Abstract
The ErbB2 and ErbB3 proteins together constitute a functional coreceptor for heregulin (neuregulin). Heregulin stimulates the phosphorylation of both coreceptor constituents and initiates a variety of other signaling events, which include phosphorylation of the Shc protein. The role of Shc in heregulin-stimulated signal transduction through the ErbB2.ErbB3 coreceptor was investigated here. Heregulin was found to promote ErbB3/Shc association in NIH-3T3 cells expressing endogenous ErbB2 and recombinant ErbB3. A mutant ErbB3 protein was generated in which Tyr-1325 in a consensus Shc phosphotyrosine-binding domain recognition site was mutated to Phe (ErbB3-Y/F). This mutation abolished the association of Shc with ErbB3 and blocked the activation of mitogen-activated protein kinase by heregulin. Whereas heregulin induced mitogenesis in NIH-3T3 cells transfected with wild-type ErbB3 cDNA, this mitogenic response was markedly attenuated in NIH-3T3 cells transfected with the ErbB3-Y/F cDNA. These results showed a specific interaction of Shc with the ErbB3 receptor protein and demonstrated the importance of this interaction in the activation of mitogenic responses by the ErbB2. ErbB3 heregulin coreceptor complex.
Highlights
Factors [3], have been identified as a family of ligands for this receptor
By mutating the corresponding tyrosine residue in the putative Shc binding site of the rat ErbB3 receptor protein, we have in the present study examined the heregulin-stimulated interaction of Shc with the ErbB3 receptor, and we have investigated the role of Shc in mitogenesis mediated by the ErbB21⁄7ErbB3 coreceptor complex
Nonclonal cells expressing ErbB3-Y/F showed a significantly attenuated mitogenic response when compared with cells expressing ErbB3-WT. These results indicated that the association of Shc with the ErbB3 protein and the ensuing activation of the Ras/mitogen-activated protein kinase (MAPK) signaling pathway contributed to the mitogenic potential of the ErbB21⁄7ErbB3 heregulin coreceptor
Summary
Factors [3], have been identified as a family of ligands for this receptor. ErbB3 is unique among ErbB/HER family members in that it has an impaired protein tyrosine kinase activity, which has been attributed to the substitution of amino acid residues invariantly conserved in protein tyrosine kinases [4, 5]. The Tyr-1325 3 Phe Point Mutation in ErbB3 Abolishes Heregulin-dependent ErbB3/Shc Association—To assay the association of Shc with the wild-type and mutant ErbB3 receptor proteins, lysates of stably transfected NIH-3T3 cells were immunoprecipitated with an Shc-specific antibody and subsequently immunoblotted with an ErbB3-specific antibody.
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