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)

Bradykinin activates adenylate cyclase via a pathway that involves the 'up-stream' regulation of phospholipase D (PLD)-catalysed hydrolysis of phosphatidylcholine and activation of protein kinase C (PKC) in airway smooth muscle [Stevens, Pyne, Grady and Pyne (1994) Biochem. J. 297, 233-239]. Coincident signal (Gs alpha and PKC) amplification of the cyclic AMP response can be completely attenuated either by diverting PLD-derived phosphatidate or by inhibiting PKC. In this regard, the coincident signal detector type II adenylate cyclase is expressed as a 110/112 kDa polypeptide in these cells. PKC alpha is not involved in the activation of adenylate cyclase, since a B2-receptor antagonist (NPC567, 10 microM) blocked its bradykinin-stimulated translocation to the membrane and was without effect against both bradykinin-stimulated PLD activity and cyclic AMP formation. Cyclic AMP formation can also be activated by platelet-derived growth factor (PDGF), via a PKC-dependent pathway, although the magnitude of the response is less than that elicited by bradykinin. Nevertheless, these results indicate that multiple receptor types employ PKC to initiate cyclic AMP signals. PDGF (10 ng/ml) elicited the marked sustained activation of extracellular-signal-regulated kinase-2 (ERK-2), whereas bradykinin (1 microM) provoked only modest transient activation of ERK-2. Deoxyadenosine (0.1 mM), a P-site inhibitor of adenylate cyclase, blocked bradykinin-stimulated cyclic AMP formation and converted the activation of ERK-2 into a sustained response. Thus the PKC-stimulated cyclic AMP response can limit the activation of ERK-2 in response to bradykinin. These studies indicate that the integration of distinct signal pathways by adenylate cyclase can determine the kinetics of ERK activation, an enzyme that appears to be important for mitogenic progression.
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PMID:Protein kinase C-dependent cyclic AMP formation in airway smooth muscle: the role of type II adenylate cyclase and the blockade of extracellular-signal-regulated kinase-2 (ERK-2) activation. 799 98

Stable clones of NIH 3T3 fibroblasts transfected with the cDNA of either the wild-type or deletion forms of the rat type I (or cerebellar) inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) were investigated. The delta form, missing the NH2-terminal sequence that includes the IP3-binding site, is expected to be still assembled with wild-type subunits to yield a tetrameric Ca2+ channel across the endoplasmic reticulum membrane; the s form, missing the membrane-spanning sequences, is expected to remain as a soluble monomer in the cytosol. With respect to control clones transfected with the vector only, the synthesis fo IP3Rs was markedly stimulated in the receptor-transfected clones. The mass accumulation, however, was increased only moderately (deletion forms = 15-30% of the endogenous IP3R), apparently because of a compensatory increase in receptor turnover. Coordinate changes in IP3 generation and Ca2+ release were revealed in the delta clones by experiments in both intact and permeabilized cells. In these clones, the IP3R was more sensitive to IP3, and IP3 generation at the ATP P2u surface receptor was decreased. This latter effect was due neither to a defect in G protein coupling nor to changes in phospholipase C expression, but to down-regulation of the P2u receptor. In the cells expressing the s- and delta-IP3R subunits, no differences with respect to the controls were observed in epidermal growth factor-induced DNA synthesis, whereas long-term growth stimulated by serum was reduced. Even more marked, especially in the delta clones (-90%), was the inhibition of cell transformation induced by autocrine stimulation with transforming growth factor alpha of the overexpressed epidermal growth factor receptors or by other growth factor receptors and oncogenes (platelet-derived growth factor/platelet-derived growth factor receptor beta, HER2/neu, and v-erbB). These effects appear not to be connected to the signaling processes mediated by tyrosine phosphorylation since the latter was unchanged in the delta clones. These results demonstrate for the first time (a) that the changes in cellular homeostasis directly induced by deleted IP3R subunits (increased receptor synthesis and increased IP3R sensitivity) are largely compensated by indirect coordinate changes apparently aimed to keep near normal the signaling properties of the cells; (b) that modulation of intracellular Ca2+ channels induces profound consequences that differentially affect growth and oncogenesis; and (c) that IP3Rs and the Ca2+ stores are important cross-roads of intracellular signaling pathways.
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PMID:Stable expression of truncated inositol 1,4,5-trisphosphate receptor subunits in 3T3 fibroblasts. Coordinate signaling changes and differential suppression of cell growth and transformation. 803 82

Permeabilized rat kidney cells rapidly released glucose 6-phosphate dehydrogenase (G6PD) following stimulation with peptide growth factors (Stanton, R.C., Seifter, J.L., Boxer, D.C., Zimmerman, E., and Cantley, L. C. (1991) J. Biol. Chem. 266, 12442-12448). To evaluate the signal transduction pathways mediating release of G6PD, two cell lines transfected with wild type or mutant platelet-derived growth factor (PDGF) receptors (PDGFR) were studied using two permeabilization protocols. G6PD release was evaluated by enzyme activity and Western blot analysis. PDGF caused a significant increase in G6PD release in 1 min in cells transfected with wild type PDGFR. PDGF did not stimulate G6PD release in cells transfected with tyrosine kinase-deficient PDGFR. PDGF did not stimulate G6PD release in cells transfected with partially autophosphorylation-deficient PDGFR in which four known signaling proteins do not associate with the PDGFR. The PDGF-stimulated release of G6PD was partially restored in PDGFR mutants in which either phosphatidylinositol-3-kinase or phospholipase C gamma 1 could associate with the PDGFR. Lastly, there was no basal or PDGF-stimulated phosphorylation of G6PD. We conclude that release of G6PD: 1) requires intrinsic PDGFR tyrosine kinase activity; 2) requires PDGFR autophosphorylation; 3) is mediated by signaling proteins that associate with the PDGFR; 4) is not mediated by direct phosphorylation of G6PD.
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PMID:Signal transduction proteins that associate with the platelet-derived growth factor (PDGF) receptor mediate the PDGF-induced release of glucose-6-phosphate dehydrogenase from permeabilized cells. 818 86

The murine phosphotyrosine phosphatase, Syp, is a widely-expressed cytoplasmic enzyme that contains two SH2 domains. Syp is physically associated with activated receptors for epidermal growth factor (EGF) and platelet-derived growth factor (PDGF), apparently through its SH2 domains. This phosphatase is rapidly phosphorylated in cells treated with PDGF or EGF, and is constitutively phosphorylated in v-src transformed cells. Here we report that either the N-terminal or C-terminal Syp SH2 domain alone bound to the activated beta PDGF receptor or EGF-receptor in vitro, and that the two SH2 domains linked together exhibited synergistic binding. Substitution of the Tyr1009 autophosphorylation site in the C-terminal tail of activated beta PDGFR with Phe abolished the in vitro binding of either SH2 domain to the activated receptor. A 9 amino acid phosphopeptide corresponding to the Tyr1009 autophosphorylation site of the beta PDGFR inhibited association of the Syp SH2 domains with the receptor. These results indicate that the Syp SH2 domains have an intrinsic specificity for the Tyr1009 autophosphorylation site of the beta PDGFR that dictates binding of the intact Syp phosphatase, and suggest that both SH2 domains have a related binding specificity. Phosphoamino acid analysis of Syp from PDGF-stimulated cells indicated that PDGF primarily induces Syp phosphorylation on tyrosine residues. The mouse Syp gene has been mapped to chromosome 5F region by the fluorescence in situ hybridization. These findings suggest specific functions for Syp in signal transduction downstream of receptor tyrosine kinases.
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PMID:Receptor-binding, tyrosine phosphorylation and chromosome localization of the mouse SH2-containing phosphotyrosine phosphatase Syp. 818 48

Human platelets contain platelet-derived growth factor (PDGF) in their alpha-granules which is released during platelet exocytosis. We show by immunoprecipitation and 125I-PDGF binding experiments that human platelets have functionally active PDGF alpha-receptors, but not beta-receptors. The PDGF alpha-receptor (PDGFR-alpha) was identified as a 170-kDa glycosylated protein-tyrosine kinase as found in other cell types. Stimulation of platelets with 0.1 unit/ml thrombin resulted in a significant increase (2-5-fold) of the tyrosine phosphorylation of the PDGFR-alpha, as determined by immunoprecipitation with phosphotyrosine antiserum as well as with PDGFR-alpha antiserum. The observed thrombin-induced autophosphorylation of the PDGFR-alpha was inhibited by the addition of a neutralizing monoclonal PDGF antibody. Thus, our results suggest that the platelet PDGFR-alpha is stimulated in an autocrine manner by PDGF secreted during platelet activation. Preincubation of platelets with PDGF inhibited thrombin-induced platelet aggregation and secretion of ATP + ADP and beta-hexosaminidase. Thrombin-induced platelet aggregation was also reversed when PDGF was added 30 s after thrombin stimulation. Inhibition of the autocrine PDGF pathway during platelet activation by the PDGF antibody led to a potentiation of thrombin-induced beta-hexosaminidase secretion. Thus, the PDGFR-alpha takes part in a negative feedback regulation during platelet activation. Our demonstration of PDGF alpha-receptors on human platelets and its inhibitory function during platelet activation identifies a new possible role of PDGF in the regulation of thrombosis.
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PMID:Negative feedback regulation of human platelets via autocrine activation of the platelet-derived growth factor alpha-receptor. 818 64

Mitogenic stimulation of connective tissue cells by transforming growth factor-beta (TGF-beta) has two unusual properties; entry into S-phase is delayed compared with that induced by other mitogens, and the dose response is biphasic, with low concentrations stimulating and high concentrations inhibiting or having no effect. A hypothesis that provides an explanation for both of these properties is that TGF-beta stimulates proliferation indirectly by inducing synthesis of platelet-derived growth factor (PDGF) A-chain, which in turn stimulates proliferation via autocrine activation of the PDGF receptor alpha-subunit (PDGFR alpha). High concentrations of TGF-beta reduce PDGFR alpha expression and break the autocrine loop. We tested this hypothesis by determining whether TGF-beta and interleukin-1 alpha can induce DNA synthesis in connective tissue (3T3) cells derived from the Patch mouse line in which the PDGFR alpha gene is deleted. We found that these cells do respond mitogenically to TGF-beta and interleukin-1 alpha, indicating that PDGF A-chain induction is not the sole mechanism of mitogenic stimulation. Reestablishing PDGFR alpha expression via transfection with a human PDGFR alpha construct enhanced the response to TGF-beta. Neutralizing anti-PDGF antiserum reduced TGF-beta stimulation of PDGFR alpha-expressing 3T3 cells by about 35%. We conclude that induction of PDGF A-chain/PDGFR alpha autocrine stimulation does contribute to the ability of TGF-beta to stimulate connective tissue cells, but that there is, in addition, a PDGF-independent pathway.
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PMID:Platelet-derived growth factor (PDGF) receptor alpha-subunit mutant and reconstituted cell lines demonstrate that transforming growth factor-beta can be mitogenic through PDGF A-chain-dependent and -independent pathways. 818 75

The 44-amino-acid E5 protein of bovine papillomavirus type 1 is a highly hydrophobic protein which appears to transform cells through the activation of growth factor receptors. To investigate the specificity of E5-growth factor receptor interactions required for mitogenic signaling, we utilized a nontumorigenic, murine myeloid cell line (32D) which is strictly dependent on interleukin-3 (IL-3) for sustained proliferation in culture. This IL-3 dependence can be functionally substituted by the expression of a variety of surrogate growth factor receptors and the addition of the corresponding ligand. Several receptor cDNAs for the alpha- and beta-type platelet-derived growth factor receptors [alpha PDGFR and beta PDGFR], the epidermal growth factor receptor, and the colony-stimulating factor 1 receptor) were transfected into 32D cells constitutively expressing the E5 protein to test for IL-3-independent growth. Only beta PDGFR was capable of abrogating the IL-3 dependence of 32D cells. The proliferative signal induced by the coexpression of beta PDGFR and E5 was accompanied by stable complex formation between these proteins, constitutive tyrosine phosphorylation of the receptor, and tumorigenicity in nude mice. The lack of cooperative interaction between E5 and the epidermal growth factor receptor, the colony-stimulating factor 1 receptor, and the highly related alpha PDGFR was paralleled by the inability of E5 to bind to these receptors and failure to increase receptor tyrosine phosphorylation. Thus, these data indicate that the ability of E5 to induce sustained proliferation and transformation of 32D cells is a direct consequence of specific interaction between the E5 protein and the beta PDGFR signaling complex and the subsequent stimulation of receptor tyrosine phosphorylation.
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PMID:The bovine papillomavirus type 1 E5 transforming protein specifically binds and activates the beta-type receptor for the platelet-derived growth factor but not other related tyrosine kinase-containing receptors to induce cellular transformation. 820 16

The expression of platelet-derived growth factor- beta (PDGF-beta) receptors in the microvasculature of human healing wounds and colorectal adenocarcinoma was investigated. Frozen sections were subjected to double immunofluorescence staining using monoclonal antibodies (MAbs) specific for pericytes (MAb 225.28 recognizing the high-molecular weight-melanoma-associated antigen, expressed by activated pericytes during angiogenesis), endothelial cells (MAb PAL-E), laminin, as well as PDGF-beta receptors (MAb PDGFR-B2) and its ligand PDGF-B chain (MAb PDGF 007). Stained sections were analyzed by computer-aided imaging processing that allowed for a numerical quantification of the degree of colocalization of the investigated antigens. An apparent background colocalization, varying between 23 and 35%, between markers for cells not expected to co-localize was recorded. This background could be due to limitations of camera resolution, to out-of-focus fluorescence, and to interdigitations of the investigated structures. In all six tumor specimens, co-localization of PDGF-beta receptors and PAL-E was not different from the background co-localization, whereas that of PDGF-beta receptors and high-molecular weight-melanoma-associated antigen was significantly higher with mean values between 57 and 71%. Qualitatively, the same pattern was obtained in the two investigated healing wounds. PDGF-B chain did not co-localize with either PAL-E or high-molecular weight-melanoma-associated antigen, but PDGF-B chain-expressing cells were, however, frequently found juxtaposed to the microvasculature. The expression of PDGF-beta receptors on pericytes in activated microvessels and the presence of PDGF-B chain-expressing cells in close proximity to the microvasculature of healing wounds and colorectal adenocarcinoma is compatible with a role for PDGF in the physiology of the microvasculature in these conditions.
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PMID:Microvascular pericytes express platelet-derived growth factor-beta receptors in human healing wounds and colorectal adenocarcinoma. 823 54

The Src homology (SH) region 2 binds to phosphorylated tyrosine residues and SH3 domains may interact with cytoskeletal molecules and GTPase-activating proteins for Rho/Rac proteins (the small GTP-binding proteins related to Ras). The recently cloned Ash/Grb-2 protein, a 25-28 kDa molecule composed entirely of SH2 and SH3 domains, is a mammalian homolog of the Caenorhabditis elegans Sem-5 protein, which communicates between a receptor protein tyrosine kinase and a Ras protein. In the present study the function of Ash/Grb-2 was investigated by microinjecting cells with an anti-Ash antibody. The antibody abolished both S phase entry and the reorganization of actin assembly to ruffle formation upon stimulation with epidermal growth factor (EGF) and platelet-derived growth factor (PDGF). On the other hand, anti-Ash antibody had no effect on S phase entry or actin stress fiber formation induced by either serum or lysophosphatidic acid. Since the induction of DNA synthesis, ruffle induction and stress fiber formation involve a function of Ras, Rac activation and Rho activation respectively, the findings strongly suggest that Ash plays a critical role in the signaling of both pathways downstream from growth factor receptors to Ras and Rac. Consistent with this, Ash co-precipitated with EGF receptor from EGF-stimulated cells. Other proteins of approximately 21, 29, 135 and 160 kDa were also detected in the anti-Ash antibody immunoprecipitates, suggesting a role of Ash as a linker molecule in signal transduction downstream of growth factor receptors.
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PMID:Ash/Grb-2, a SH2/SH3-containing protein, couples to signaling for mitogenesis and cytoskeletal reorganization by EGF and PDGF. 825 73

The expression of platelet-derived growth factor (PDGF), PDGF-alpha receptor (PDGFR alpha) and PDGF-beta receptor (PDGFR beta) was studied in normal ovaries and ovarian neoplasms by immunohistochemical analysis. PDGF was detected in tumor cells in 33 of 45 malignant tumor samples but in none of 20 benign tumors (P < 0.001) or 11 normal ovaries (P < 0.001). In borderline tumors, 4 of 7 tissues stained positive in tumor cells. PDGFR alpha was detected in tumor cells in 16 of 45 malignant tumors, while no epithelial staining was found in 16 benign tumors (P = 0.002) or in 10 normal ovaries (P = 0.023). In 1 of 7 borderline neoplasms, tumor cells expressed PDGFR alpha. Neither normal epithelium nor tumor cells stained positive with antibodies against PDGFR beta. Patients with ovarian cancer and PDGFR alpha-positive tumor cells demonstrated an overall shorter survival compared to those who had negatively stained tumors (P < 0.005). A similar correlation was found in patients having stage III ovarian cancer (P < 0.01), which further supports an independent role for PDGFR alpha as a prognostic factor. Thus, the concomitant expression of PDGF and PDGFR alpha in tumor cells is related to progression of malignant ovarian tumors, indicating a functional role of PDGF via autocrine growth stimulation.
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PMID:Expression and prognostic significance of platelet-derived growth factor and its receptors in epithelial ovarian neoplasms. 840 26


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