Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Platelet-derived growth factor (PDGF) is a cationic glycoprotein of approximately 30 kDa, composed of two subunits. These subunit chains are termed A (18 kDa) and B (12-14 kDa) with high homology of the peptide sequences, including 8 cysteine residues at identical positions. Three isoforms of PDGF, AA, BB homodimers and AB heterodimer are distributed in the different tissues and cell lines suggesting that these isoforms have different functions. Two types of PDGF receptors alpha, and beta with Mr of 160-180 kDa are seen on the cell surface. PDGFR alpha can bind to both A and B subunits of the PDGD, while PDGFR beta, only B subunit. PDGF (AA) combines alpha alpha, PDGF (AB) makes dimers of alpha alpha and alpha beta, and PDGF (BB) can make three types of dimers, alpha alpha, alpha beta, and beta beta. These dimeric PDGFRs are active forms and phosphorylate its own domain and other neighbor specific proteins. The substrates of the receptor kinase are phospholipase C-gamma, GTPase activating protein (GAP), serine/threonine kinase Raf-1 and others. These molecules are thought to transfer information of the PDGFs on its receptors to the nucleus.
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PMID:[Function, molecular structure and gene expression regulation of Platelet-derived growth factor]. 143 82

In conclusion, a multigene family (ERK) encoding protein kinases that have the capacity to convert tyrosine kinase signals to serine/threonine phosphorylation signals has been identified in animal and yeast cells. Protein kinases from this family have been shown to be phosphorylated on tyrosine and threonine in response to mitogens, as well as to have the capacity to autophosphorylate on these amino acid residues. In contrast, they apparently phosphorylate exogenous substrates on serine and/or threonine. Studies with cultured cells, Xenopus, and sea star oocytes have furthered our understanding of possible functions of Erks in vivo. These enzymes respond immediately to extracellular signals and are involved in G0-G1 transition (cultured cells), as well as in the M phase of oocyte maturation (Xenopus and sea star oocytes). Their usage of MAPs as substrates in vivo suggests a possible role of Erks in microtubule reorganization. ERK-encoded protein kinases use c-Jun, EGF receptor, and Raf-1 as potential substrates and can also reactivate dephosphorylated S6 kinase in vitro. Taken together, these data suggest that these enzymes play an important role in relaying the mitogenic signal by phosphorylating down-stream kinases and specific transcriptional factors, as well as having possible feedback function in the process of signal transduction. The results from the study of the yeast enzymes are pertinent to Erk activation in cells with nonmitogenic responses described above. In such cases, Erk protein kinases may act directly or indirectly on cyclins to arrest division and permit differentiation. The pathways influenced by ERK-like gene products in animal and yeast cells suggest that, depending on the downstream targets of substrates, transcriptional changes in a particular cell may occur to drive the cell cycle or, alternatively, withdrawal from the cell cycle may lead to specific differentiation events.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Erks: their fifteen minutes has arrived. 150 18

Four different Waardenburg syndromes have been defined based upon observed phenotypes. These syndromes are responsible for approximately 2% of subjects with profound congenital hearing loss. At present, Waardenburg syndromes have not been mapped to particular human chromosomes. One or more of the mouse mutant alleles, Ph (patch), s (piebald), Sp (splotch), and Mior (microphthalmia-Oak Ridge) and the hamster mutation Wh (anophthalmic white) may be homologous to mutations causing Waardenburg syndromes. In heterozygotes, phenotypic effects of these four mouse mutations and the hamster mutation are similar to the phenotypes produced by different Waardenburg syndrome mutations. The chromosomal locations and syntenic relationships associated with three of the four mouse mutant genes have been used to predict human chromosomal locations for Waardenburg syndromes: (1) on chromosome 2q near FN1 (fibronectin 1), (2) on chromosome 3p near the proto-oncogene RAF1 or 3q near RHO (rhodopsin), and (3) on chromosome 4p near the proto-oncogene KIT. Waardenburg syndromes show extensive intrafamilial phenotypic variability. Results of our studies with the hamster mutation Wh suggest that this variability may be explained in part by modifier genes segregating within families.
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PMID:Mouse and hamster mutants as models for Waardenburg syndromes in humans. 224 70

Human monoblastoid leukemia U937 cells differentiate to monocyte/macrophage upon treatment with phorbol ester, 12-o-tetradecanoylphorbol-13-acetate (TPA). Previous studies, including our own, have demonstrated that drug-induced differentiation of leukemia cells is associated with genetic and enzymatic activations of protein tyrosine phosphatases (PTPases). In this study, to further investigate a relationship between PTPase activation and leukemic differentiation, we established TPA-resistant U937 variant UT16 cells. Unlike known TPA-resistant cells whose resistance is mainly due to lack or down modulation of protein kinase C (PKC), UT16 cells showed TPA-induced activation of PKC, Raf-1, and ERK/MAP kinases similar to the parental U937 cells. Interestingly, however, UT16 cells exhibited altered binding activity of AP-1 complexes, decreased ability to induce c-jun and c-fos gene expressions, and failure to differentiate to a monocytic lineage. Based on these observations, UT16 cells could be considered a novel type of TPA-resistant cell. Among UT16 cells, most of TPA-inducible PTPase genes, PTP-1C, PTP-MEG2, P19-PTP, HPTP epsilon, and PTP-U1, did not respond to TPA. Consistently, TPA increased PTPase enzymatic activity in U937 but not in UT16 cells. Taken together, activation of PTPases is well correlated with TPA-induced differentiation of U937 cells. These findings indicate that gene expression and enzymatic activity of some PTPase isozymes described here are regulated by a TPA-mediated signaling event and are likely to be used as biomarkers for the monocytic differentiation of myeloid leukemia cells.
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PMID:Phorbol ester-resistant monoblastoid leukemia cells with a functional mitogen-activated protein kinase cascade but without responsive protein tyrosine phosphatases. 747 24

A consensus cyclic AMP response element (CRE) in the murine prostaglandin synthase-2 (PGS2) promoter is essential for pgs2 gene expression induced by pp60v-src, the v-src oncogene product. In this study, we investigate (i) the transcription factors active at the PGS2 "CRE site" in response to v-src activation and (ii) the signal transduction pathways by which pp60v-src activates these transcription factors. Transient transfection assays with pgs2 promoter/luciferase reporter chimeric genes suggest that c-Jun mediates v-src-induced pgs2 gene expression. Antibody supershift experiments demonstrate that c-Jun can participate in a complex with the pgs2 promoter CRE site. Moreover, in vitro immuno-complex assays demonstrate that pp60v-src expression strongly activates c-Jun N-terminal kinase (JNK1) enzyme activity. Serines 63 and 73, the sites of c-Jun phosphorylation by JNK, are essential for v-src-induced, pgs2 promoter-mediated luciferase expression. Cotransfection studies with plasmids expressing wild-type JNK, dominant-negative JNK, and dominant-negative MEKK-1 confirm that activation of the Ras/MEKK-1/JNK/c-Jun pathway is required for v-src-induced pgs2 gene expression. Overexpression of either wild-type ERK-1 or ERK-2 proteins also potentiate v-src-mediated luciferase expression driven by the pgs2 promoter, and expression of dominant-negative mutants of ERK-1, ERK-2, or Raf-1 attenuate this response. Thus, in response to v-src expression, a Ras/MEKK-1/JNK signal transduction pathway activating c-Jun and a Ras/Raf-1/ERK pathway converge to mediate pgs2 gene expression via the CRE site in the pgs2 promoter.
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PMID:v-src induces prostaglandin synthase 2 gene expression by activation of the c-Jun N-terminal kinase and the c-Jun transcription factor. 749 26

Signaling via the fibroblast growth factor receptor 1 (FGFR1, flg) was analyzed in Ba/F3 hematopoietic cells expressing either wild-type or a mutant FGF receptor (Y766F) unable to activate phospholipase C-gamma (PLC-gamma) and stimulate phosphatidylinositol (PI) hydrolysis. Stimulation of cells expressing wild-type or mutant FGFR with acidic FGF (aFGF) caused similar activation of Ras. However, an approximately 3-fold reduced activation of Raf-1 and MAP kinase was observed in aFGF-stimulated cells expressing mutant receptors as compared to cells expressing wild-type FGF receptors. Comparison of phosphopeptide maps of Raf-1 immunoprecipitated from the two cell types activated by either aFGF or the phorbol ester (12-O-tetradecanoylphorbol-13-acetate) suggests that Raf-1 is phosphorylated by both Ras-dependent and PLC-gamma-dependent mechanisms. In spite of the differential effect on Raf-1 and MAP kinase activation, aFGF stimulated similar proliferation of cells expressing wild-type or mutant receptors indicating that Ras-dependent activation of Raf-1 and MAP kinase is sufficient for transduction of FGFR mitogenic signals. Ras may also activate signal transduction pathways that are complementary or parallel to the MAP kinase pathway to stimulate cell proliferation.
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PMID:Reduced activation of RAF-1 and MAP kinase by a fibroblast growth factor receptor mutant deficient in stimulation of phosphatidylinositol hydrolysis. 753 87

We have attempted to dissect signaling pathways involved in transmitting activating signals from the cell surface to the nucleus by reconstituting them in the baculovirus/Sf9 cell system. We have used this system to coexpress different combinations of the critical signaling proteins pp60v-src, p21v-ras, Raf-1 and ERK-1 and assayed the effects of resulting signaling cascades on the modifications of coexpressed transcription factors c-jun or c-fos. We observe that activation of ERK-1 via Raf-1 and p21ras dependent signals can result in the hyperphosphorylation of c-jun. In contrast, c-fos appears to be the target of two Raf-1 activated modifying signals: one independent of ERK-1 and the other dependent on ERK-1 stimulation. Thus, coexpression of c-fos with pp60v-src, p21v-ras or constitutively active forms of Raf-1 results in a dramatic reduction of its electrophoretic mobility in the absence of coexpressed ERK-1. Activation of this ERK-1-independent pathway together with the ERK-1 dependent pathway that modifies c-jun results in additional modification of c-fos. Our observation of a Raf-1 activated, ERK-independent signaling pathway is consistent with previous reports that constitutively active Raf-1 can, in some cell types, result in transformation or differentiation without activation of ERKs. Our data indicate the presence of multiple Raf-1 activated pathways that lead to modification of transcription factors.
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PMID:Reconstitution of signal transduction from the membrane to the nucleus in a baculovirus expression system: activation of Raf-1 leads to hypermodification of c-jun and c-fos via multiple pathways. 754 94

The molecular mechanism underlying the cAMP inhibition of nuclear activation events in T lymphocytes is unknown. Recently, the activation of fibroblasts and muscle cells are shown to be antagonized by cAMP through the inhibition of mitogen-activated protein (MAP) kinases signaling pathway. Whether a similar antagonism may account for the late inhibitory effect of cAMP in T cell was examined. Surprisingly, extracellular signal regulated kinase 2 (ERK1, ERK2, and ERK3) of MAP kinase were poorly inhibited by cAMP. High concentration of cAMP also only weakly antagonized Raf-1 in T cells. The resistance of ERK and Raf-1 to cAMP clearly distinguishes T cells from fibroblasts. In contrast, another MAP kinase homologue c-Jun N-terminal kinase (JNK) was inhibited by cAMP in good correlation with that of IL-2 suppression. Moreover, JNK was antagonized by a delayed kinetics which is characteristic of cAMP inhibition. Despite that both ERK and JNK are essential for T cell activation, selective inhibition by cAMP further supports the specific role of JNK in T cell activation.
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PMID:c-Jun N-terminal kinase but not mitogen-activated protein kinase is sensitive to cAMP inhibition in T lymphocytes. 762 20

One Ras-dependent protein kinase cascade leading from growth factor receptors to the ERK (extracellular signal-regulated kinases) subgroup of mitogen-activated protein kinases (MAPKs) is dependent on the protein kinase Raf-1, which activates the MEK (MAPK or ERK kinase) dual specificity kinases. A second protein kinase cascade leading to activation of the Jun kinases (JNKs) is dependent on MEKK (MEK kinase). A dual-specificity kinase that activates JNK, named JNKK, was identified that functions between MEKK and JNK. JNKK activated the JNKs but did not activate the ERKs and was unresponsive to Raf-1 in transfected HeLa cells. JNKK also activated another MAPK, p38 (Mpk2; the mammalian homolog of HOG1 from yeast), whose activity is regulated similarly to that of the JNKs.
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PMID:Identification of a dual specificity kinase that activates the Jun kinases and p38-Mpk2. 771 21

Raf-1 is a serine/threonine protein kinase positioned downstream of Ras in the mitogen-activated protein kinase cascade. Using a yeast two-hybrid strategy to identify other proteins that interact with and potentially regulate Raf-1, we isolated a clone encoding the carboxyl-terminal half of the G beta 2 subunit of heterotrimeric G-proteins. In vitro, purified G beta gamma subunits specifically bound to a GST fusion protein encoding amino acids 1-330 of Raf-1 (Raf/330). Binding assays with truncation mutants of GST-Raf indicate that the region located between amino acids 136 and 239 is a primary determinant for interaction with G beta gamma. In competition experiments, the carboxyl terminus of beta-adrenergic receptor kinase (beta ARK) blocked the binding of G beta gamma to Raf/330; however, the Raf-1-binding proteins, Ras and 14-3-3, had no effect. Scatchard analysis of in vitro binding between Raf/330 and G beta gamma revealed an affinity of interaction (Kd = 163 +/- 36 nM), similar to that seen between G beta gamma and beta ARK (Kd = 87 +/- 24 nM). The formation of native heterotrimeric G alpha beta gamma complexes, as measured by pertussis toxin ADP-ribosylation of G alpha, could be disrupted by increasing amounts of Raf/330, with an EC50 of approximately 200 nM, in close agreement with the estimated binding affinity. In vivo complexes of Raf-1 and G beta gamma were isolated from human embryonic kidney 293-T cells transfected with epitope-tagged G beta 2. The identification and characterization of this novel interaction raises several possibilities for signaling cross-talk between growth factor receptors and those receptors coupled to heterotrimeric G-proteins.
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PMID:A direct interaction between G-protein beta gamma subunits and the Raf-1 protein kinase. 778 77


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