ErbB2 is necessary for induction of carcinoma cell invasion by ErbB familyreceptor tyrosine kinases

The epidermal growth factor (EGF) family of tyrosine kinase receptors (ErbB 1, -2, -3, and -4) and their ligands are involved in cell differentiation, proliferation, migration, and carcinogenesis. However, it has proven diffic ult to link a given ErbB receptor to a specific biological process since mo st cells express multiple ErbB members that heterodimerize, leading to rece ptor cross-activation. In this study, we utilize carcinoma cells depleted o f ErbB2, but not other ErbB receptor members, to specifically examine the r ole of ErbB2 in carcinoma cell migration and invasion. Cells stimulated wit h EGF-related peptides show increased invasion of the extracellular matrix, whereas cells devoid of functional ErbB2 receptors do not. ErbB2 facilitat es cell invasion through extracellular regulated kinase (ERK) activation an d coupling of the adaptor proteins, p130CAS and c-CrkII, which regulate the actin-myosin cytoskeleton of migratory cells. Overexpression of ErbB2 in c ells devoid of other ErbB receptor members is sufficient to promote ERK act ivation and CAS/Crk coupling, leading to cell migration. Thus, ErbB2 serves as a critical component that couples ErbB receptor tyrosine kinases to the migration/invasion machinery of carcinoma cells.