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Query: UNIPROT:P04626 (erbB-2)
 5,251 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The earliest substrates to the transmembrane insulin receptor tyrosine kinase, that would function in insulin signalling, are likely to be associated with the plasma membrane. Rat liver plasma membrane 180,000 M(r) protein (p180) is a substrate to the insulin receptor in vitro [Goren et al. (1990) Cellular Signalling 2, 537-555]. The question as to whether p180 is a substrate in vivo was addressed. Half ml 0.9% NaCl or 500 micrograms insulin was injected into rat livers. Purified plasma membrane glycoproteins from the livers were assayed for in vitro phosphorylation reaction products and endogenous tyrosine-phosphorylated proteins. Membranes from insulin-injected rat livers contained phosphorylated p180 and phosphorylated insulin receptor beta-subunit, whereas saline-injected rat liver membranes contained neither. These data suggested that p180 is an in vivo substrate to the insulin receptor. In vitro p180 is tyrosine-phosphorylated in the absence of insulin. p180, therefore, may be the epidermal growth factor (EGF) receptor or another tyrosine kinase that could be part of a phosphorylation cascade initiated by insulin. Two different experiments suggested that p180 is not the EGF receptor: (i) two-dimensional gel electrophoresis (first dimension--non-equilibrium pH-gradient gel electrophoresis) indicated that p180 is a more basic glycoprotein than EGF receptor; and (ii) based on reverse-phase high pressure liquid chromatography, the tryptic-phosphopeptides of carboxymethyl-Sepharose-purified phosphorylated-p180 were different from those of A431 cell phosphorylated-EGF receptor. Similarly, two different experiments demonstrated that p180 is not a tyrosine kinase: (i) gel-permeation chromatography separated the insulin receptor from p180 and only insulin receptor was autophosphorylated in vitro; and (ii) membrane proteins not bound to immobilized ATP contained p180. Thus, p180 can associate with the insulin receptor and be phosphorylated in vitro and in vivo; however, p180 does not function in an insulin receptor-mediated phosphorylation cascade.
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PMID:Plasma membrane p180, which insulin receptor phosphorylates in vivo, is not a tyrosine kinase. 834 20

A variety of eucaryotic polypeptide growth factors are synthesized as transmembrane precursors. Many of these precursors are released from plasma membranes by proteolytic cleavage and converted into soluble mature proteins. A number of studies, however, indicate that bound growth factor precursors can be biologically active, suggesting a role for these membrane-associated ligands in cell-cell communication. Secreted heregulin is a 45-kDa growth factor with homology to epidermal growth factor. This growth factor binds directly to HER-3 and HER-4 and activates heterodimeric receptor complexes composed of the type I receptor tyrosine kinases, i.e. HER-1, HER-2, HER-3, and HER-4. Heregulin was originally detected in the conditioned medium of the human breast cancer cell line MDA-MB-231 and purified based on its ability to stimulate phosphorylation of p185(HER-2/neu). In the current study, the biologic activity of plasma membrane-anchored heregulin was evaluated in human breast cells. Transmembrane heregulin binds to cells expressing p180(HER-3), induces p185(HER-2/neu) phosphorylation, and increases DNA synthesis in cells overexpressing the HER-2/neu gene product. In addition, when cells containing heregulin receptors are co-cultured with heregulin-producing cells, specific in vivo associations are observed. This study demonstrates that transmembrane heregulin is functionally active and suggest it is capable of playing a role in cell-cell communication and subsequent signal transduction in vivo.
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PMID:The transmembrane heregulin precursor is functionally active. 1149 99