Mutation of a Shc Binding Site Tyrosine Residue in ErbB3/HER3 Blocks Heregulin-dependent Activation of Mitogen-activated Protein Kinase

• Published in: The Journal of biological chemistry 1998-08, Vol.273 (33), p.20996-21002
• Main Authors: Vijapurkar, Ulka, Cheng, Kunrong, Koland, John G.
• Format: Article
• Language: English
• Subjects: 3T3 Cells; Androstadienes - pharmacology; Animals; Base Sequence; Calcium-Calmodulin-Dependent Protein Kinases - metabolism; Carrier Proteins - pharmacology; DNA Primers; DNA Replication - drug effects; Enzyme Activation; Enzyme Inhibitors - pharmacology; ErbB Receptors - genetics; ErbB Receptors - metabolism; Glycoproteins - pharmacology; Mice; Mutagenesis, Site-Directed; Neuregulin-1; Phosphatidylinositol 3-Kinases - metabolism; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Rats; Receptor, ErbB-3; Signal Transduction; Thymidine - metabolism; Transfection; Tritium; Tyrosine - genetics; Tyrosine - metabolism; Wortmannin
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.273.33.20996

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.