Heregulin-dependent regulation of HER2/neu oncogenic signaling by heterodimerization with HER3.

摘要: Abstract Amplification and/or overexpression of HER2/neu and HER3 genes have been implicated in the development cancer humans. The fact that these receptor tyrosine kinases (RTKs) are frequently coexpressed tumor-derived cell lines heterodimers form high affinity binding sites for heregulin (HRG) suggests a novel mechanism signal definition, diversification or amplification. In cells expressing HER2 HER3, phosphorylation is markedly increased upon exposure to recombinant HRG. ATP site mutants demonstrate transphosphorylation by HER2, but not vice versa. HRG-induced results substrate pattern distinct from enhances association with SHC phosphoinositol 3-kinase transfected 293 mammary carcinoma-derived MCF-7 cells. physiological relevance HER2/HER3 heterodimerization demonstrated HRG-dependent transformation NIH 3T3 coexpressing two receptors. These findings acquisition expanded signaling capacities provide molecular basis involvement heteroactivation human malignancies.