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)

The murine myeloid progenitor cell line 32D was recently shown to undergo monocytic differentiation when protein kinase C-delta (PKC-delta) was overexpressed and activated by 12-O-tetradecanoylphorbol-13-acetate (TPA) (H. Mischak, J.H. Pierce, J. Goodnight, M.G. Kazanietz, P.M. Blumberg, and J.F. Mushinski, J. Biol. Chem. 268:20110-20115, 1993). Tyrosine phosphorylation of PKC-delta occurred when PKC-delta-transfected 32D cells were stimulated by TPA (W. Li, H. Mischak, J.-C. Yu, L.-M. Wang, J.F. Mushinski, M.A. Heidaran, and J.H. Pierce, J. Biol. Chem. 269:2349-2352, 1994). In order to elucidate the role played by PKC-delta in response to activation of a receptor tyrosine kinase, we transfected platelet-derived growth factor beta receptor (PDGF-beta R) alone (32D/PDGF-beta R) or together with PKC-delta (32D/PDGF-beta R/PKC-delta) into 32D cells. NIH 3T3 cells which endogenously express both PDGF-alpha R and PDGF-beta R were also transfected with PKC-delta (NIH 3T3/PKC-delta). Like TPA treatment, PDGF-BB stimulation caused striking phosphorylation of PKC-delta in vivo and translocation of some PKC-delta from the cytosol fraction to the membrane fraction in both cell systems. Some of the phosphorylation induced by PDGF-BB treatment was found to be on a tyrosine residue(s). Tyrosine-phosphorylated PKC-delta was observed only for the membrane fraction after stimulation with PDGF-BB or TPA. The enzymatic activity of PKC-delta in the membrane fraction also increased after stimulation with TPA or PDGF, providing a positive correlation between PKC-delta tyrosine phosphorylation and its activation. Overnight treatment of 32D/PDGF-beta R/PKC-delta cells with PDGF-BB induced monocytic differentiation as judged by an increase in expression of cell surface macrophage differentiation markers. PDGF-BB had much weaker effects on 32D/PDGF-beta R cell differentiation, suggesting that increased PKC-delta expression enhanced monocytic differentiation. These results indicate that PKC-delta is a downstream molecule in the PDGFR signaling pathway and may play a pivotal role in PDGF-beta R-mediated cell differentiation.
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PMID:Stimulation of the platelet-derived growth factor beta receptor signaling pathway activates protein kinase C-delta. 793 92

To determine the capability of alpha PDGFR to couple with chemotactic signaling, we established 32D cells expressing wild type alpha PDGFR (alpha RWT), a kinase-defective mutant of alpha PDGFR (alpha R627R), or wild type beta PDGFR (beta RWT). Using a modified Boyden chamber, we showed that PDGF induced significant cell migration of 32D cells expressing alpha RWT or beta RWT, but not of those expressing alpha R627R. Furthermore, the cell migration was largely reduced in each case when the same concentration of PDGF was present in both chambers, suggesting that cell migration observed in 32D expressing alpha RWT is mainly due to alpha PDGFR-mediated chemotaxis. Consistent with these results, PDGF-AA induced significant cell migration of NIH3T3 fibroblasts, which was markedly blocked by the presence of excess neutralizing polyclonal antibody to PDGF-AA. These results provide evidence that alpha PDGFR kinase activity is essential for mediating ligand-induced chemotactic and chemokinetic responses in two different cell types.
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PMID:The alpha PDGFR tyrosine kinase mediates locomotion of two different cell types through chemotaxis and chemokinesis. 798 May 24

A series of 63 3-substituted quinoline derivatives has been prepared and tested for inhibition of cell-free platelet derived growth factor receptor tyrosine kinase (PDGF-RTK) activity. The compounds were generally prepared either by a Friedlander condensation between an aryl-acetaldehyde and an o-aminobenzaldehyde or by a palladium-catalyzed coupling between an aryl bromide or triflate and an organostannane or organozinc chloride. The presence of 6,7-dimethoxy groups on the quinoline ring was found to be advantageous although not essential for potent inhibition of PDGF-RTK. A lipophilic group attached to the quinoline 3-position contributed substantially to activity. The lipophilic groups generally consisted of monocyclic aromatics or small alkynyl, alkenyl, and alkyl groups. Optimum activity of ca. < or = 20 nM (IC50) was observed when 6,7-dimethoxyquinoline was substituted in the 3-position with 4-methoxyphenyl (15d), 3-fluoro-4-methoxyphenyl (17m), 3-fluorophenyl (17b), 4-hydroxyphenyl (24), 6-methoxypyridin-3-yl (15o), 5-pyridin-2(1H)-one (23), trans-beta-styryl (15e), thiophene-3-yl (2e), 5-chlorothiophene-2-yl (15f), or cyclopentenyl (17n) groups. Most of the compounds in the series were tested for inhibition of cell-free epidermal growth factor receptor tyrosine kinase activity and found to be inactive.
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PMID:A new series of PDGF receptor tyrosine kinase inhibitors: 3-substituted quinoline derivatives. 803 19

Dianilinophthalimides represent a novel class of inhibitors of the EGF-receptor protein tyrosine kinase with a high degree of selectivity versus other tyrosine and serine/threonine kinases. Steady-state kinetic analysis of compound 3, which showed potent inhibitory activity, revealed competitive type kinetics relative to ATP. Despite a highly symmetrical structure of compound 3, X-ray studies revealed an unsymmetrical propeller-shaped conformation of the molecule which differs clearly from that of the constitutionally related staurosporine aglycons. These conformational differences may explain the reversal of the selectivity profile of compound 3 relative to the staurosporine aglycons. In cellular assays compounds 3 and 4 have been shown to inhibit EGF-induced receptor autophosphorylation, c-fos induction and EGF-dependent proliferation of Balb/c MK cells. This inhibition was selective as compounds had no effect on PDGF-induced receptor autophosphorylation and c-fos induction. Furthermore, compound 3 showed potent antitumor activity in vivo at well-tolerated doses.
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PMID:Dianilinophthalimides: potent and selective, ATP-competitive inhibitors of the EGF-receptor protein tyrosine kinase. 815 12

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 effects of regional heterogeneity on the accuracy of histological grading of gliomas are well known, but little has been reported about its implications for other diagnostic modalities. This study investigated the relationships of regional heterogeneity in tumor proliferative activity, measured by Ki-67 labeling indices (LI), and histological grades for 16 regionally sampled glioma resections. There was a strong correlation between histological grades and Ki-67 LI in individual regions (p < 0.001), and both methods demonstrated comparable heterogeneity. Heterogeneity increased with tumor grade, probably as an expression of the increased genetic instability that accompanies tumor progression. Similarly, regions with comparable proliferative activity tended to cluster, paralleling clonal expansion. Thus, both histological grading and Ki-67 LI are subject to heterogeneity-induced sampling errors that limit their diagnostic accuracy, particularly in small biopsies. However, fewer grading errors occurred when using both methods together than when using either method alone, suggesting that the use of multiple techniques may reduce the adverse effects of regional heterogeneity on diagnostic accuracy. Regional heterogeneity appears to be a ubiquitous feature of gliomas: it also has been reported in karyotype, p53 oncogene mutations, and PDGF and EGFR expression. The effects of regional heterogeneity on new methods for studying gliomas need to be considered.
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PMID:Regional heterogeneity in the proliferative activity of human gliomas as measured by the Ki-67 labeling index. 822 80

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

Portions of the extracellular domain of the platelet-derived growth factor receptor beta (PDGFR-beta) were expressed as fusion proteins with a hexa His tag in E. coli. Following purification by Ni chelate chromatography, the recombinant receptors were tested in cross-competition studies with 125I-labelled PDGF-AA and -BB. Although of lower affinity than the native receptor (IC50 values of 10(-8) M) the recombinant molecules retained ligand binding specificity and neutralized the mitogenic effect of PDGF-BB. These data indicate that the ligand binding region lies within the first four immunoglobulin-like domains on PDGFR-beta. This E. coli expression system could be further used as a rapid and economical means to produce mutated receptors and map the ligand binding domain.
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PMID:Production of platelet-derived growth factor receptor (PDGFR-beta) in E. coli. Mapping ligand binding domain. 831 71

There are two PDGF receptor proteins (PDGFR alpha and PDGFR beta) which are proposed to function as subunits to form a high-affinity dimeric PDGF receptor. One aspect of this model about which there is still disagreement is whether PDGF-AB can bind to cells that express only PDGFR beta and, if so, whether PDGF-AB can act as an agonist or an antagonist. To address this question, we derived 3T3 cell lines from Patch mutant mouse embryos in which the PDGFR alpha gene is deleted but which express normal levels of PDGFR beta. Comparison between the binding and response properties of mutant and wild type 3T3 cell lines allowed us to define the contribution that PDGFR alpha makes to the ability of a cell to bind, and respond to, PDGF-AB. We found that PDGF-AB binds to PDGFR alpha-negative 3T3 cells and can induce DNA synthesis, PDGFR beta dimerization, and phosphorylation on tyrosine. In addition we found that PDGF-AB binding and stimulation of these activities is strongly temperature-dependent, whereas PDGF-AB binding and activation of PDGFR beta in the presence of PDGFR alpha is not. However, 3T3 cells that do not express PDGFR alpha require for activation PDGF-AB concentrations that were nearly 100-fold greater than for cells that do express PDGFR alpha. These results suggest that neither PDGF-AA nor PDGF-AB are likely to be physiologically significant activators of cells unless the cells express PDGFR alpha.
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PMID:PDGF-AB requires PDGF receptor alpha-subunits for high-affinity, but not for low-affinity, binding and signal transduction. 844 Jul 29

The beta-type receptor of platelet-derived growth factor (beta PDGFR) is a class III transmembrane receptor with tyrosine kinase activity. The beta PDGFR gene is located on mouse chromosome 18 close to the c-fms gene which codes for the colony stimulating factor-1 receptor (CSF-1R). We previously reported that in a high percentage of myeloblastic leukemias induced by the Friend helper murine leukemia virus (F-MuLV), proviruses were integrated in the first intron of the c-fms gene leading to an enhanced expression of c-fms mRNA. Since activation by proviral insertion can act at long distance, we studied beta PDGF receptor gene expression in murine myeloblastic leukemias. This gene was found to be frequently expressed but the level of beta PDGF receptor mRNA was weak and not related to proviral activation. High affinity binding sites were expressed on myeloblastic cells and ligand binding induced cell proliferation. To determine whether beta PDGFR expression is a common feature in hematopoietic cells, we tested cell lines belonging to other hematopoietic lineages. We found that multipotent stem and mast cell lines also expressed the beta PDGF receptor gene. This suggests that PDGF, known as a mitogen for connective tissue cells, could also play a role in normal hematopoiesis.
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PMID:Expression of functional beta-platelet-derived growth factor receptors on hematopoietic cell lines. 848 8


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