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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Overexpression and amplification of the erbB-2 (neu) is thought to play a major role in mammary cancer. Although studies suggest that Neu is directly involved in the genesis of mammary tumors, the molecular mechanism by which Neu induces tumors is not well understood. Recently, we have demonstrated that the activity of c-Src tyrosine kinase is elevated in Neu-induced mammary tumors and this elevated activity correlates with its capacity to physically associate with Neu. To explore whether other members of the c-Src family are activated in these mammary tumors, we measured the in vitro kinase activity of the c-Yes and Fyn kinases in protein extracts derived from mammary tumor tissue and morphological normal adjacent tissue. These analyses revealed that c-Yes kinase activity was elevated in Neu-induced tumors by comparison to the adjacent tissue. By contrast, no significant activation of the Fyn kinase was noted in these tumors. Activation of c-Yes tyrosine kinase correlated with the capacity of c-Yes to associate with Neu in vivo in lysates derived from primary tumor samples. Studies with Rat.2 fibroblasts overexpressing activated Neu revealed that c-Src requires the presence of tyrosine phosphorylated Neu for its ability to interact with Neu in vivo. Moreover, analyses using radiolabeled c-Yes SH2 fusion protein revealed that this interaction is likely occurring in a direct fashion. Although both c-Src and c-Yes kinase associate with Neu in vivo, a tyrosine phosphorylated protein of 89 kd (p89) was found associated with c-Src but not with c-Yes in cell lysates derived from mammary epithelial cells transformed by either Neu or PyV middle T antigen. Furthermore, this tyrosine phosphorylated protein was not detected in c-Src complexes derived from fibroblasts transformed by either Neu or PyV middle T. These observations suggest that p89 associates with c-Src only in mammary epithelial cells and not in fibroblasts.
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PMID:Activation of Src family kinases in Neu-induced mammary tumors correlates with their association with distinct sets of tyrosine phosphorylated proteins in vivo. 747 8

Sodium butyrate (SB), a naturally occurring short-chain fatty acid, was investigated for its therapeutic value as an antiproliferative agent for vascular smooth muscle cells (SMCs). At 5-mmol/L concentration, SB had no significant effect on rat SMC proliferation. However, at the same concentration, SB inhibited platelet-derived growth factor (PDGF)-AA-, -AB-, and -BB-induced proliferation of SMCs. Exposure of SMCs to PDGF-BB resulted in activation of receptor intrinsic tyrosine kinase activity and autophosphorylation of beta-PDGF-receptor (beta-PDGFR). The activated beta-PDGFR physically associated and phosphorylated signaling molecules such as ras-GTPase activating protein (GAP) and phospholipase C gamma (PLC gamma). SB, in the absence of PDGF-BB, caused neither beta-PDGFR tyrosine phosphorylation nor phosphorylation and association of GAP and PLC gamma with beta-PDGFR. PDGF-BB-enhanced activation of receptor intrinsic tyrosine kinase activity and autophosphorylation of tyrosine residues of beta-PDGFR were unaffected by SB irrespective of whether SMCs were preincubated with SB before exposure to PDGF-BB plus SB or incubated concomitantly with PDGF-BB plus SB. Likewise, phosphorylation and association of GAP and PLC gamma with PDGF-BB-activated beta-PDGFR were unaffected. In addition, SB did not block PDGF-BB-stimulated, PLC gamma-mediated production of inositol triphosphate. Similarly, PDGF-BB-induced beta-PDGFR degradation was unaffected when SMCs were exposed to PDGF-BB plus SB, and SB by itself had no influence on beta-PDGFR degradation. Unlike beta-PDGFR kinase activity, mitogen-activated protein kinase (MAP-kinase) activity was stimulated by SB by about 2.7-fold. Exposure of SMCs to PDGF-BB caused an approximately 11.4-fold increase in MAP-kinase activity and this increase in activity was not significantly affected when cells were coincubated with PDGF-BB and SB (10.3-fold). However, pretreatment of SMCs with SB for 30 minutes and subsequent incubation in PDGF-BB plus SB abolished most of the PDGF-BB-induced MAP-kinase activity (4.6-fold). Transcription of growth response genes such as c-fos, c-jun, and c-myc were induced by PDGF-BB, and their induction was suppressed, particularly c-myc, by incubating SMCs with PDGF-BB plus SB. Similarly, preincubation of cells with SB for 30 minutes and subsequent incubation in PDGF-BB plus SB diminished PDGF-BB-induced transcription of c-fos, c-jun, and c-myc. However, SB by itself had no significant effect on c-fos, c-jun, and c-myc transcription.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Sodium butyrate inhibits platelet-derived growth factor-induced proliferation of vascular smooth muscle cells. 748 53

Adipocytic-cytosolic non-receptor protein tyrosine kinase (CytPTK) when activated can substitute for the insulin receptor tyrosine kinase (InsRTK), in manifesting several insulin effects in insulin-receptor independent fashion. Our aims here were to utilize PolyGlu4Tyr, a good experimental exogenous substrate for protein tyrosine kinases (PTKs) in general, for studying qualitative and quantitative parameters of CytPTKs extracted from different tissue cytosols. At the same time, we would search for a unique specific marker specifically characterizing CytPTKs. High speed supernatants of spleen, thymus, smooth muscle, lung and kidney were found to be rich in CytPTK activities. Their specific activities being 6- to 13-fold that of liver or adipose cytosols. Brain, testis and adrenal cytosols were an intermediate source of CytPTK activity, whereas CytPTK activity of heart and skeletal muscle was low. It was also evaluated that the capacity of the cytosol to phosphorylate PolyGlu4Tyr is 15-50% that of the non-stimulated Triton X-100 extractable plasma membrane PTKs. Fractionation of the cytosols on superose 12 column revealed several CytPTKs within the same tissue, their peaks ranging between 30 and 450 kDa. Immunoblotting analysis showed Fyn and Lyn were present in most tissue cytosols. Upon immunoprecipitation, however, with anti-Fyn or anti-Lyn, negligible amounts (< 2%) of the total cellular CytPTK were precipitated. Thus, these general markers of CytPTKs comprise only a minor proportion of the total intracellular PolyGlu4Tyr phosphorylating capacity. To see whether a specific marker for CytPTK could be detected, we also examined the requirement of CytPTKs for divalent ions, their preferred phosphate donor and their sensitivity to inhibition by known PTK inhibitors. We found that the order of reactivity with divalent cations was Co2+ > Mn2+ > Mg2+, while Zn2+ and Ca2+ did not support CytPTK activity. The best phosphate donor was ATP (ED50 = 5 microM), but other nucleoside 3-phosphates could substitute for ATP at high concentrations. With respect to these parameters, no basic difference exists between cytosolic and plasma-membrane PTKs. The PTK inhibitors, genestein and quercetin, inhibited both cytosolic and membranal PTKs at micromolar concentrations. In contrast, staurosporine was a potent inhibitor of CytPTKs (IC50 5-20 nM) and a poor inhibitor of membranal PTKs (IC50 10-40 microM). One of the conclusions we can draw from this study is that tissue cytosols contain PolyGlu4Tyr phosphorylating capacity in quantities greater than previously assumed and that the low level of phosphotyrosine found in cells is not the result of limited intracellular levels of CytPTKs.
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PMID:Non-receptor cytosolic protein tyrosine kinases from various rat tissues. 749 84

Hepatocyte growth factor receptor is identified as a heterodimeric tyrosine kinase encoded by the c-met gene. This study was designed to determine how the c-met/hepatocyte growth factor receptor participates in the intracellular events involved in rat liver regeneration induced by administration of carbon tetrachloride. Expression of the rat c-met mRNA increased, peaking 24 h after carbon tetrachloride administration almost in parallel with MET protein expression. Histochemical studies demonstrated that expression of the rat c-met was enhanced in cells surrounding the damaged areas, and also that the distribution of cells expressing MET was almost in accordance with that of cells expressing proliferating cells nuclear antigen. The MET protein underwent intense tyrosine phosphorylation peaking at 12 h after carbon tetrachloride administration, and prior to DNA synthesis. Phospholipase C gamma and phosphatidylinositol 3-kinase, intracellular signal transducing molecules containing Src homology 2 domain, were associated with the MET protein following tyrosine phosphorylation in vivo. These observations suggest that expression and tyrosine phosphorylation of MET protein associated with signal transducing molecules may provide a mechanism whereby hepatocyte growth factor exerts its action on hepatocyte growth during rat liver regeneration induced by carbon tetrachloride administration.
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PMID:Expression and phosphorylation of rat c-met/hepatocyte growth factor receptor during rat liver regeneration. 749 89

Receptor-type tyrosine kinases (RTKs) constitute a family of proteins involved in growth and developmental processes. Class III RTKs are characterized by an extracellular region composed of five immunoglobulin-like domains and by a split tyrosine kinase domain. Some of the class III RTKs perform major functions in hematopoiesis and are the focus of this review. They are the colony-stimulating factor-1 (CSF1) and Steel factor (SLF) receptors, encoded by the FMS and KIT protooncogenes, respectively, and the product of the FLT3/FLK2 gene. The structural, biochemical, functional, and pathological features of these three receptors and genes are reviewed.
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PMID:Hematopoietic receptors of class III receptor-type tyrosine kinases. 750 35

We have shown that members of the erbB family undergo homodimer and heterodimer formation. The rat p185c-neu and the epidermal growth factor receptor (EGFR) can associate into an active heterodimeric tyrosine kinase. Overexpression of these two receptors also results in a transformed phenotype. We now show that mutant Neu proteins resulting from a point mutation at the ATP-binding site (N757) or cytoplasmic domain deletions (N691stop) are still able to undergo EGF-induced heterodimerization with EGFR. Analysis of heterodimer formation between EGFR and truncated Neu proteins revealed that heterodimerization is preferred over homodimerization of EGFR. N757 can be transphosphorylated by associated EGFR upon EGF stimulation. However, the heterodimer composed of EGFR and N691stop is kinase inactive. These results provided evidence that the Neu ectodomain is sufficient to associate with EGFR physically, and the cytoplasmic domain interaction is required for heterodimeric kinase activation, indicating that Neu/c-erbB2 is not just a simple substrate for EGFR but a transactivator as well.
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PMID:Heterodimerization of epidermal growth factor receptor and wild-type or kinase-deficient Neu: a mechanism of interreceptor kinase activation and transphosphorylation. 750 75

Fibroblast growth factors (FGF) regulate the growth and differentiation of cells through complex combinatorial signaling pathways. There are nine ligands that interact with a family of four tyrosine kinase FGF receptors (FGFR). Diversity in FGF signaling is determined in part by the affinity of specific ligand-receptor pairs. Alternative splicing in the FGFR ligand binding domain generates additional receptor isoforms with novel ligand affinities. For example, splicing events in the ligand binding domain of FGFR2 dramatically increases its affinity for keratinocyte growth factor (KGF/FGF-7). We have identified an alternatively spliced form of the FGFR3 mRNA, corresponding to known splice variants of FGFRs 1 and 2. We demonstrate both by binding studies on genetically engineered soluble receptors and by the mitogenic response of growth factor-dependent cell lines that this splice variant of FGFR3 (FGFR3 IIIb), by binding only acidic FGF (aFGF/FGF-1), has the most restricted ligand binding properties of any FGFR thus far described. Furthermore, by constructing a chimeric receptor that contains the homologous exon from FGFR2, we demonstrate that this single domain from FGFR2 is sufficient to confer upon FGFR3 the ability to bind KGF/FGF-7. The uniquely limited repertoire of ligands that interact with this receptor suggests that a novel ligand for FGFR3 IIIb exists.
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PMID:Fibroblast growth factor receptor (FGFR) 3. Alternative splicing in immunoglobulin-like domain III creates a receptor highly specific for acidic FGF/FGF-1. 751 69

Signaling through the B cell antigen receptor (BCR) results in rapid increases in tyrosine phosphorylation on a number of proteins. The BCR associates with two classes of tyrosine kinase: Src-family kinase (Src-protein-tyrosine kinase [PTK]; Lyn, Fyn, Blk, or Lck) and Syk kinase. We have investigated the interaction between the Src-PTK and the Syk kinase in the BCR signaling. In contrast to wild-type B cells, BCR-mediated tyrosine phosphorylation of Syk and activation of its in vitro kinase activity were profoundly reduced in lyn-negative cells. The requirement of the Src-PTK to induce tyrosine phosphorylation and activation of Syk was also demonstrated by cotransfection of syk and src-PTK cDNAs into COS cells. These results suggest that the Src-PTK associated with BCR phosphorylates the tyrosine residue(s) of Syk upon receptor stimulation, enhancing the activity of Syk.
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PMID:Syk activation by the Src-family tyrosine kinase in the B cell receptor signaling. 751 17

The expression of Cek5, a receptor-type tyrosine kinase of the Eph subclass, and its variant form Cek5+ were examined in the chick neural retina during development. Cek5 is present at high levels at all stages of retinal development examined, while Cek5+ is most abundant during differentiation. Cek5 mRNA expression and immunoreactivity are evenly distributed in the undifferentiated retina. With differentiation, Cek5 becomes concentrated in the inner and outer plexiform layers. While only moderate changes in Cek5 protein expression are observed throughout retinal development, Cek5 phosphorylation on tyrosine in vivo is dramatically increased during differentiation. This suggests that the Cek5 ligand is expressed at high levels and causes Cek5 activation. Thus, Cek5 is likely to play an active role in retinal morphogenesis, particularly during the establishment of interneuronal contacts.
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PMID:Cek5, a tyrosine kinase of the Eph subclass, is activated during neural retina differentiation. 751 63

Activation of the RET protooncogene tyrosine kinase (tk) by fusion with other genes is a frequent finding in papillary thyroid carcinoma. The tk domain of proto-RET can be fused either with the D10S170 gene generating the RET/PTC1 transforming sequence or with sequences belonging to the gene encoding the regulatory subunit RIA of c-AMP-dependent protein kinase A, thus forming the RET/PTC2 oncogene. We have previously shown that an inversion of chromosome 10, inv(10)(q11.2q21), is responsible for the generation of the RET/PTC1. Here we report that a chromosomal translocation, t(10;17)(q11.2;q23), juxta-poses the tk domain of the RET protooncogene, which resides on chromosome 10, to a 5' portion of the RIA gene on chromosome 17, leading to the formation of the chimeric transforming gene RET/PTC2. The finding of the transforming protein in primary tumor cell extracts supports the conclusion that RET/PTC2 activation plays a role in papillary thyroid tumorigenesis.
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PMID:A t(10;17) translocation creates the RET/PTC2 chimeric transforming sequence in papillary thyroid carcinoma. 751 46


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