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

The neu/erbB-2 protooncogene encodes a transmembrane tyrosine kinase homologous to receptors for polypeptide growth factors. The oncogenic potential of the presumed receptor is released through multiple genetic mechanisms including a point mutation, truncation of non-catalytic sequences and overexpression. The latter mechanism appears to be relevant to human cancers as elevated expression of the neu/erbB-2 gene is frequently observed in solid tumors of various adenocarcinomas. It is therefore conceivable that strategies aimed at the biochemical mechanism of action of the neu/erbB-2 tyrosine kinase may contribute to the treatment of certain human cancers. To this aim we undertook a multiple research approach consisting of the following directions: (i) The neu/erbB-2 ligand--a systematic screening of potential biological sources of the hypothetical hormone molecule, that presumably binds to the neu/erbB-2 protein, resulted in detection of a candidate activity in the medium of certain cultured transformed cells. Partial purification indicated that the factor is a 30-35 kDa glycoprotein. Further studies revealed several biochemical characteristics of the factor that may be helpful for complete purification and structural analysis of this novel hormone. (ii) Signal transduction by neu/erbB-2--using a chimeric receptor approach and various mutants we found that all the oncogenic forms of the neu/erbB-2 are constitutively coupled, both physically and functionally, to a multi-protein complex of signaling molecules. The latter includes the phosphatidylinositol-specific phospholipase C gamma and a phosphatidylinositol kinase. Thus, the metabolism of inositol lipids is probably a major biochemical pathway utilized by the neu/erbB-2 tyrosine kinase. (iii) Tumor inhibitory antibodies--we generated a panel of monoclonal antibodies to the presumed receptor. Surprisingly, some antibodies almost completely inhibited the growth of tumor cells in athymic mice, whereas one antibody significantly accelerated the rate of tumor growth in animals. Interestingly, the inhibitory antibodies conferred a mature phenotype to cultured breast cancer cells, implicating terminal differentiation in tumor retardation.
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PMID:Signal transduction by the neu/erbB-2 receptor: a potential target for anti-tumor therapy. 135 18

Several cytoplasmic tyrosine kinases contain a conserved, non-catalytic stretch of approximately 100 amino acids called the src homology 2 (SH2) domain, and a region of approximately 50 amino acids called the SH3 domain. SH2/SH3 domains are also found in several other proteins, including phospholipase C-gamma (PLC gamma). Recent studies indicate that SH2 domains promote association between autophosphorylated growth factor receptors such as the epidermal growth factor (EGF) receptor and signal transducing molecules such as PLC gamma. Because SH2 domains bind specifically to protein sequences containing phosphotyrosine, we examined their capacity to prevent tyrosine dephosphorylation of the EGF and other receptors with tyrosine kinase activity. For this purpose, various SH2/SH3 constructs of PLC gamma were expressed in Escherichia coli as glutathione-S-transferase fusion proteins. Our results show that purified SH2 domains of PLC gamma are able to prevent tyrosine dephosphorylation of the EGF receptor and other receptors with tyrosine activity. The inhibition of tyrosine dephosphorylation paralleled the capacity of various SH2-containing constructs to bind to the EGF receptor, suggesting that the tyrosine phosphatase and the SH2 domain compete for the same tyrosine phosphorylation sites in the carboxy-terminal tail of the EGF receptor. Analysis of the phosphorylation sites protected from dephosphorylation by PLC gamma-SH2 revealed substantial inhibition of dephosphorylation of Tyr992 at 1 microM SH2. This indicates that Tyr992 and its flanking sequence is the high-affinity binding site for SH2 domains of PLC gamma.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:SH2 domains prevent tyrosine dephosphorylation of the EGF receptor: identification of Tyr992 as the high-affinity binding site for SH2 domains of phospholipase C gamma. 153 35

The 145-kDa phospholipase C isozyme, PLC-gamma, is an excellent substrate for the epidermal growth factor (EGF) receptor both in vivo and in vitro. We now demonstrate that EGF treatment of HSC-1 cells, a human squamous cell carcinoma-derived cell line that expresses high levels of the EGF receptor, rapidly induces tyrosine phosphorylation of two-thirds of the total cellular PLC-gamma pool. A two-step immunoaffinity protocol was used for large-scale isolation of phosphorylated PLC-gamma from the cytosol of EGF-treated HSC-1 cells. Phosphorylated PLC-gamma was digested with trypsin, then phosphotyrosine-containing peptides were purified by phosphotyrosine affinity chromatography and reverse-phase high performance liquid chromatography. The two major phosphotyrosine-containing tryptic peptides were sequenced. Comparison of the sequence data with the bovine brain PLC-gamma amino acid sequence indicated that the major, EGF-sensitive tyrosine phosphorylation sites of human PLC-gamma correspond to the bovine brain PLC-gamma tyrosine residues 771 and 1254. The former residue is adjacent to regions of PLC-gamma that contain high homology to the non-catalytic, amino-terminal region of the src tyrosine kinase. The latter residue lies near the carboxyl terminus of the PLC-gamma molecule. The accompanying manuscript (Kim J.W., Sim, S.S., Kim, U-H., Nishibe, S., Wahl, M. I., Carpenter, G., and Rhe, S. G. (1990) J. Biol. Chem. 265, 3940-3943) identifies these same 2 residues plus 2 additional tyrosine phosphorylation sites through large-scale in vitro phosphorylation of purified bovine brain PLC-gamma by the EGF receptor.
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PMID:Identification of two epidermal growth factor-sensitive tyrosine phosphorylation sites of phospholipase C-gamma in intact HSC-1 cells. 168 11