; MAPK phosphorylates receptor residues threonine 171 and serine 246, whereas multiple CDK complexes modify serines 224 and 232. Mutations in these kinases have opposite effects on receptor transcriptional activity in vivo. Receptor-dependent transcriptional enhancement is reduced in yeast strains deficient in the catalytic (p34CDC28) or certain regulatory (cyclin) subunits of CDK complexes and is increased in a strain devoid of the mammalian MAPK homologs FUS3 and KSS1. These findings indicate that the glucocorticoid receptor is a target for multiple kinases in vivo, which either positively or negatively regulate receptor transcriptional enhancement. The control of receptor transcriptional activity via phosphorylation provides an increased array of regulatory inputs that, in addition to steroid hormones, can influence receptor function.
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Rinaldo, Cinzia, Andrea Prodosmo, Francesca Siepi, and Silvia Soddu. "HIPK2: a multitalented partner for transcription factors in DNA damage response and developmentThis paper is one of a selection of papers published in this Special Issue, entitled 28th International West Coast Chromatin and Chromosome Conference, and has undergone the Journal's usual peer review process." Biochemistry and Cell Biology 85, no. 4 (August 2007): 411–18. http://dx.doi.org/10.1139/o07-071.
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Protein phosphorylation is a widely diffuse and versatile post-translational modification that controls many cellular processes, from signal transduction to gene transcription. The homeodomain-interacting protein kinases (HIPKs) belong to a new family of serine–threonine kinases first identified as corepressors for homeodomain transcription factors. Different screenings for the identification of new partners of transcription factors have indicated that HIPK2, the best characterized member of the HIPK family, is a multitalented coregulator of an increasing number of transcription factors and cofactors. The aim of this review is to describe the different mechanisms through which HIPK2 regulates gene transcription.
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Samson, André L., Sarah E. Garnish, Joanne M. Hildebrand, and James M. Murphy. "Location, location, location: A compartmentalized view of TNF-induced necroptotic signaling." Science Signaling 14, no. 668 (February 2, 2021): eabc6178. http://dx.doi.org/10.1126/scisignal.abc6178.
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Necroptosis is a lytic, proinflammatory cell death pathway, which has been implicated in host defense and, when dysregulated, the pathology of many human diseases. The central mediators of this pathway are the receptor-interacting serine/threonine protein kinases RIPK1 and RIPK3 and the terminal executioner, the pseudokinase mixed lineage kinase domain–like (MLKL). Here, we review the chronology of signaling along the RIPK1-RIPK3-MLKL axis and highlight how the subcellular compartmentalization of signaling events controls the initiation and execution of necroptosis. We propose that a network of modulators surrounds the necroptotic signaling core and that this network, rather than acting universally, tunes necroptosis in a context-, cell type–, and species-dependent manner. Such a high degree of mechanistic flexibility is likely an important property that helps necroptosis operate as a robust, emergency form of cell death.
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Roux, Philippe P., and John Blenis. "ERK and p38 MAPK-Activated Protein Kinases: a Family of Protein Kinases with Diverse Biological Functions." Microbiology and Molecular Biology Reviews 68, no. 2 (June 2004): 320–44. http://dx.doi.org/10.1128/mmbr.68.2.320-344.2004.
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SUMMARY Conserved signaling pathways that activate the mitogen-activated protein kinases (MAPKs) are involved in relaying extracellular stimulations to intracellular responses. The MAPKs coordinately regulate cell proliferation, differentiation, motility, and survival, which are functions also known to be mediated by members of a growing family of MAPK-activated protein kinases (MKs; formerly known as MAPKAP kinases). The MKs are related serine/threonine kinases that respond to mitogenic and stress stimuli through proline-directed phosphorylation and activation of the kinase domain by extracellular signal-regulated kinases 1 and 2 and p38 MAPKs. There are currently 11 vertebrate MKs in five subfamilies based on primary sequence homology: the ribosomal S6 kinases, the mitogen- and stress-activated kinases, the MAPK-interacting kinases, MAPK-activated protein kinases 2 and 3, and MK5. In the last 5 years, several MK substrates have been identified, which has helped tremendously to identify the biological role of the members of this family. Together with data from the study of MK-knockout mice, the identities of the MK substrates indicate that they play important roles in diverse biological processes, including mRNA translation, cell proliferation and survival, and the nuclear genomic response to mitogens and cellular stresses. In this article, we review the existing data on the MKs and discuss their physiological functions based on recent discoveries.
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Li, Xinghui, Wei Gong, Hao Wang, Tianliang Li, Kuldeep S. Attri, Robert E. Lewis, Andre C. Kalil, et al. "O-GlcNAc Transferase Suppresses Inflammation and Necroptosis by Targeting Receptor-Interacting Serine/Threonine-Protein Kinase 3." Immunity 50, no. 3 (March 2019): 576–90. http://dx.doi.org/10.1016/j.immuni.2019.01.007.
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Li, Xinghui, Wei Gong, Hao Wang, Tianliang Li, Kuldeep S. Attri, Robert E. Lewis, Andre C. Kalil, et al. "O-GlcNAc Transferase Suppresses Inflammation and Necroptosis by Targeting Receptor-Interacting Serine/Threonine-Protein Kinase 3." Immunity 50, no. 4 (April 2019): 1115. http://dx.doi.org/10.1016/j.immuni.2019.03.008.
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Naik, Ulhas P., and Meghna U. Naik. "Inhibition of Polo-Like Kinase 3 by CIB1 Facilitates Outside-In Signaling through αIIbβ3 in Platelets." Blood 108, no. 11 (November 16, 2006): 214. http://dx.doi.org/10.1182/blood.v108.11.214.214.
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Abstract Integrin αIIbβ3, the platelet fibrinogen receptor, is involved in bi-directional signaling during platelet activation. It has been shown that the β3 subunit of this receptor is phosphorylated on both threonine and tyrosine. Although, the role of tyrosine phosphorylation is well studied, the role of threonine phosphorylation is not well understood. Here we identify the kinase responsible for threonine phosphoruylation of β3 and provide a mechanistic significance of this phosphorylation in outside-in signaling. We found that calcium- and integrin-binding protein 1 (CIB1), which specifically interacts with the cytoplasmic domain of αIIb, is not involved in inside-out signaling, but regulates outside-in signaling through αIIbβ3. CIB1 is known to interact with and regulate several serine/threonine protein kinases. Among these, p21 activated kinase 1 (PAK-1) is highly expressed in platelets. We found that CIB1 does not colocalize with PAK-1 during outside in signaling induced by adhesion of platelets to immobilized fibrinogen. When searched for the expression of other kinases that are known to interact with CIB1, we found that polo-like kinase 3 (Plk3) is expressed in platelets and is responsible for the constitutive phosphorylation of β3. Plk3 is constitutively active in resting platelets but is rendered inactive during outside in signaling as a result of CIB1 binding in a calcium dependent manner. Plk3 becomes colocalized with CIB1 at the filopodia when platelets change shape in response to an agonist and remain associated with both CIB1 and αIIb as platelets spread on immobilized fibrinogen, as indicated by immunoprecipitation experiments. These results suggest that in resting platelets, constitutively active Plk3 maintains β3 in a threonine phosphorylated state which is nonpermissive for activation. Upon platelet activation by agonist CIB1 associates with Plk3 and renders it inactive in a calcium-dependent manner. This allows serine/threonine phosphatases, such as PP1-c to dephosphorylate β3 on threonine and facilitate outside-in signaling. Thus we have identified the kinase responsible for threonine phosphorylation of β3 and have provided a possible mechanism of the regulation of outside-in signaling.
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Heasley, L. E., and G. L. Johnson. "The beta-PDGF receptor induces neuronal differentiation of PC12 cells." Molecular Biology of the Cell 3, no. 5 (May 1992): 545–53. http://dx.doi.org/10.1091/mbc.3.5.545.
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Expression of the mouse beta-PDGF receptor by gene transfer confers PDGF-dependent and reversible neuronal differentiation of PC12 pheochromocytoma cells similar to that observed in response to NGF and basic FGF. A common property of the PDGF, NGF, and basic FGF-induced differentiation response is the requirement for constant exposure of cells to the growth factor. To test the hypothesis that a persistent level of growth factor receptor signaling is required for the maintenance of the neuronal phenotype, we examined the regulation of the serine/threonine-specific MAP kinases after either short- (10 min) or long-term (24 h) stimulation with growth factors. Mono Q FPLC resolved two peaks of growth factor-stimulated MAP kinase activity that coeluted with tyrosine phosphorylated 41- and 43-kDa polypeptides. MAP kinase activity was markedly stimulated (approximately 30-fold) within 5 min of exposure to several growth factors (PDGF, NGF, basic FGF, EGF, and IGF-I), but was persistently maintained at 10-fold above basal activity after 24 h only by the growth factors that also induce PC12 cell differentiation (PDGF, NGF, and basic FGF). Thus the beta-PDGF receptor is in a subset of tyrosine kinase-encoded growth factor receptors that are capable of maintaining continuous signals required for differentiation of PC12 cells. These signals include the constitutive activation of cytoplasmic serine/threonine protein kinases.
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Kanner, S. B., A. B. Reynolds, and J. T. Parsons. "Tyrosine phosphorylation of a 120-kilodalton pp60src substrate upon epidermal growth factor and platelet-derived growth factor receptor stimulation and in polyomavirus middle-T-antigen-transformed cells." Molecular and Cellular Biology 11, no. 2 (February 1991): 713–20. http://dx.doi.org/10.1128/mcb.11.2.713.
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The monoclonal antibody 2B12 is directed toward p120, a 120-kDa cellular protein originally identified as a protein tyrosine kinase substrate in cells expressing membrane-associated oncogenic variants of pp60src. In this report, we show that p120 was tyrosine phosphorylated in avian cells expressing membrane-associated, enzymatically activated variants of c-src, including variants having structural alterations in the src homology regions 2 and 3. In contrast, p120 was not tyrosine phosphorylated in cells expressing enzymatically activated, nonmyristylated pp60src. Furthermore, p120 was tyrosine phosphorylated in avian cells expressing middle T antigen, the transforming protein of polyomavirus, as well as in rodent cells stimulated with either epidermal growth factor (EGF) or platelet-derived growth factor. Analysis of the time course of p120 tyrosine phosphorylation in EGF-stimulated cells revealed a rapid onset of tyrosine phosphorylation. In addition, both the extent and duration of p120 phosphorylation increased when cells overexpressing the EGF receptor were stimulated with EGF. Biochemical analysis showed that p120 (in both normal and src-transformed cells) was membrane associated, was myristylated, and was phosphorylated on serine and threonine residues. Hence, p120 appears to be a substrate of both nonreceptor- and ligand-activated transmembrane receptor tyrosine kinases and of serine/threonine kinases and is perhaps a component of both mitogen-stimulated and tyrosine kinase oncogene-induced signaling pathways.
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Kanner, S. B., A. B. Reynolds, and J. T. Parsons. "Tyrosine phosphorylation of a 120-kilodalton pp60src substrate upon epidermal growth factor and platelet-derived growth factor receptor stimulation and in polyomavirus middle-T-antigen-transformed cells." Molecular and Cellular Biology 11, no. 2 (February 1991): 713–20. http://dx.doi.org/10.1128/mcb.11.2.713-720.1991.
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The monoclonal antibody 2B12 is directed toward p120, a 120-kDa cellular protein originally identified as a protein tyrosine kinase substrate in cells expressing membrane-associated oncogenic variants of pp60src. In this report, we show that p120 was tyrosine phosphorylated in avian cells expressing membrane-associated, enzymatically activated variants of c-src, including variants having structural alterations in the src homology regions 2 and 3. In contrast, p120 was not tyrosine phosphorylated in cells expressing enzymatically activated, nonmyristylated pp60src. Furthermore, p120 was tyrosine phosphorylated in avian cells expressing middle T antigen, the transforming protein of polyomavirus, as well as in rodent cells stimulated with either epidermal growth factor (EGF) or platelet-derived growth factor. Analysis of the time course of p120 tyrosine phosphorylation in EGF-stimulated cells revealed a rapid onset of tyrosine phosphorylation. In addition, both the extent and duration of p120 phosphorylation increased when cells overexpressing the EGF receptor were stimulated with EGF. Biochemical analysis showed that p120 (in both normal and src-transformed cells) was membrane associated, was myristylated, and was phosphorylated on serine and threonine residues. Hence, p120 appears to be a substrate of both nonreceptor- and ligand-activated transmembrane receptor tyrosine kinases and of serine/threonine kinases and is perhaps a component of both mitogen-stimulated and tyrosine kinase oncogene-induced signaling pathways.
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Xu, Yang, Ji Zhang, Lingsong Ma, Shoucai Zhao, Shizun Li, Tingting Huang, and Zhaohu Chu. "The Pathogenesis of Necroptosis-Dependent Signaling Pathway in Cerebral Ischemic Disease." Behavioural Neurology 2018 (July 22, 2018): 1–7. http://dx.doi.org/10.1155/2018/6814393.
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Necroptosis is the best-described form of regulated necrosis at present, which is widely recognized as a component of caspase-independent cell death mediated by the concerted action of receptor-interacting protein kinase 1 (RIPK1) and receptor-interacting protein kinase 3 (RIPK3). Mixed-lineage kinase domain-like (MLKL) was phosphorylated by RIPK3 at the threonine 357 and serine 358 residues and then formed tetramers and translocated onto the plasma membrane, which destabilizes plasma membrane integrity leading to cell swelling and membrane rupture. Necroptosis is downstream of the tumor necrosis factor (TNF) receptor family, and also interaction with NOD-like receptor pyrin 3 (NLRP3) induced inflammasome activation. Multiple inhibitors of RIPK1 and MLKL have been developed to block the cascade of signal pathways for procedural necrosis and represent potential leads for drug development. In this review, we highlight recent progress in the study of roles for necroptosis in cerebral ischemic disease and discuss how these modifications delicately control necroptosis.
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Rochat-Steiner, Véronique, Karin Becker, Olivier Micheau, Pascal Schneider, Kim Burns, and Jürg Tschopp. "Fist/Hipk3." Journal of Experimental Medicine 192, no. 8 (October 16, 2000): 1165–74. http://dx.doi.org/10.1084/jem.192.8.1165.
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Fas is a cell surface death receptor that signals apoptosis. Several proteins have been identified that bind to the cytoplasmic death domain of Fas. Fas-associated death domain (FADD), which couples Fas to procaspase-8, and Daxx, which couples Fas to the Jun NH2-terminal kinase pathway, bind independently to the Fas death domain. We have identified a 130-kD kinase designated Fas-interacting serine/threonine kinase/homeodomain-interacting protein kinase (FIST/HIPK3) as a novel Fas-interacting protein. Binding to Fas is mediated by a conserved sequence in the COOH terminus of the protein. FIST/HIPK3 is widely expressed in mammalian tissues and is localized both in the nucleus and in the cytoplasm. In transfected cell lines, FIST/HIPK3 causes FADD phosphorylation, thereby promoting FIST/HIPK3–FADD–Fas interaction. Although Fas ligand–induced activation of Jun NH2-terminal kinase is impaired by overexpressed active FIST/HIPK3, cell death is not affected. These results suggest that Fas-associated FIST/HIPK3 modulates one of the two major signaling pathways of Fas.
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Thomas, Daniel, Joanna Woodcock, Jason A. Powell, Emma F. Barry, Angel F. Lopez, and Mark A. Guthridge. "Lipid and Protein Substrates of PI3K in Cytokine Receptor Survival Signalling: Deregulation in Leukemia." Blood 112, no. 11 (November 16, 2008): 3864. http://dx.doi.org/10.1182/blood.v112.11.3864.3864.
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Abstract New therapeutic approaches to acute myeloid leukemia (AML) must ultimately target cell survival pathways in leukemic cells in order to be effective. We have identified a serine residue (Ser585) in the cytoplasmic domain of the common GM-CSF and IL-3 receptor beta subunit which is phosphorylated in response to sub-picomolar concentrations of growth factor and is involved in signalling cytokine-mediated survival via 14-3-3 zeta phosphoserine adaptor. While Serine 585 is tightly controlled in non-transformed haematopoietic cells from normal donors, Serine 585 is constitutively phosphorylated in AML blasts suggesting a role in AML cell survival and a novel target for anti-leukaemic therapy. We attempted to isolate Ser585 kinase activity from leukemic blasts and characterise this activity in response to serine/threonine kinase inhibitors in biochemical and biological assays. Results: Cell extracts from primary AML blasts (>99% blasts by flow/morphology) obtained from adult patients were fractionated and assayed for intrinsic serine 585 peptide (13-mer) kinase activity via 32P gamma-ATP in vitro kinase assay. A single peak of Ser585 kinase activity was isolated and tested against a panel of serine/threonine kinase inhibitors. Kinase activity was selectively sensitive to LY294002, wortmannin and quercelin suggesting a role for the PI3K family of kinases in activating this residue. Ser585 kinase activity was also directly present in both p85 and p110 alpha PI3K immunoprecipitates from AML blasts and leukemic cell lines tested on both Ser585 peptide and recombinant beta cytoplasmic domain protein substrates. Serine 585 phosphorylation induced by sub-picomolar concentrations of GM-CSF in TF1.8 cells was inhibited by three different isoform selective p110 alpha inhibitors used at low nanomolar ranges consistent with reported IC50s. These results suggest a novel role for protein kinase rather than lipid kinase activity of PI3K alpha subunit in low dose cytokine signalling. We also show induction of serine phosphorylation of p85 PI3K regulatory subunit on Ser608 by GM-CSF, a previously reported protein substrate of PI3K. Furthermore, p110 alpha and delta inhibitors abrogate GM-CSF dependent survival of murine lineage negative bone marrow progenitor cells and also exert apoptotic activity on flow-sorted CD34+CD38−CD123+ sub-populations of primary AML blasts. Conclusions: Inhibition of Ser585 phosphorylation by targetting PI3K protein kinase activity by isoform selective inhibitors represents a novel approach toward the eradication of residual leukemic stem cells.
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Schaap, D., J. van der Wal, W. J. van Blitterswijk, R. L. van der Bend, and H. L. Ploegh. "Diacylglycerol kinase is phosphorylated in vivo upon stimulation of the epidermal growth factor receptor and serine/threonine kinases, including protein kinase C-ε." Biochemical Journal 289, no. 3 (February 1, 1993): 875–81. http://dx.doi.org/10.1042/bj2890875.
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In signal transduction, diacylglycerol (DG) kinase attenuates levels of the second messenger DG by converting it to phosphatidic acid. A previously cloned full-length human 86 kDa DG kinase cDNA was expressed as fusion protein in Escherichia coli, to aid in the generation of DG-kinase-specific monoclonal antibodies suitable for immunoprecipitation experiments. To investigate whether phosphorylation of DG kinase is a possible mechanism for its regulation, COS-7 cells were transiently transfected with the DG kinase cDNA and phosphorylation of the expressed DG kinase was induced by various stimuli. Activation of both cyclic AMP-dependent protein kinase and protein kinase C (PKC) resulted in phosphorylation of DG kinase on serine residues in vivo, and both kinases induced this phosphorylation within the same tryptic phosphopeptide, suggesting that they may exert similar control over DG kinase. No phosphorylation was observed upon ionomycin treatment, intended to activate Ca2+/calmodulin-dependent kinases. Co-transfections of DG kinase with either PKC-alpha or PKC-epsilon cDNA revealed that both protein kinases, when stimulated, are able to phosphorylate DG kinase. For PKC-epsilon, DG kinase is the first in vivo substrate identified. Stimulation with epidermal growth factor (EGF) of COS-7 cells transfected with both DG kinase and EGF-receptor cDNA results mainly in phosphorylation of DG kinase on tyrosine. Since the EGF receptor has an intrinsic tyrosine kinase activity, this finding implies that DG kinase may be a direct substrate for the activated EGF receptor.
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Wright, Jocelyn H., Xueyan Wang, Gerard Manning, Brandon J. LaMere, Phuong Le, Shirley Zhu, Deepak Khatry, et al. "The STE20 Kinase HGK Is Broadly Expressed in Human Tumor Cells and Can Modulate Cellular Transformation, Invasion, and Adhesion." Molecular and Cellular Biology 23, no. 6 (March 15, 2003): 2068–82. http://dx.doi.org/10.1128/mcb.23.6.2068-2082.2003.
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ABSTRACT HGK (hepatocyte progenitor kinase-like/germinal center kinase-like kinase) is a member of the human STE20/mitogen-activated protein kinase kinase kinase kinase family of serine/threonine kinases and is the ortholog of mouse NIK (Nck-interacting kinase). We have cloned a novel splice variant of HGK from a human tumor line and have further identified a complex family of HGK splice variants. We showed HGK to be highly expressed in most tumor cell lines relative to normal tissue. An active role for this kinase in transformation was suggested by an inhibition of H-RasV12-induced focus formation by expression of inactive, dominant-negative mutants of HGK in both fibroblast and epithelial cell lines. Expression of an inactive mutant of HGK also inhibited the anchorage-independent growth of cells yet had no effect on proliferation in monolayer culture. Expression of HGK mutants modulated integrin receptor expression and had a striking effect on hepatocyte growth factor-stimulated epithelial cell invasion. Together, these results suggest an important role for HGK in cell transformation and invasiveness.
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Larose, L., J. J. Rondeau, H. Ong, and A. De Léan. "Phosphorylation of atrial natriuretic factor R1 receptor by serine/threonine protein kinases: evidences for receptor regulation." Molecular and Cellular Biochemistry 115, no. 2 (October 1992): 203–11. http://dx.doi.org/10.1007/bf00230332.
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PLUSKEY, Scott, Mohammad MAHROOF-TAHIR, Debbie C. CRANS, and David S. LAWRENCE. "Vanadium oxoanions and cAMP-dependent protein kinase: an anti-substrate inhibitor." Biochemical Journal 321, no. 2 (January 15, 1997): 333–39. http://dx.doi.org/10.1042/bj3210333.
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Vanadium oxoions have been shown to elicit a wide range of effects in biological systems, including an increase in the quantity of phosphorylated proteins. This response has been attributed to the inhibition of protein phosphatases, the indirect activation of protein kinases via stimulation of enzymes at early steps in signal transduction pathways and/or the direct activation of protein kinases. We have evaluated the latter possibility by exploring the effects of vanadate, decavanadate and vanadyl cation species on the activity of the cAMP-dependent protein kinase (PKA), a serine/threonine kinase. Vanadate, in the form of monomer, dimer, tetramer and pentamer species, neither inhibits nor activates PKA. In marked contrast, decavanadate is a competitive inhibitor (Ki = 1.8ŷ0.1 mM) of kemptide (Leu-Arg-Arg-Ala-Ser-Leu-Gly), a peptide-based substrate. This inhibition pattern is especially surprising, since the negatively charged decavanadate would not be predicted to bind to the region of the active site of the enzyme that accommodates the positively charged kemptide substrate. Our studies suggest that decavanadate can associate with kemptide in solution, which would prevent kemptide from interacting with the enzyme. Vanadium(IV) also inhibits the PKA-catalysed phosphorylation of kemptide, but with an IC50 of 366ŷ10 ƁM. However, in this case V4+ appears to bind to the Mg2+-binding site, since it can substitute for Mg2+. In the absence of Mg2+, the optimal concentration of vanadium(IV) for the PKA-catalysed phosphorylation of kemptide is 100 ƁM, with concentrations above 100 ƁM being markedly inhibitory. However, even at the optimal 100 ƁM V4+ concentration, the Vmax and Km values (for kemptide) are significantly less favourable than those obtained in the presence of 100 ƁM Mg2+. In summary, we have found that oxovanadium ions can directly alter the activity of the serine/threonine-specific PKA.
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Hoang, Quyen T. N., Yun-Jeong Han, and Jeong-Il Kim. "Plant Phytochromes and their Phosphorylation." International Journal of Molecular Sciences 20, no. 14 (July 13, 2019): 3450. http://dx.doi.org/10.3390/ijms20143450.
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Extensive research over several decades in plant light signaling mediated by photoreceptors has identified the molecular mechanisms for how phytochromes regulate photomorphogenic development, which includes degradation of phytochrome-interacting factors (PIFs) and inactivation of COP1-SPA complexes with the accumulation of master transcription factors for photomorphogenesis, such as HY5. However, the initial biochemical mechanism for the function of phytochromes has not been fully elucidated. Plant phytochromes have long been known as phosphoproteins, and a few protein phosphatases that directly interact with and dephosphorylate phytochromes have been identified. However, there is no report thus far of a protein kinase that acts on phytochromes. On the other hand, plant phytochromes have been suggested as autophosphorylating serine/threonine protein kinases, proposing that the kinase activity might be important for their functions. Indeed, the autophosphorylation of phytochromes has been reported to play an important role in the regulation of plant light signaling. More recently, evidence that phytochromes function as protein kinases in plant light signaling has been provided using phytochrome mutants displaying reduced kinase activities. In this review, we highlight recent advances in the reversible phosphorylation of phytochromes and their functions as protein kinases in plant light signaling.