Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:O76050 (neu)
 3,969 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The HER2/neu gene encodes a receptor tyrosine kinase that is highly homologous to the epidermal growth factor receptor. Overexpression of the receptor in mammary and ovarian carcinoma correlates with poor patient prognosis. To determine how the overexpression of a normal receptor leads to the generation of an oncogenic signal, we compared the patterns of tyrosine phosphorylation in tumor-derived human cell lines expressing high levels of p185HER2/neu. In intact SKBR3 cells, basal phosphorylation of p185HER2/neu was not detected. However, pretreatment of cells with the tyrosine phosphatase inhibitor, sodium orthovanadate, led to the detection of phosphotyrosine on phospholipase C-gamma (PLC-gamma), GTPase-activating protein but not on the RAF-1 kinase. Strikingly, PLC-gamma was detected in a complex which contained multiple tyrosine-phosphorylated polypeptides. This complex was detected only in cytoplasmic fractions and had a distinct composition in different p185HER2/neu-overexpressing cell lines. Although GTPase-activating protein has been found previously in association with proteins of 190 and 62 kDa in fibroblasts, in SKBR3 cells it was found associated with multiple additional tyrosine-phosphorylated polypeptides. These experiments show that SKBR3 cells possess high levels of protein tyrosine phosphatase that can act upon p185HER2/neu. Moreover, they reveal, for the first time, the presence of PLC-gamma and GTPase-activating protein in cytosolic complexes containing a variety of other tyrosine-phosphorylated polypeptides. These observations suggest novel possibilities for the specific definition of receptor-generated signals in tumor cells.
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PMID:Tyrosine phosphatase inhibition permits analysis of signal transduction complexes in p185HER2/neu-overexpressing human tumor cells. 134 42

The functional consequences of heterodimer formation between the epidermal growth factor receptor (EGFr) and the p185c-neu receptor tyrosine kinase include increased mitogenic and transformation potencies. To determine the possible alteration of signal transduction pathways resulting from this heteromeric complex, the capacity of several signaling proteins to associate with the heterodimeric receptors has been assayed. The in vivo interaction with the EGFr/p185c-neu heterodimer of several signal transduction proteins, including phospholipase C-gamma 1 (PLC-gamma 1), the p85 subunit of phosphotidylinositol 3-kinase, the ras GTPase activating protein, SHC, NCK, p72RAF, and the tyrosine phosphatase SHPTP2, was measured by coimmunoprecipitation. The binding of these signaling proteins to a complex composed of EGFr and a kinase-inactive form of p185 (p185K757M) was not impaired, even though the mitogenic and transformation activity of this complex had been abrogated. In addition, the EGF-induced phosphorylation of GAP, p85, and PLC-gamma 1 did not correlate with the dominant-negative action of p185K757M on EGFr function. Thus, substrate association and phosphorylation do not correlate stringently with the mitogenic and transforming activity of this receptor complex, suggesting additional pathways or mechanisms vital to EGFr/p185c-neu heterodimeric signaling.
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PMID:Association of signaling proteins with a nonmitogenic heterodimeric complex composed of epidermal growth factor receptor and kinase-inactive p185c-neu. 856 95