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

Stimulation of the erythropoietin receptor (EPO-R) or the interleukin-2 receptor (IL-2-R) by their respective ligands has been reported to activate tyrosine phosphorylation of the cytoplasmic protein, Shc. We have recently characterized a cell line, CTLL-EPO-R, that contains functional cell-surface receptors for both EPO and IL-2. Although stimulation with IL-2 or IL-15 resulted in the rapid, dose-dependent tyrosine phosphorylation of Shc, stimulation with EPO failed to activate Shc. EPO, IL-2, and IL-15 activated the tyrosine phosphorylation of the adaptor protein, Shp2, and the association of Shp2/Grb2/cytokine receptor complexes. In addition, EPO, IL-2, and IL-15 activated Raf1 and ERK2, demonstrating that the Raf1/MEK/MAP kinase pathway was activated. These results indicate that multiple biochemical pathways are capable of conferring a mitogenic signal in CTLL-EPO-R. EPO can activate the Raf1/MEK/MAP kinase pathway via Shc-dependent or Shc-independent pathways, and Shc activation is not required for EPO-dependent cell growth in CTLL-EPO-R.
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PMID:Erythropoietin activates Raf1 by an Shc-independent pathway in CTLL-EPO-R cells. 897 77

Type I interferons (IFNs-alpha and IFN-beta) bind to a common receptor to exert strong antiproliferative activity on a broad range of cell types, including interleukin-6 (IL-6)-dependent myeloma cells. In this study, we investigated the effect of IFN-beta pretreatment on IL-6-stimulated mitogenic signaling in the human myeloma cell line U266. IL-6 induced transient tyrosine phosphorylation of the IL-6-receptor signal-transducing subunit gp130, the gp130-associated protein tyrosine kinases Jak1,Jak2, and Tyk2, the phosphotyrosine phosphatase PTP1D/Syp, the adaptor protein Shc and the mitogen-activated protein kinase Erk2, and accumulation of GTP-bound p21ras. Prior treatment of U266 cells with IFN-beta downregulated IL-6-induced tyrosine phosphorylation of gp130, Jak2, PTP1D/Syp, Shc, and Erk2, and GTP-loading of p21ras. Further analysis indicated that treatment with IFN-beta disrupted IL-6-induced binding of PTP1D/Syp to gp130 and the adaptor protein Grb2; IFN-beta pretreatment also interfered with IL-6-induced interaction of Shc with Grb2 and a 145-kD tyrosine-phosphorylated protein. These results suggest a novel mechanism whereby type I IFNs interrupt IL-6-promoted mitogenesis of myeloma cells in part by preventing the formation of essential signaling complexes leading to p21ras activation.
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PMID:Interferon-beta interrupts interleukin-6-dependent signaling events in myeloma cells. 897

Taxol, a natural product with significant anti-tumor activity, stabilizes microtubules and arrests cells in the G2/M phase of the cell cycle. It has been reported that taxol has additional effects in cells, including an increase in tyrosine phosphorylation of proteins and activation of MAP kinase. We investigated a possible effect of taxol on tyrosine phosphorylation of Shc and on formation of the Shc/Grb-2 complex in the murine macrophage-like cell line RAW 264.7. Shc, an SH2 domain containing adaptor protein, was immunoprecipitated from lysates of taxol-treated cells with anti-phosphotyrosine antibody and its identity determined by Western blotting with anti-Shc antibody. Non-denatured Shc containing protein complexes were immunoprecipitated with anti-Shc antibody, and analysis with an anti-Grb2 antibody revealed the presence of the 24-kDa Grb2 protein. Taxol also activated Raf-1 kinase and ERK1/ERK2 MAP kinases in these cells. These results demonstrate that taxol affects tyrosine phosphorylation of Shc and this may result in the activation of the Raf-1/MAPK cascade.
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PMID:Taxol induces tyrosine phosphorylation of Shc and its association with Grb2 in murine RAW 264.7 cells. 900 67

The focal adhesion kinase (FAK), a protein-tyrosine kinase (PTK), associates with integrin receptors and is activated by cell binding to extracellular matrix proteins, such as fibronectin (FN). FAK autophosphorylation at Tyr-397 promotes Src homology 2 (SH2) domain binding of Src family PTKs, and c-Src phosphorylation of FAK at Tyr-925 creates an SH2 binding site for the Grb2 SH2-SH3 adaptor protein. FN-stimulated Grb2 binding to FAK may facilitate intracellular signaling to targets such as ERK2-mitogen-activated protein kinase. We examined FN-stimulated signaling to ERK2 and found that ERK2 activation was reduced 10-fold in Src- fibroblasts, compared to that of Src- fibroblasts stably reexpressing wild-type c-Src. FN-stimulated FAK phosphotyrosine (P.Tyr) and Grb2 binding to FAK were reduced, whereas the tyrosine phosphorylation of another signaling protein, p130cas, was not detected in the Src- cells. Stable expression of residues 1 to 298 of Src (Src 1-298, which encompass the SH3 and SH2 domains of c-Src) in the Src- cells blocked Grb2 binding to FAK; but surprisingly, Src 1-298 expression also resulted in elevated p130cas P.Tyr levels and a two- to threefold increase in FN-stimulated ERK2 activity compared to levels in Src- cells. Src 1-298 bound to both FAK and p130cas and promoted FAK association with p130cas in vivo. FAK was observed to phosphorylate p130cas in vitro and could thus phosphorylate p130cas upon FN stimulation of the Src 1-298-expressing cells. FAK-induced phosphorylation of p130cas in the Src 1-298 cells promoted the SH2 domain-dependent binding of the Nck adaptor protein to p130cas, which may facilitate signaling to ERK2. These results show that there are additional FN-stimulated pathways to ERK2 that do not involve Grb2 binding to FAK.
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PMID:Fibronectin-stimulated signaling from a focal adhesion kinase-c-Src complex: involvement of the Grb2, p130cas, and Nck adaptor proteins. 903 97

Functional interactions between protein kinase A (PKA) and epidermal growth factor receptor (EGF-R) signalling pathways have been suggested. Unlike the type II isoform of PKA (PKAII), the type I (PKAI) and/or its regulatory subunit RIalpha are generally overexpressed in cancer cells and are induced following transforming growth factor alpha (TGF alpha)/EGF-R-dependent transformation. Downregulation of RIalpha/PKAI inhibits TGF alpha expression and EGF-R-dependent signalling. We have previously shown that addition of EGF to quiescent human normal epithelial MCF-10A cells determines PKAI expression and cell membrane translocation before cells enter S phase, while PKAI inhibition prevents S phase entry. Constitutive overexpression of PKAI confers the ability to grow in serum free medium, bypassing EGF requirement. Here we demonstrate a direct interaction of PKAI, but not of PKAII, with the activated EGF-R, that occurs within 5 min following EGF treatment of MCF-10A cells. Moreover, induction of mitogen-activated protein kinase (MAPK) activity following EGF-R activation is mimicked by PKAI overexpression and inhibited by downregulators of PKAI. Finally, the PKAI-EGF-R association occurs through the binding of RIalpha to the SH3 domain(s) of Grb2 adaptor protein, thus allowing the recruitment of the PKAI holoenzyme to the activated EGF-R. This is the first demonstration of a direct interaction of PKAI with the activated EGF-R macromolecular signalling complex.
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PMID:The RIalpha subunit of protein kinase A (PKA) binds to Grb2 and allows PKA interaction with the activated EGF-receptor. 905 Sep 91

In the present study we have investigated a possible role for the proline-rich SH2 domain protein Shb as a regulator of expression or activity of certain SH3 domain proteins and MAP kinase. The expression of the Shb binding proteins Eps8, Src, and p85 PI3-kinase, PI3-kinase activity, and MAP kinase activation were assessed in wild-type NIH3T3 cells and in NIH3T3 cells overexpressing the Shb cDNA. In addition, the expression of the SH3 domain STAT1 proteins was assessed in wild-type and Shb overexpressing cells. The Eps8 protein content and Eps8 mRNA steady-state levels were downregulated, whereas the protein contents of Src and p85 PI3-kinase were unaffected by Shb overexpression. There was, however, an increased basal PI3-kinase activity in Shb transfected cells after a 3-h serum starvation. Increased steady-state levels of STAT1 mRNA were accompanied by an increased STAT1 protein content in Shb overexpressing cells. Shb overexpression was not associated with an altered activation of p44 or p42 MAP kinases in response to PDGF stimulation. The data presented in this study suggest novel functions for the adaptor protein Shb regulating the expression of certain signal-transducing SH3 domain proteins and modulating PI3-kinase activity.
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PMID:Modulation of Src homology 3 proteins by the proline-rich adaptor protein Shb. 908 67

Platelet-derived growth factor (PDGF) and serum, but not epidermal growth factor (EGF), stimulated sphingosine kinase activity in Swiss 3T3 fibroblasts and increased intracellular concentrations of sphingosine 1-phosphate (SPP), a sphingolipid second messenger (Olivera, A., and Spiegel, S. (1993) Nature 365, 557-560). We report herein that DL-threo-dihydrosphingosine (DHS), a competitive inhibitor of sphingosine kinase that prevents PDGF-induced SPP formation, specifically inhibited the activation of two cyclin-dependent kinases (p34(cdc2) kinase and Cdk2 kinase) induced by PDGF, but not by EGF. SPP reversed the inhibitory effects of DHS on PDGF-stimulated cyclin-dependent kinases and DNA synthesis, demonstrating that the DHS effects were mediated via inhibition of sphingosine kinase. DHS also markedly reduced PDGF-stimulated but not EGF-stimulated mitogen-activated protein kinase activity and DNA binding activity of activator protein-1. Examination of the early signaling events of PDGF action revealed that DHS did not affect PDGF-induced autophosphorylation of the growth factor receptor or phosphorylation of the SH2/SH3 adaptor protein Shc and its association with Grb2. This sphingosine kinase inhibitor did not abrogate activation of phosphatidylinositol 3-kinase by PDGF. In agreement, treatment with SPP had no effect on these responses but did, however, potently stimulate phosphorylation of Crk, another SH2/SH3 adaptor protein. Moreover, DHS inhibited PDGF-stimulated, but not EGF-stimulated, Crk phosphorylation. Thus, regulation of sphingosine kinase activity defines divergence in signal transduction pathways of PDGF and EGF receptors leading to mitogen-activated protein kinase activation.
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PMID:Divergence in signal transduction pathways of platelet-derived growth factor (PDGF) and epidermal growth factor (EGF) receptors. Involvement of sphingosine 1-phosphate in PDGF but not EGF signaling. 909 30

rZIP is an approx. 32 kDa, multi-domain protein of Dictyostelium discoideum whose structural motifs include a RING (zinc-binding) domain, a leucine zipper, a glutamine repeat, an SH3-binding region and a consensus phosphorylation site for MAP kinase. In vitro, rZIP forms homodimers and interacts specifically with the SH3 domain(s) of the Nck adaptor protein. rZIP is expressed maximally during cell differentiation at approximately equivalent levels in all cells. Disruption of the rZIP gene rzpA results in altered cellular aggregation, impaired slug migration, and aberrant patterning of prespore and prestalk cells, the major progenitor classes. In rzpA- strains, prespore-specific genes are overexpressed and prestalk expression zones are reduced. Conversely, constitutive overexpression of rzpA markedly decreases prespore-specific gene expression and significantly increases the expression of prestalk-specific genes. Further, induced transdifferentiation of prespore cells into prestalk cells is inhibited in rzpA-slugs. In light of these patterning defects, we suggest that the RING/zipper protein rZIP plays an important role in early cell fate decisions in Dictyostelium, acting as a positive regulator of prestalk differentiation and an inhibitor of prespore differentiation.
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PMID:rZIP, a RING-leucine zipper protein that regulates cell fate determination during Dictyostelium development. 910 7

Nck, an adaptor protein composed of one SH2 and three SH3 domains, is a common target for a variety of cell surface receptors. We have identified a novel mammalian serine/threonine kinase that interacts with the SH3 domains of Nck, termed Nck Interacting Kinase (NIK). This kinase is most homologous to the Sterile 20 (Ste20) family of protein kinases. Of the members of this family, GCK and MSST1 are most similar to NIK in that they bind neither Cdc42 nor Rac and contain an N-terminal kinase domain with a putative C-terminal regulatory domain. Transient overexpression of NIK specifically activates the stress-activated protein kinase (SAPK) pathway. Both the kinase domain and C-terminal regulatory region of NIK are required for full activation of SAPK. NIK likely functions upstream of MEKK1 to activate this pathway; a dominant-negative MEK kinase 1 (MEKK1) blocks activation of SAPK by NIK. MEKK1 and NIK also associate in cells and this interaction is mediated by regulatory domains on both proteins. Two other members of this kinase family, GCK and HPK1, contain C-terminal regulatory domains with homology to that of NIK. These findings indicate that the C-terminal domain of these proteins encodes a new protein domain family and suggests that this domain couples these kinases to the SAPK pathway, possibly by interacting with MEKK1 or related kinases.
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PMID:NIK is a new Ste20-related kinase that binds NCK and MEKK1 and activates the SAPK/JNK cascade via a conserved regulatory domain. 913 44

The Met/Hepatocyte Growth Factor (HGF) receptor tyrosine kinase is oncogenically activated through a rearrangement that creates a hybrid gene Tpr-Met. The resultant chimeric p65(Tpr-Met) protein is constitutively phosphorylated on tyrosine residues in vivo and associates with a number of SH2-containing signaling molecules including the p85 subunit of PI-3 kinase and the Grb2 adaptor protein, which couples receptor tyrosine kinases to the Ras signaling pathway. Mutation of the binding site for Grb2 impairs the ability of Tpr-Met oncoprotein to transform fibroblasts, suggesting that the activation of the Ras/MAP kinase signaling pathway through Grb2 may be essential for cellular transformation. To test this hypothesis dominant-negative mutants of Grb2 with deletions of the SH3 domains were introduced into Tpr-Met transformed fibroblasts. Cells overexpressing the mutants were found to be morphologically reverted and exhibited reduced growth in soft agar. Surprisingly, the Grb2 mutants blocked activation of the JNK/SAPK but not MAP kinase activity induced by the Tpr-Met oncoprotein. Additionally, cells expressing dominant-negative Grb2 mutants had reduced PI-3-kinase activity and dominant-negative mutants of Rac1 blocked both Tpr-Met-induced transformation and activation of JNK. These experiments reveal a novel link between Met and the JNK pathway, which is essential for transformation by this oncogene.
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PMID:Activation of the JNK pathway is essential for transformation by the Met oncogene. 918 10


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