Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04626 (erbB-2)
 5,251 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The c-erbB-2 gene was first identified by virtue of its cross-hybridization with v-erbB. Nucleotide sequence analysis of complementary DNA clones suggested that the c-erbB-2 gene encodes a growth factor receptor similar to that for EGF. Antibodies against the carboxyl terminal sequence of the c-erbB-2 protein immunoprecipitated a 185-kDa glycoprotein which showed protein-tyrosine kinase activity in vitro. Despite the extensive similarity between the c-erbB-2 protein and EGF receptor, neither EGF nor TGF-alpha bound to the c-erbB-2 protein. Phosphorylation of the c-erbB-2 protein was stimulated by TPA via protein kinase C in vivo. EGF also induced phosphorylation of the c-erbB-2 protein. This phosphorylation occurred not only on serine and threonine residues but also on tyrosine residues. Preliminary data suggested that the latter was mediated by the kinase activity of the EGF receptor. Southern blot analysis of DNAs from primary tumors revealed that the c-erbB-2 gene tends to be amplified in adenocarcinomas, mostly of the stomach and the breast. By screening both human genomic and cDNA libraries using v-yes DNA as a probe, we obtained DNA clones of the c-yes gene, the pseudogene of c-yes, c-fgr gene and c-src gene and two novel yes-related genes, fyn and lyn. Complete nucleotide sequence analysis of the cDNA clones of c-yes, fyn and lyn revealed that these genes encode proteins similar to p60src both in size and sequence.
 ...
PMID:[The erbB-related protooncogenes encoding growth factor receptors]. 349 52

Previous results have shown that tumor promoters modify the properties of the epidermal growth factor (EGF) receptor through the activation of protein kinase C. Diacylglycerol-generating factors such as platelet-derived growth factor (PDGF) and p28sis should activate protein kinase C and alter EGF receptor properties in a similar manner. To test directly the involvement of protein kinase C in the action of media from v-sis-transformed cells on the EGF receptor, Swiss 3T3 cells were first extensively treated with various concentrations of the tumor-promoter phorbol dibutyrate (PDBu) This treatment reduced levels of active protein kinase C in the cells, making them less responsive to subsequent rechallenge with the tumor promoter. The results demonstrate that there are at least two components to the action of media from v-sis transformed cells on EGF binding: a labile factor that confers protein kinase C independence and a stable factor that appears to be dependent on protein kinase C. The action of the first factor cannot be mimicked by transforming growth factor-beta or EGF in either the presence or absence of PDGF. The action of the second factor is similar to that of PDGF. These findings indicate that heterologous regulation of the EGF receptor can occur through both protein kinase C-dependent and -independent pathways.
 ...
PMID:Growth factors modify the epidermal growth factor receptor through multiple pathways. 358 59

We have recently reported that a polypeptide mitogen, the embryonal carcinoma-derived growth factor (ECDGF), induces phosphorylation of the epidermal growth factor (EGF) receptor in intact C3H 10T 1/2 mouse fibroblasts with concomittant loss of high affinity EGF binding sites. This phenomenon appears to be mediated through an activation of protein kinase C. Several groups have described an acidic 80,000 dalton protein substrate of protein kinase C. In this paper, we demonstrate that the addition of ECDGF or the phorbol ester TPA to intact C3H 10T 1/2 cells results in the enhanced phosphorylation of this 80 kd protein in vivo. Furthermore, this response is demonstrable in vitro. Thus the addition of ECDGF, the phorbol ester TPA, protein kinase C or phosphoinositidase C to crude membranes prepared from C3H 10T 1/2 cells resulted in the enhanced phosphorylation of this protein. Data obtained by phosphopeptide mapping of the 80 kd protein show that the ECDGF-induced activation of protein kinase C in our membrane preparations is comparable with that obtained in vivo. The availability of an in vitro system in which this response is preserved should now allow a detailed biochemical analysis of the steps between binding of a mitogen to its receptor and the activation of protein kinase C.
 ...
PMID:Embryonal carcinoma-derived growth factor activates protein kinase C in vivo and in vitro. 359 64

Tumor promoters cause a variety of effects in cultured cells, at least some of which are thought to result from activation of the Ca2+-phospholipid-stimulated protein kinase C. One action of tumor promoters is the modulation of the binding and phosphorylation of the epidermal growth factor (EGF) receptor in A431 cells. To determine if these compounds act on the EGF receptor by substituting for the endogenous activator of C kinase, diacylglycerol, we compared the effects of the potent tumor promoter 12-O-tetradecanoyl phorbol 13-acetate (TPA) with those of the synthetic diacylglycerol analog 1-oleyl 2-acetyl diglycerol (OADG). When A431 cells were treated with TPA, the subcellular distribution of C kinase activity shifted from a predominantly cytosolic location to a membrane-associated state; OADG also caused the disappearance of cytosolic C kinase activity. The shift in the subcellular distribution of C kinase, caused by TPA or OADG, correlated with changes in binding and phosphorylation of the EGF receptor. OADG, like TPA, caused loss of binding to an apparent high affinity class of receptors, blocked EGF-induced tyrosine phosphorylation of the EGF receptor, and stimulated phosphorylation of the EGF receptor at both serine and threonine residues. No difference between the phosphopeptide maps of receptors from cells treated with OADG or TPA was observed. Thus, it appears that tumor promoters can exert their effects on the EGF receptors by substituting for diacylglycerol, presumably by activating protein kinase C. Further, these results suggest that endogenously produced diacylglycerol may have a role in normal growth regulatory pathways.
 ...
PMID:Diacylglycerol modulates binding and phosphorylation of the epidermal growth factor receptor. 609 36

Tyrosine-specific phosphorylation of the epidermal growth factor (EGF) receptor in hormonally stimulated A431 cells is blocked by three chemically distinct classes of tumor promoters. Tumor-promoting esters of the diterpene phorbol (phorbol 12-myristate 13-acetate, beta-phorbol 12,13-dibutyrate, and beta-phorbol 12,13-didecanoate), indole alkaloids (teleocidin and lyngbyatoxin A), and polyacetates ( aplysiatoxin and debromoaplysiatoxin ) all inhibited EGF-stimulated phosphorylation of the receptor. Non-tumor-promoting analogs (beta-phorbol, alpha-phorbol 12,13-didecanoate, and hydrolyzed teleocidin) had no effect on the levels of receptor phosphorylation. The ED50 values of the inhibitory effect (0.1-3 ng/ml) reflected the relative tumor-promoting abilities of these compounds in vivo. None of the tumor promoters tested significantly decreased the overall specific binding of 125I-labeled EGF to A431 cells. Scatchard analysis, however, revealed two apparent EGF receptors in this cell type. The dose-responses for tumor-promoter inhibition of EGF receptor tyrosine phosphorylation and high-affinity EGF binding were similar, suggesting that the same initial event is responsible for both effects. This demonstrates a correlation between modulation of EGF receptor binding and phosphorylation of tyrosine by tumor promoters. The data suggest a possible role for protein kinase C, the putative cellular receptor for these tumor promoters, in the mechanism of action.
 ...
PMID:Tumor promoters block tyrosine-specific phosphorylation of the epidermal growth factor receptor. 632 89

The derivation and properties of JB6 mouse epidermal clonal cell lines are reviewed and the conclusions that can be drawn from studies with the JB6 mouse epidermal system are summarized. Promoter induced mitogenic stimulation, epidermal growth factor (EGF) receptor binding and stimulated hexose transport are apparently not required for promotion of neoplastic transformation in JB6 cells by phorbol esters and other promoters. Phorbol ester receptor binding (or protein kinase C activation) and switched-off collagen synthesis may be required but definitive proof is not available. Decreased cell surface ganglioside GT synthesis, elevated superoxide, and one or more genes that determine promotion sensitivity appear to distinguish sensitive from resistant cells and to be required for promotion of neoplastic transformation in JB6 cells. The hypothesis is proposed that GT is a target for reactive oxygen elevated by 12-O-tetradecanoylphorbol-13-acetate (TPA) exposure and that GT oxidation produces decreased GT net synthesis which in turn leads to promotion of transformation. Finally evidence is presented suggesting the involvement of at least two genes in transformation of JB6 cells by TPA, one in induction, the other in maintenance of transformation.
 ...
PMID:Membrane and genetic events in tumor promotion: studies with promoter resistant variants of JB6 cells. 639 88

Calphostin-C with perylenequinone structure is known to bind the regulatory domain of protein kinase C (PKC) and to inhibit kinase activity in vitro in a light-dependent fashion. We have found that calphostin-C induces substantial serine and threonine phosphorylation of the epidermal growth factor (EGF) receptor in a light-dependent fashion in the EGF receptor-hyperproducing squamous carcinoma cell line NA. Tryptic phospho-peptide mapping and phospho-amino acid analysis revealed that calphostin-C-enhanced phosphorylation was on threonine 669, serine 671, serine 1046/1047, and serine 1166. However, calphostin-C did not inhibit phosphorylation of the 80 K protein, a cytosolic major substrate of PKC (MARCKS). Staurosporine, a potent PKC inhibitor with affinity for the catalytic domain of PKC, inhibited phosphorylation of the 80 K protein and 12-O-tetradecanoyl-13-phorbol acetate induction of EGF receptor phosphorylation but did not inhibit the calphostin-C induction of the EGF receptor phosphorylation. These results suggest that the target of calphostin-C in vivo is different from that of staurosporine and thus calphostin-C in vivo does not inhibit PKC. Furthermore, calphostin-C enhanced the internalization of phosphorylated EGF receptor. Thus, calphostin-C apparently activates a novel signal transduction pathway which involves phosphorylation and internalization of the EGF receptor via light-dependent mechanism.
 ...
PMID:Calphostin-C stimulates epidermal growth factor receptor phosphorylation and internalization via light-dependent mechanism. 750 75

Calphostin-C is a compound possessing the ability to inhibit protein kinase C (PKC) by oxidative modification in vitro and to enhance the epidermal growth factor (EGF) receptor phosphorylation in vivo in a light-dependent manner. Here, we found that calphostin-C induced c-fos and c-jun mRNA accumulation in the lung adenocarcinoma cell line A549 in a light-dependent manner. Nuclear run-on assay revealed that this mRNA accumulation took place at the transcription level. However, unlike in vitro, calphostin-C did not inhibit cytosolic PKC activity in vivo, and the gene expression induced by calphostin-C was inhibited by another PKC inhibitor, staurosporine. Thus, it was suggested that calphostin-C activates cytosolic PKC-dependent signaling pathway to the induction of "early-response gene" expression in a light-dependent manner.
 ...
PMID:Light-dependent induction of early-response gene expression by calphostin-C. 752 61

The receptors for insulin-like growth factor 1 (IGF1) and insulin are related heterotetrameric proteins which, like the epidermal growth factor (EGF) receptor, possess intrinsic ligand-stimulated tyrosine protein kinase activity. In Rat 1 fibroblasts, stimulation of mitogen-activated protein (MAP) kinase via the IGF1 receptor and the Gi-coupled receptor for lysophosphatidic acid (LPA), but not via the EGF receptor, is sensitive both to pertussis toxin treatment and to cellular expression of a specific G beta gamma subunit-binding peptide. The IGF1, LPA, and EGF receptor-mediated signals are all sensitive to inhibitors of tyrosine protein kinases, require p21ras activation, and are independent of protein kinase C. These data suggest that some tyrosine kinase growth factor receptors (e.g. IGF1 receptor) and classical G protein-coupled receptors (e.g. LPA receptor) employ a similar mechanism for mitogenic signaling that involves both tyrosine phosphorylation and G beta gamma subunits derived from pertussis toxin-sensitive G proteins.
 ...
PMID:G beta gamma subunits mediate mitogen-activated protein kinase activation by the tyrosine kinase insulin-like growth factor 1 receptor. 762 49

The stimulation of both phospholipase A2 (PLA2) enzymic activity and the production of prostaglandin E2 (PGE2) by transforming growth factor-alpha (TGF-alpha) and Ca2+ ionophore A23187 in TEA3A1 rat thymic epithelial cells were studied. TGF-alpha by itself at various concentrations (5-200 ng/ml) had no effect on the stimulation of PGE2 production. A23187 (1 microgram/ml) by itself stimulated PGE2 production on average by 18-fold over the control. When TGF-alpha (50 ng/ml) was added to the cells in the presence of A23187, a synergistic stimulation (on average 45-fold) of PGE2 production was observed. Synergistic stimulation was also observed at the level of arachidonic acid released from phospholipid pools, suggesting the activation of PLA2 enzymic activity. We have found that this synergistic activation of PLA2 enzymic activity and subsequent stimulation of PGE2 production required the activation of epidermal growth factor (EGF) receptor tyrosine kinase and Ca2+ influx. This was shown by the fact that genistein, an inhibitor of tyrosine kinase, blocks the synergistic stimulation by TGF-alpha and A23187 and by the fact that the stimulation of PGE2 production by TGF-alpha and A23187 is dependent on the culture-medium Ca2+ concentrations. The requirement for Ca2+ influx instead of intracellular mobilization of Ca2+ was shown by the fact that PGE2 production was not stimulated when cells were treated with TGF-alpha and thapsigargin. Moreover, the synergistic stimulation of PGE2 production by TGF-alpha and A23187 was not affected in protein kinase C down-modulated cells. In addition, the synergistic stimulation was not observed in cells treated with either phorbol 12-myristate 13-acetate (PMA) and TGF-alpha or PMA and A23187, and in cells treated with TGF-alpha and thapsigargin. The requirement for the activation of receptor tyrosine kinase seems to be specific to the EGF receptor, since a synergistic stimulation of PGE2 production was not observed when cells are treated with either insulin-like growth factor-I or fibroblast growth factor-I in the presence of A23187.
 ...
PMID:Activation of phospholipase A2 and stimulation of prostaglandin E2 production by transforming growth factor-alpha in rat thymic epithelial cells requires influx of calcium. 768 26


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>