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)

gp130 is a common signal transducer for the interleukin-6-related cytokines. To delineate the gp130-mediated growth signal, we established a series of pro-B cell lines expressing chimeric receptors composed of the extracellular domain of the granulocyte colony-stimulating factor receptor and the transmembrane and cytoplasmic domains of gp130. The second tyrosine (from the membrane) of gp130, which was required for the tyrosine phosphorylation of SHP-2, its association with GRB2, and activation of a MAP kinase, was essential for mitogenesis, but not for anti-apoptosis. On the other hand, the tyrosine in the YXXQ motifs essential for STAT3 activation was required for bcl-2 induction and anti-apoptosis. Furthermore, dominant-negative STAT3 inhibited anti-apoptosis. These data demonstrate that two distinct signals, mitogenesis and anti-apoptosis, are required for gp130-induced cell growth and that STAT3 is involved in anti-apoptosis.
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PMID:Two signals are necessary for cell proliferation induced by a cytokine receptor gp130: involvement of STAT3 in anti-apoptosis. 893 72

Homodimerization of the erythropoietin (EPO) receptor (EPO-R) in response to EPO binding transiently activates the receptor-associated protein tyrosine kinase JAK2. Tyrosine phosphorylation of the EPO-R creates "docking sites" for SH2 domain(s) in signaling molecules such as the protein tyrosine phosphatases SH-PTP1 and SH-PTP2, phosphoinositide 3-kinase (PI3 kinase), and STAT5. However, little is known about the specific intracellular signals essential for proliferation and differentiation of erythroid progenitors. Here we show that an EPO-R containing only one cytosolic (phospho)tyrosine residue, Y479, induces a signal transduction pathway sufficient for proliferation and differentiation of fetal liver progenitors of erythroid colony-forming units from EPO-R(-/-) mice as well as for proliferation of cultured hematopoietic cells. This cascade involves sequential EPO-induced recruitment of PI3 kinase to the EPO-R and activation of mitogen-activated protein kinase activity, independent of the Shc/Grb2-adapter pathway and of STAT5. Protein kinase C epsilon may be one of the mediators connecting PI3 kinase with the mitogen-activated protein kinase signaling cascade. Our results identify a signaling cascade important in vivo for erythroid cell proliferation and differentiation.
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PMID:Identification of a novel pathway important for proliferation and differentiation of primary erythroid progenitors. 909 38

Chimeric receptors containing the entire or various cytoplasmic domains of either gp130 or leukemia inhibitory factor receptor alpha (LIFR) were used to identify signaling molecules and regions of these polypeptides required for the stimulation of mitogen-activated protein kinase (MAPK). Coexpression of dominant-negative Jak2 inhibited chimeric receptor-stimulated MAPK activity by approximately 70%, while expression of dominant-negative Ras completely blocked MAPK activation by either receptor polypeptide. Deletion analysis identified a 24-amino acid region of gp130 that was necessary for maximal stimulation of MAPK, and contained box 3 (positions 120-129) and a consensus tyrosine binding motif (Tyr-118) for the protein-tyrosine phosphatase, SHP2. Expression of receptors lacking this region or of chimeric gp130(Y118F) point mutants inhibited MAPK activity by approximately 55%, suggesting that Tyr-118, but not box 3, was required during activation of MAPK by gp130. Similarly, expression of chimeric LIFR constructs lacking box 3 maximally stimulated MAPK activity, while those lacking Tyr-115, a putative SHP2 binding site, inhibited stimulation of MAPK by this polypeptide. Our results demonstrate that gp130 and LIFR stimulate MAPK activity through box 3-independent mechanisms involving: (i) effects at Tyr-118 and Tyr-115, respectively, for maximal stimulation of MAPK activity and (ii) a Jak/Tyk-dependent pathway that, together with Tyr-118- or Tyr-115-generated signals, converges at the level of Ras during activation of MAPK by cytokine.
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PMID:Box 3-independent signaling mechanisms are involved in leukemia inhibitory factor receptor alpha- and gp130-mediated stimulation of mitogen-activated protein kinase. Evidence for participation of multiple signaling pathways which converge at Ras. 919 77

Co-clustering of Fc gamma RIIb and B-cell receptor (BCR) inhibits cell activation by interrupting BCR stimulated signal transduction. The immunoreceptor tyrosine-based inhibitory motif (ITIM) of Fc gamma RIIb becomes tyrosyl phosphorylated (P-ITIM) upon co-clustering with BCR then P-ITIM interacts with several signalling molecules, some of which negatively regulate the cell activation process. The molecules recruited by the P-ITIM of human Fc gamma RIIb have not been characterised yet. In order to affinity isolate the potential functional partner molecules of human Fc gamma RIIb, synthetic peptides were designed to cover almost the entire intracellular Fc gamma RIIb domain, including Fc gamma RIIb2 specific sequences and stretches containing the phosphorylated and non-phosphorylated ITIM. We report here that several tyrosyl phosphorylated proteins bind to the P-ITIM peptide from both resting and activated B-cell lysates, the 53-56 kDa being the most prominent one. A fraction of the 53-56 kDa bands were identified as the protein tyrosine kinase (PTK), Lyn which also bound to ITIM peptide, pointing to its role in initiating Fc gamma RIIb-mediated negative regulation. Among the P-ITIM associated tyr phosphorylated components, the 145 kDa one was identified as the inositol polyphosphate 5-phosphatase, SHIP and the 72 kDa protein as the protein tyrosine phosphatase (PTP) SHP2, whereas SHP1 was not detected. Phosphatase activity assays showed that P-ITIM bound about five times higher SHIP and four times higher PTP activity than the ITIM containing peptide. Furthermore, we detected PKC and MAPK in both ITIM and P-ITIM peptides precipitated samples. Since human B-cells express both Fc gamma RIIb1 and Fc gamma RIIb2, differing in a 19 amino acid insert in the cytoplasmic tail of the former, we investigated the components binding to Fc gamma RIIb1 and Fc gamma RIIb2 specific sequences. Synthetic peptide representing Fc gamma RIIb1 and Fc gamma RIIb2 specific sequences weakly bound unidentified tyr phosphorylated proteins at 50-56 kDa, while the insert itself did not bind a detectable amount of protein. Neither of the ITIM or P-ITIM bound molecules were observed in samples precipitated with peptides corresponding to Fc gamma RIIb1 or Fc gamma RIIb2 specific sequences. These observations suggest that protein kinases associate with both ITIM and P-ITIM of human Fc gamma RIIb, Lyn being responsible for the tyrosyl phosphorylation of ITIM. SHIP and SHP2 phosphatases selectively bind to the phosphorylated ITIM. Based on these data we assume that SHIP and SHP2 recruited in vivo to the Fc gamma RIIb co-clustered BCR are responsible for the Fc gamma RIIb mediated negative regulation of human B-cell activation.
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PMID:Fc gamma receptor type IIb induced recruitment of inositol and protein phosphatases to the signal transductory complex of human B-cell. 923 45

Ciliary neurotrophic factor, along with other neuropoietic cytokines, signals through the shared receptor subunit gp130 [1-3], leading to the tyrosine phosphorylation of a number of substrates [4,5], including the transcription factors STAT1 and STAT3 and the protein tyrosine phosphatase SHP-2 [6,7] [8]. SHP-2 (also known as PTP1D, SHPTP2, Syp and PTP2C) is a positive regulatory molecule required for the activation of the mitogen-activated protein kinase pathway and the stimulation of gene expression in response to epidermal growth factor, insulin and platelet-derived growth factor stimulation [9-11]. We have previously shown that cytokines that signal via the gp130 receptor subunit activate transcription of the vasoactive intestinal peptide (VIP) gene through a 180 bp cytokine response element (CyRE) [12,13]. To characterize the role of SHP-2 in the regulation of gp130-stimulated gene expression, we examined the regulation of the VIP CyRE in two systems that prevented ligand-dependent SHP-2 phosphorylation. Inhibition of SHP-2, either by mutating the tyrosine residue in gp130 that mediates the SHP-2 interaction, or by expression of dominant-negative SHP-2, resulted in dramatic increases in gp130-dependent gene expression, through the VIP CyRE and more specifically through multimerized STAT-binding sites. These data suggest that SHP-2 has a negative role in gp130 signaling by modulating STAT-mediated transcriptional activation.
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PMID:The protein tyrosine phosphatase SHP-2 negatively regulates ciliary neurotrophic factor induction of gene expression. 928 12

SHP-1 and SHP-2 are intracellular protein tyrosine phosphatases containing two adjacent src homology 2 domains that target these phosphatases to cell surface receptor signaling complexes and play a role in receptor signal transduction. In this report the PC12 cell system was used to investigate the potential roles of SHP-1 and SHP-2 in the induction of neuronal differentiation by nerve growth factor (NGF). By using neurite outgrowth as a marker for differentiation, the effects of transfected constructs of SHP-1 and SHP-2 were assessed. Overexpression of a catalytically inactive SHP-2, but not a catalytically inactive SHP-1, blocked NGF-stimulated neurite outgrowth. The mitogen-activated protein kinase (MAPK) signaling cascade is important for the morphological differentiation in PC12 cells, and both SHP-1 and SHP-2 have been implicated to act upstream of MAPK in other receptor signaling systems. A positive role for SHP-2 but not SHP-1 in the activation of MAPK by NGF was demonstrated by introduction of the SHP-2 phosphatase mutants along with hemagglutinin-tagged MAPK. Coexpression studies with the SHP-2 mutant along with mutant forms of MAPK kinase suggested that SHP-2 functions upstream of MAPK kinase and MAPK in NGF-induced neurite outgrowth.
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PMID:A role for the SHP-2 tyrosine phosphatase in nerve growth-induced PC12 cell differentiation. 928 26

The human insulin receptor substrate-1 (hIRS-1) is a key intracellular protein involved in various cytokine signaling pathways associated with cell growth. We have previously demonstrated that stable transfection and overexpression of hIRS-1 in human hepatoblastoma cells in vitro leads to the constitutive activation of the mitogen-activated protein kinase (MAPK) cascade. In this setting, hIRS-1 acts as a dominant oncogene and will induce neoplastic transformation of NIH 3T3 cells. In the present study, the biologic effects of hIRS-1 overexpression in the liver was analyzed using both clinical tumor samples and a newly developed transgenic mouse model. We have found that approximately 40% of 22 human hepatocellular carcinoma (HCC) tumors had enhanced (>200%) hIRS-1 gene expression compared with adjacent non-involved liver tissue. There was a significant relationship between the level of hIRS-1 overexpression and the tumor size; this finding suggests a possible role for hIRS-1 in tumor progression. To determine if downstream signal transduction cascades were activated by overexpression of hIRS-1 in hepatocytes, we established a transgenic mouse model using an hIRS-1 construct driven by an albumin promoter/enhancer element to direct liver specific expression. The overexpressed hIRS-1 protein was found to be tyrosyl phosphorylated and interacted with downstream SH2-containing molecules such as the p85 subunit of phosphatidylinositol-3 kinase (PI3K), Grb2 adaptor, and SHP2 phosphatase proteins. The functional consequences of hIRS-1 overexpression were reflected by constitutive activation of both the MAPK and PI3K signal transduction cascades. More important, overexpression of hIRS-1 in the transgenic liver led to increased hepatocyte DNA synthesis. Our findings indicate that hIRS-1 overexpression induces downstream signaling molecules associated with hepatocyte growth and may potentially enhance tumor progression of HCC.
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PMID:Biological effects of human insulin receptor substrate-1 overexpression in hepatocytes. 930 88

SHPS-1 is a 120 kDa glycosylated receptor-like protein that contains immunoglobulin-like domains in its extracellular region and four potential tyrosine phosphorylation for SH2 domain binding sites in its cytoplasmic region. Epidermal growth factor (EGF) stimulated the rapid tyrosine phosphorylation of SHPS-1 and subsequent association of SHPS-1 with SHP-2, a protein tyrosine phosphatase containing SH2 domains, in Chinese hamster ovary cells overexpressing human EGF receptors. In the cells overexpressing SHPS-1, the tyrosine phosphorylation of SHPS-1 was more evident than that observed in parent cells. However, overexpression of SHPS-1 alone did not affect the activation of MAP kinase in response to EGF. These results suggest that SHPS-1 may be involved in the recruitment of SHP-2 from the cytosol to the plasma membrane in response to EGF.
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PMID:Epidermal growth factor stimulates the tyrosine phosphorylation of SHPS-1 and association of SHPS-1 with SHP-2, a SH2 domain-containing protein tyrosine phosphatase. 934 56

Vascular endothelial growth factor A (here referred to as VEGF) is an endothelium-specific growth factor that binds to two distinct receptor tyrosine kinases, designated Flt-1 and KDR/Flk-1. VEGF stimulates autophosphorylation of both receptors, but little is known about their signal transduction properties. In this study, we used porcine aortic endothelial (PAE) cells overexpressing KDR (PAE/KDR) to evaluate the interaction of KDR with intracellular proteins and compared them with Flt-1-expressing PAE cells (PAE/Flt-1). VEGF-induced stimulation of KDR results in the association and phosphorylation of the 46-, 52-, and 66-kDa isoforms of Shc and the induction of Shc-Grb2 complex formation. In a similar fashion, KDR associates with Grb2 and Nck in a ligand-dependent fashion, suggesting Shc, Grb2, and Nck as potential candidates involved in the regulation of endothelial function. Another strong candidate is mitogen-activated protein (MAP) kinase, which is strongly activated in response to VEGF stimulation as demonstrated by phosphorylation of the specific substrate myelin basic protein. Inhibition of MAP kinase activation by PD98059, a specific MAP kinase kinase inhibitor, results in inhibition of VEGF-induced proliferation of PAE/KDR cells. In contrast, VEGF-induced stimulation of Flt-1 does not activate MAP kinase in PAE/Flt-1 cells. In this study we provide the first two examples of molecules potentially capable of functionally counteracting the endothelial response to VEGF, namely SHP-1 and SHP-2. These two SH2 protein-tyrosine phosphatases physically associate with KDR secondary to VEGF stimulation, raising the interesting possibility that both molecules participate in the generation and/or modulation of VEGF-induced signals. Taken together, our results substantially broaden the spectrum of KDR-associating molecules, indicating that endothelial function and angiogenesis are regulated by a diverse network of signal transduction cascades.
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PMID:The vascular endothelial growth factor receptor KDR activates multiple signal transduction pathways in porcine aortic endothelial cells. 940 64

The 120 kD product of the c-Cbl oncogene is a prominent substrate of protein tyrosine kinases that lacks a known catalytic activity but possesses an array of binding sites for cytoplasmic signalling proteins. An oncogenic form of Cbl was recently identified in the 70Z/3 pre-B cell lymphoma which has a small deletion at the N-terminus of the Ring finger domain. This form of Cbl, termed 70Z-Cbl, exhibits an enhanced level of tyrosine phosphorylation compared with c-Cbl. Here we demonstrate that the expression of 70Z-Cbl induces a tenfold enhancement in the kinase activity of the EGF receptor in serum-starved and EGF-stimulated cells. In serum-starved cells this results in EGF receptor autophosphorylation and the recruitment of Grb2, Shc and Sos1 but does not induce a corresponding increase in MAP kinase activity. Furthermore the expression of 70Z-Cbl greatly enhances EGF-induced tyrosine phosphorylation of the protein tyrosine phosphatase SHP-2. We also show that the Cbl/EGF receptor complex is predominantly associated with CrkII and is distinct to the Grb2/Shc/Sos1 complex that associates with the EGF receptor. These findings therefore demonstrate a biochemical effect of an oncogenic Cbl protein and support predictions from C. elegans that Cbl functions as regulator of receptor tyrosine kinases.
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PMID:Tyrosine kinase activity of the EGF receptor is enhanced by the expression of oncogenic 70Z-Cbl. 941 34


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