Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Hematopoietic progenitor kinase 1 (HPK1), a mammalian Ste20-related serine/threonine protein kinase, is a hematopoietic-specific upstream activator of the c-Jun N-terminal kinase. Here, we provide evidence to demonstrate the involvement of HPK1 in T cell receptor (TCR) signaling. HPK1 was activated and tyrosine-phosphorylated with similar kinetics following TCR/CD3 or pervanadate stimulation. Co-expression of protein-tyrosine kinases, Lck and Zap70, with HPK1 led to HPK1 activation and tyrosine phosphorylation in transfected mammalian cells. Upon TCR/CD3 stimulation, HPK1 formed inducible complexes with the adapters Nck and Crk with different kinetics, whereas it constitutively interacted with the adapters Grb2 and CrkL in Jurkat T cells. Interestingly, HPK1 also inducibly associated with linker for activation of T cells (LAT) through its proline-rich motif and translocated into glycolipid-enriched microdomains (also called lipid rafts) following TCR/CD3 stimulation, suggesting a critical role for LAT in the regulation of HPK1. Together, these results identify HPK1 as a new component of TCR signaling. T cell-specific signaling molecules Lck, Zap70, and LAT play roles in the regulation of HPK1 during TCR signaling. Differential complex formation between HPK1 and adapters highlights the possible involvement of HPK1 in multiple signaling pathways in T cells.
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PMID:Involvement of hematopoietic progenitor kinase 1 in T cell receptor signaling. 1127 7

A compelling body of evidence suggests a role for Thy-1 (CD90), a cell surface glycoprotein of mouse T lymphocytes, in signal transduction resulting in T cell activation. Despite more than 3 decades of investigation, intracellular biochemical events governing the Thy-1 signaling cascade are only vaguely understood. We have employed selective pharmacological inhibitors of signaling molecules to compare downstream elements participating in the Thy-1 signal transduction pathway with those involved in the T cell receptor (TCR)/CD3-associated signaling pathway. Mitogenic anti-Thy-1 or anti-CD3 monoclonal antibody (mAb) were used to cause T cells from C57BL/6 mice to proliferate in the presence or absence of different pharmacological inhibitors. Cyclosporine A, herbimycin A, LY294002, calphostin C and PD98059 all inhibited anti-Thy-1-induced T lymphocyte proliferation, indicating the involvement of calcineurin, protein tyrosine kinases, phosphatidylinositol 3-kinase, protein kinase C, and MEK1 (MAPK kinase 1), respectively, in Thy-1 signaling. Similar results were obtained when T cells were stimulated through the TCR with anti-CD3 monoclonal antibody in the presence or absence of the different inhibitors. Interestingly, the p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580 augmented anti-Thy-1-induced T cell proliferation, whereas anti-CD3-induced proliferative response was partially suppressed by the same inhibitor. The Thy-1 signal transduction pathway, therefore, shares a requirement for calcineurin and several major kinase families with the TCR signaling pathway. However, Thy-1 and TCR-associated signaling pathways are differentially regulated by p38 MAPK.
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PMID:Selective pharmacological inhibitors reveal differences between Thy-1- and T cell receptor-mediated signal transduction in mouse T lymphocytes. 1135 81

The p38 and JNK stress-activated MAPK signal transduction pathways are activated by T cell receptor (TCR) signaling and are required for IFN-gamma production by TH1 effector cells. Here, we show that the expression of GADD45gamma is induced during T cell activation and that the level of expression is higher in TH1 cells than in TH2 cells. TH1 cells from GADD45gamma(-/-) mice are severely compromised in their abilities to activate p38 and JNK in response to TCR signaling, produce much less IFN-gamma upon restimulation, and are deficient in activation-induced cell death (AICD). Additionally, GADD45gamma deficiencies caused reduced contact hypersensitivity in mice. Thus, GADD45gamma mediates activation of the p38 and JNK pathways and effector function of TH1 cells.
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PMID:GADD45gamma mediates the activation of the p38 and JNK MAP kinase pathways and cytokine production in effector TH1 cells. 1137 60

The linker for activation of T cells (LAT) is essential for signaling through the T cell receptor (TCR). Following TCR stimulation, LAT becomes tyrosine-phosphorylated, creating docking sites for other signaling proteins such as phospholipase C-gamma(1) (PLC-gamma(1)), Grb2, and Gads. In this study, we have attempted to identify the critical tyrosine residues in LAT that mediate TCR activation-induced mobilization of intracellular Ca(2+) and activation of the MAP kinase Erk2. By using the LAT-deficient Jurkat derivative, J.CaM2, stable cell lines were established expressing various tyrosine mutants of LAT. We show that three specific tyrosine residues (Tyr(132), Tyr(171), and Tyr(191)) are necessary and sufficient to achieve a Ca(2+) flux following TCR stimulation. These tyrosine residues function by reconstituting PLC-gamma(1) phosphorylation and recruitment to LAT. However, these same tyrosines can only partially reconstitute Erk activation. Full reconstitution of Erk requires two additional tyrosine residues (Tyr(110) and Tyr(226)), both of which have the Grb2-binding motif YXN. This reconstitution of Erk activation requires that the critical tyrosine residues be on the same molecule of LAT, suggesting that a single LAT molecule nucleates multiple protein-protein interactions required for optimal signal transduction.
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PMID:Identification of the minimal tyrosine residues required for linker for activation of T cell function. 1139 91

Tolerance in vivo and its in vitro counterpart, anergy, are defined as the state in which helper T lymphocytes are alive but incapable of producing IL-2 and expanding in response to optimal antigenic stimulation. Anergy is induced when the T cell receptor (TCR) is engaged by antigen in the absence of costimulation or IL-2. This leads to unique intracellular signaling events that stand in contrast to those triggered by coligation of the TCR and costimulatory receptors. Specifically, anergy is characterized by lack of activation of lck, ZAP 70, Ras, ERK, JNK, AP-1, and NF-AT. In contrast, anergizing stimuli appear to activate the protein tyrosine kinase fyn, increase intracellular calcium levels, and activate Rap1. Moreover, anergizing TCR signals result in increased intracellular concentrations of the second messenger cAMP. This second messenger upregulates the cyclin-dependent kinase (cdk) inhibitor p27kip1, sequestering cyclin D2-cdk4, and cyclin E/cdk2 complexes and preventing progression of T cells through the G1 restriction point of the cell cycle. In contrast, costimulation through CD28 prevents p27kip1 accumulation by decreasing the levels of intracellular cAMP and promotes p27kip1 down-regulation due to direct degradation of the protein via the ubiquitin-proteasome pathway. Subsequent autocrine action of IL-2 leads to further degradation of p27kip1 and entry into S phase. Understanding the biochemical and molecular basis of T cell anergy will allow the development of new assays to evaluate the immune status of patients in a variety of clinical settings in which tolerance has an important role, including cancer, autoimmune diseases, and organ transplantation. Precise understanding of these biochemical and molecular events is necessary in order to develop novel treatment strategies against cancer. One of the mechanisms by which tumors down-regulate the immune system is through the anergizing inactivation of helper T lymphocytes, resulting in the absence of T cell help to tumor-specific CTLs. Although T-cells specific for tumor associated antigens are detected in cancer patients they often are unresponsive. Reversal of the defects that block the cell cycle progression is mandatory for clonal expansion of tumor specific T cells during the administration of tumor vaccines. Reversal of the anergic state of tumor specific T cells is also critical for the sufficient expansion of such T cells ex vivo for adoptive immunotherapy. On the other hand, understanding the molecular mechanisms of anergy will greatly improve our ability to design novel clinical therapeutic approaches to induce antigen-specific tolerance and prevent graft rejection and graft-versus-host disease. Such treatment approaches will allow transplantation of bone marrow and solid organs between individuals with increasing HLA disparity and therefore expand the donor pool, enable reduction in the need for nonspecific immunosuppression, minimize the toxicity of chemotherapy, and reduce the risk of opportunistic infections.
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PMID:Helper T cell anergy: from biochemistry to cancer pathophysiology and therapeutics. 1143 20

The protein tyrosine kinase ZAP-70 plays a pivotal role involved in signal transduction through the T cell receptor and CD2. Defects in ZAP-70 result in severe combined immunodeficiency. We report that Herpesvirus saimiri, which does not code for a ZAP-70 homologue, can replace this tyrosine kinase. H. saimiri is an oncogenic virus that transforms human T cells to stable growth based on mutual CD2-mediated activation. Although CD2-mediated proliferation of ZAP-70-deficient uninfected T cells was absent, we could establish H. saimiri-transformed T cell lines from two unrelated patients presenting with ZAP-70 deficiencies. In these cell lines, CD2 and CD3 activation were restored in terms of [Ca(2+)](i), MAPK activation, cytokine production, and proliferation. Activation-induced tyrosine phosphorylation of zeta remained defective. The transformed cells expressed very high levels of the ZAP-70-related kinase Syk. This increased expression was not observed in the primary T cells from the patients and was not due to the transformation by the virus because transformed cell lines established from control T cells did not present this particularity. In conclusion, wild type H. saimiri can restore CD2- and CD3-mediated activation in signaling-deficient human T cells. It extends our understanding of interactions between the oncogenic H. saimiri and the infected host cells.
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PMID:Herpesvirus saimiri replaces ZAP-70 for CD3- and CD2-mediated T cell activation. 1146 83

B cell linker protein (BLNK) is a SLP-76-related adaptor protein essential for signal transduction from the BCR. To identify components of BLNK-associated signaling pathways, we performed a phosphorylation-dependent yeast two-hybrid analysis using BLNK probes. Here we report that the serine/threonine kinase hematopoietic progenitor kinase 1 (HPK1), which is activated upon antigen-receptor stimulation and which has been implicated in the regulation of MAP kinase pathways, interacts physically and functionally with BLNK in B cells and with SLP-76 in T cells. This interaction requires Tyr(379) of HPK1 and the Src homology 2 (SH2) domain of BLNK/SLP-76. Via homology modeling, we defined a consensus binding site within ligands for SLP family SH2 domains. We further demonstrate that the SH2 domain of SLP-76 participates in the regulation of AP-1 and NFAT activation in response to T cell receptor (TCR) stimulation and that HPK1 inhibits AP-1 activation in a manner partially dependent on its interaction with SLP-76. Our data are consistent with a model in which full activation of HPK1 requires its own phosphorylation on tyrosine and subsequent interaction with adaptors of the SLP family, providing a mechanistic basis for the integration of this kinase into antigen receptor signaling cascades.
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PMID:Hematopoietic progenitor kinase 1 associates physically and functionally with the adaptor proteins B cell linker protein and SLP-76 in lymphocytes. 1148 85

In Jurkat T lymphocytes, hydrogen peroxide (H(2)O(2)) potentiates the phosphorylation level of extracellular signal-regulated kinase 1 and 2 (ERK1/2) caused by T cell receptor (TCR) stimulation with anti-CD3 and anti-CD28 or anti-CD3 alone. Submillimolar concentrations of H(2)O(2)-induced phosphorylation of ERK1/2 and MAP/ERK kinase 1 and 2 (MEK1/2) without antigenic stimulation. H(2)O(2) also induced the electrophoretic mobility shift of Lck from 56 to 60 kDa. The MEK inhibitor, PD98059 attenuated ERK1/2 and MEK1/2 phosphorylation, as well as the migration shift of Lck induced by H(2)O(2). The phospholipase C (PLC) inhibitor, U73122, and EGTA reduced the phosphorylation of both ERK1/2 and MEK1/2 induced by H(2)O(2). Interestingly, an increase of intracellular cAMP level with forskolin or 8-(4-chlorophenylthio)-cAMP augmented ERK1/2 phosphorylation by H(2)O(2), while inhibiting MEK1/2 phosphorylation by H(2)O(2). These results demonstrate an alternative pathway that results in augmentation of ERK1/2 phosphorylation without concomitant MEK1/2 phosphorylation in T cells.
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PMID:cAMP potentiates H(2)O(2)-induced ERK1/2 phosphorylation without the requirement for MEK1/2 phosphorylation. 1149 22

Rac2 is a hematopoietic-specific GTPase acting as a molecular switch to mediate both transcriptional activation and cell morphological changes. We have examined the effect of Rac2 deficiency during T cell activation. In Rac2(-/-) T cells, proliferation was reduced upon stimulation with either plate-bound anti-CD3 or T cell receptor-specific antigen. This defect is accompanied with decreased activation of mitogen activated protein kinase extracellular signal-regulated kinase (ERK)1/2 and p38, and reduced Ca(2)+ mobilization. TCR stimulation-induced actin polymerization is also reduced. In addition, anti-CD3 cross-linking-induced T cell capping is reduced compared with wild-type T cells. These results indicate that Rac2 is important in mediating both transcriptional and cytoskeletal changes during T cell activation. The phenotypic similarity of Rac2(-/-) to Vav(-/-) cells implicates Rac2 as a downstream mediator of Vav signaling.
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PMID:Deficiency of small GTPase Rac2 affects T cell activation. 1158 14

The Tec kinases Rlk and Itk are critical for full T cell receptor (TCR)-induced activation of phospholipase C-gamma and mitogen-activated protein kinase. We show here that the mutation of Rlk and Itk impaired activation of the transcription factors NFAT and AP-1 and production of both T helper type 1 (TH1) and TH2 cytokines. Consistent with these biochemical defects, Itk-/- mice did not generate effective TH2 responses when challenged with Schistosoma mansoni eggs. Paradoxically, the more severely impaired Rlk-/-Itk-/- mice were able to mount a TH2 response and produced TH2 cytokines in response to this challenge. In addition, Rlk-/-Itk-/- cells showed impaired TCR-induced repression of the TH2-inducing transcription factor GATA-3, suggesting a potential mechanism for TH2 development in these hyporesponsive cells. Thus, mutations that affect Tec kinases lead to complex alterations in CD4+ TH cell differentiation.
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PMID:Mutation of Tec family kinases alters T helper cell differentiation. 1170 66


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