Mutation of a Shc binding site tyrosine residue in ErbB3/HER3 blocks heregulin-dependent activation of mitogen-activated protein kinase.
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.
Vijapurkar
U
U
Department of Pharmacology, the University of Iowa College of Medicine, Iowa City, Iowa 52242-1109, USA.
Cheng
K
K
Koland
J G
JG
D016475:3T3 Cells; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D001483:Base Sequence; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002352:Carrier Proteins / Q000494:pharmacology; D017931:DNA Primers; D004261:DNA Replication / Q000187:drug effects; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D006023:Glycoproteins / Q000494:pharmacology; D051379:Mice; D016297:Mutagenesis, Site-Directed; D020890:Neuregulin-1; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D020893:Receptor, ErbB-3; D015398:Signal Transduction; D013936:Thymidine / Q000378:metabolism; D014162:Transfection; D014316:Tritium; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism*; D000077191:Wortmannin
D000730:Androstadienes; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002352:Carrier Proteins; D017931:DNA Primers; D004791:Enzyme Inhibitors; D066246:ErbB Receptors; D006023:Glycoproteins; D020890:Neuregulin-1; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D020893:Receptor, ErbB-3; D013936:Thymidine; D014316:Tritium; D014443:Tyrosine; D000077191:Wortmannin; C087230:heregulin beta1