Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this study, we report the cloning and characterization of a novel human Ste20-related kinase that we designated MST4. The 416 amino acid full-length MST4 contains an amino-terminal kinase domain, which is highly homologous to MST3 and SOK, and a unique carboxy-terminal domain. Northern blot analysis indicated that MST4 is highly expressed in placenta, thymus, and peripheral blood leukocytes. Wild-type but not kinase-dead MST4 can phosphorylate myelin basic protein in an in vitro kinase assay. MST4 specifically activates ERK but not JNK or p38 MAPK in transient transfected cells or in stable cell lines. Overexpression of dominant negative MEK1 or treatment with PD98059 abolishes MST4-induced ERK activity, whereas dominant-negative Ras or c-Raf-1 mutants failed to do so, indicating MST4 activates MEK1/ERK via a Ras/Raf-1 independent pathway. HeLa and Phoenix cell lines overexpressing wild-type, but not kinase-dead, MST4 exhibit increased growth rate and form aggressive soft-agar colonies. These phenotypes can be inhibited by PD98059. These results provide the first evidence that MST4 is biologically active in the activation of MEK/ERK pathway and in mediating cell growth and transformation.
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PMID:MST4, a new Ste20-related kinase that mediates cell growth and transformation via modulating ERK pathway. 1164 81

CC chemokine receptor 7 (CCR7) expression is crucial for thymocyte trafficking across the corticomedullary junction in the thymus and for lymph node homing of naive T cells. However, the induction mechanism of CCR7 expression is vastly unknown. In isolated CD4+CD8+CCR7-thymocytes, a moderate 20-h pulse stimulation with a combination of the calcium ionophore ionomycin and the protein kinase C activator phorbol myristate acetate induced CCR7 expression and CD8 downregulation. Similar changes were induced in a CD4+CD8+CCR7- T cell line upon stimulation with the same combination of reagents, but not with either one alone. These changes were inhibited by U0126, an inhibitor of the extracellular signal-regulated kinase kinase (ERKK/MEK). The transfectants expressing a constitutively active form of the MEK kinase Raf-1 became CD4+CD8+CCR7+ upon stimulation with ionomycin alone. Thus, Raf-1-mediated signals and Ca(2+)-dependent signals are essential to induce CCR7 expression in CD4+CD8+ T cells and thymocytes as well as their differentiation.
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PMID:Induction of CCR7 expression in thymocytes requires both ERK signal and Ca(2+) signal. 1170 37

A cDNA encoding a novel, human, dual-specific protein phosphatase was identified in the Incyte data base. The open reading frame predicted a protein of 184 amino acids related to the Vaccinia virus VH1 and human VH1-related (VHR) phosphatases. Expression VHR-related MKPX (VHX) was highest in thymus, but also detectable in monocytes and lymphocytes. A VHX-specific antiserum detected a protein with an apparent molecular mass of 19 kDa in many cells, including T lymphocytes and monocytes. VHX expression was not induced by T cell activation, but decreased somewhat at later time points. In vitro, VHX dephosphorylated the Erk2 mitogen-activated protein kinase with faster kinetics than did VHR, which is thought to be specific for Erk1 and 2. When expressed in Jurkat T cells, VHX had the capacity to suppress T cell antigen receptor-induced activation of Erk2 and of an NFAT/AP-1 luciferase reporter, but not an NF-kappaB reporter. Thus, VHX is a new member of the VH1/VHR group of small dual-specific phosphatases that act in mitogen-activated protein kinase signaling pathways.
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PMID:Inhibition of T cell antigen receptor signaling by VHR-related MKPX (VHX), a new dual specificity phosphatase related to VH1 related (VHR). 1173 13

Gene activation mediated by nuclear receptors is regulated in a tissue-specific manner and requires interactions between nuclear receptors and their cofactors. Here, we identified and characterized a tissue-specific coactivator, GT198, that interacts with the DNA-binding domains of nuclear receptors. GT198 was originally described as a genomic transcript that mapped to the human breast cancer susceptibility locus 17q12-q21 with unknown function. We show that GT198 exhibits a tissue-specific expression pattern in which its mRNA is elevated in testis, spleen, thymus, pituitary cells, and several cancer cell lines. GT198 is a 217-amino-acid nuclear protein that contains a leucine zipper required for its dimerization. In vitro binding and yeast two-hybrid assays indicated that GT198 interacted with nuclear receptors through their DNA-binding domains. GT198 potently stimulated transcription mediated by estrogen receptor alpha and beta, thyroid hormone receptor beta1, androgen receptor, glucocorticoid receptor, and progesterone receptor. However, the action of GT198 was distinguishable from that of the ligand-binding domain-interacting nuclear receptor coactivators, such as TRBP, CBP, and SRC-1, with respect to basal activation and hormone sensitivity. Furthermore, protein kinase A, protein kinase C, and mitogen-activated protein kinase can phosphorylate GT198 in vitro, and cotransfection of these kinases regulated the transcriptional activity of GT198. These data suggest that GT198 is a tissue-specific, kinase-regulated nuclear receptor coactivator that interacts with the DNA-binding domains of nuclear receptors.
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PMID:Identification and characterization of a tissue-specific coactivator, GT198, that interacts with the DNA-binding domains of nuclear receptors. 1173 47

Loss-of-function mutations in Whn (Hfh11, Foxn1), a winged-helix/forkhead transcription factor, cause the nude phenotype, which is characterized by the abnormal morphogenesis of the epidermis, hair follicles, and thymus. To delineate the biochemical pathway of Whn, we investigated its upstream regulation and downstream effects using primary keratinocytes from wild-type and transgenic mice. The transgenic animals express whn from the involucrin promoter, which is active in keratinocytes undergoing terminal differentiation. In wild-type cultures, as in the epidermis, Whn was induced during the early stages of terminal differentiation and declined during later stages. In transgenic keratinocytes, whn overexpression altered the terminal differentiation program, stimulating an early differentiation marker (keratin 1) and suppressing later markers (profilaggrin, loricrin, and involucrin). These results suggest a role for Whn in the stepwise or temporal regulation of differentiation, as Whn can ensure that the differentiation program is carried out in proper sequence. Before the start of differentiation, Whn levels were suppressed by the p42/p44 mitogen-activated protein kinase cascade, and this signaling pathway was rapidly inactivated as differentiation began. Thus, as keratinocytes commit to terminal differentiation, mitogen-activated protein kinase signaling decreases, which permits the induction of Whn; Whn then activates early features of the differentiation program.
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PMID:Role of the nude gene in epithelial terminal differentiation. 1184 48

The signaling cascades evoked by G protein-coupled receptors are a predominant mechanism of cellular communication. The regulators of G protein signaling (RGS) comprise a family of proteins that attenuate G protein-mediated signal transduction. Here we report the characterization of RGS13, the smallest member of the RGS family, which has been cloned from human lung. RGS13 has been found most abundantly in human tonsil, followed by thymus, lung, lymph node, and spleen. RGS13 is a GTPase-activating protein for Galpha(i) and Galpha(o) but not Galpha(s). RGS13 binds Galpha(q) in the presence of aluminum magnesium fluoride, suggesting that it bears GTPase-activating protein activity toward Galpha(q). RGS13 blocks MAPK activity induced by Galpha(i)- or Galpha(q)-coupled receptors. RGS13 also attenuates GTPase-deficient Galpha(q) (Galpha(q)QL) mediated cAMP response element activation but not transcription evoked by constitutively active Galpha(12) or Galpha(13). Surprisingly, RGS13 inhibits cAMP generation elicited by stimulation of the beta(2)-adrenergic receptor. These data suggest that RGS13 may regulate Galpha(i)-, Galpha(q)-, and Galpha(s)-coupled signaling cascades.
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PMID:Functional characterization of the G protein regulator RGS13. 1187 76

Despite the interest in the roles that mitogen-activated protein kinases (MAPKs) play in the heart, the role of the different MAPK isoforms has been relatively poorly defined. A third isoform of p38 MAPK, known variously as stress-activated protein kinase-3 (SAPK3), p38- gamma or ERK6, has been previously shown to differ from p38- alpha/ beta both in its molecular weight and its lack of inhibition by the compound SB203580. We have generated monoclonal antibodies with specificity for SAPK3 demonstrated by immunoblot analysis, immunofluorescence studies, and cloning of SAPK3 from a rat heart cDNA expression library. By immunoblotting, we confirmed high expression of SAPK3 in fast, slow and mixed fibre types of murine skeletal muscle and observed significant expression restricted to heart, lung, thymus and testes. In addition to expression in normal heart (human, mouse, rat, dog and pig), we observed constant expression in diseased human heart, as well as control and hypertrophic cultured neonatal rat cardiac myocytes. Immunolocalization in cultured cardiac myocytes followed by confocal microscopy showed punctate, non-nuclear SAPK3 staining. In contrast, p38- alpha/ beta staining was non-punctate and distributed throughout the cytosol and nucleus. Whereas treatment with Leptomycin B to prevent nuclear export processes promoted higher levels of p38- alpha/ beta staining in cardiac myocyte nuclei, there was no apparent change in SAPK3 localization under these conditions. These differences between p38- alpha/ beta and SAPK3 probably reflect the specialized functions of SAPK3 and emphasize the need to evaluate SAPK3 upstream activators and downstream targets in the heart.
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PMID:Cardiac expression and subcellular localization of the p38 mitogen-activated protein kinase member, stress-activated protein kinase-3 (SAPK3). 1199 31

The Tec family tyrosine kinase Itk is critical for efficient signaling downstream of the TCR. Biochemically, Itk is directly phosphorylated and activated by Lck. Subsequently, Itk activates phospholipase C-gamma1, leading to calcium mobilization and extracellular signal-regulated kinase/mitogen-activated protein kinase activation. These observations suggested that Itk might play an important role in positive selection and CD4/CD8 lineage commitment during T cell development in the thymus. To test this, we crossed Itk-deficient mice to three lines of TCR transgenics and analyzed progeny on three different MHC backgrounds. Analysis of these mice revealed that fewer TCR transgenic T cells develop in the absence of Itk. In addition, examination of multiple T cell development markers indicates that multiple stages of positive selection are affected by the absence of Itk, but the T cells that do develop appear normal. In contrast to the defects in positive selection, CD4/CD8 lineage commitment seems to be intact in all the TCR transgenic itk(-/-) lines tested. Overall, these data indicate that altering TCR signals by the removal of Itk does not affect the appropriate differentiation of thymocytes based on their MHC specificity, but does impact the efficiency with which thymocytes complete their maturation process.
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PMID:The absence of Itk inhibits positive selection without changing lineage commitment. 1205 26

The rat peripheral cannabinoid receptor (rCB2) was cloned from a Sprague-Dawley rat spleen cDNA library and when translated, encodes a protein of 410 amino acids. Alignment of rCB2 with mouse (mCB2) and human (hCB2) peripheral cannabinoid receptors reveals a high degree of homology except in the carboxy terminus where rCB2 is 50 and 63 residues longer than hCB2 and mCB2, respectively. PCR screening and sequencing of rat genomic DNA showed that rCB2 is encoded by three exons interrupted by two introns, one of which is polymorphic and contains a 209 base pair B2 (SINE) element. By Northern hybridization and ribonuclease protection assay (RPA), rCB2 mRNA was detected in rat spleen, testis, thymus and lung but not in rat brain, heart, kidney or liver. Like hCB2 and mCB2 receptors, rCB2 activates mitogen-activated protein kinase when it is stably expressed in Chinese Hamster Ovary (CHO) cells. The importance of the carboxy terminus in regulating CB2 receptor desensitization and internalization is well-established. Thus, the profound differences identified in this region of the CB2 receptor between species mandates caution when extrapolating experimental results from non-human models to the effects of chronic CB2 receptor stimulation in humans.
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PMID:Cloning and molecular characterization of the rat CB2 cannabinoid receptor. 1208 72

We previously reported that the STAM family members STAM1 and STAM2 are phosphorylated on tyrosine upon stimulation with cytokines through the gammac-Jak3 signaling pathway, which is essential for T-cell development. Mice with targeted mutations in either STAM1 or STAM2 show no abnormality in T-cell development, and mice with double mutations for STAM1 and STAM2 are embryonically lethal; therefore, here we generated mice with T-cell-specific double mutations for STAM1 and STAM2 using the Cre/loxP system. These STAM1(-/-) STAM2(-/-) mice showed a significant reduction in thymocytes and a profound reduction in peripheral mature T cells. In proliferation assays, thymocytes derived from the double mutant mice showed a defective response to T-cell-receptor (TCR) stimulation by antibodies and/or cytokines, interleukin-2 (IL-2) and IL-7. However, signaling events downstream of receptors for IL-2 and IL-7, such as activations of STAT5, extracellular signal-regulated kinase (ERK), and protein kinase B (PKB)/Akt, and c-myc induction, were normal in the double mutant thymocytes. Upon TCR-mediated stimulation, prolonged activations of p38 mitogen-activated protein kinase and Jun N-terminal protein kinase were seen, but activations of ERK, PKB/Akt, and intracellular calcium flux were normal in the double mutant thymocytes. When the cell viability of cultured thymocytes was assessed, the double mutant thymocytes died more quickly than controls. These results demonstrate that the STAMs are indispensably involved in T-cell development and survival in the thymus through the prevention of apoptosis but are dispensable for the proximal signaling of TCR and cytokine receptors.
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PMID:Signal-transducing adaptor molecules STAM1 and STAM2 are required for T-cell development and survival. 1244 83


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