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© The Rockefeller University Press, 0021-9525/2000//385 $5.00
The Journal of Cell Biology, Volume 148, Number 2, , 2000 385-397

Original Article

ErbB2 Is Necessary for Induction of Carcinoma Cell Invasion by Erbb Family Receptor Tyrosine Kinases



Kathryn S.R. Spencera, Diana Graus-Portab, Jie Lenga, Nancy E. Hynesb, and Richard L. Klemkea

a Department of Immunology, The Scripps Research Institute, La Jolla, California 92037
b Friedrich Miescher Institute, CH-4002 Basel, Switzerland
Department of Immunology, CAL-9, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037.858-784-7785858-784-7750

klemke{at}scripps.edu

The epidermal growth factor (EGF) family of tyrosine kinase receptors (ErbB1, -2, -3, and -4) and their ligands are involved in cell differentiation, proliferation, migration, and carcinogenesis. However, it has proven difficult to link a given ErbB receptor to a specific biological process since most cells express multiple ErbB members that heterodimerize, leading to receptor cross-activation. In this study, we utilize carcinoma cells depleted of ErbB2, but not other ErbB receptor members, to specifically examine the role of ErbB2 in carcinoma cell migration and invasion. Cells stimulated with EGF-related peptides show increased invasion of the extracellular matrix, whereas cells devoid of functional ErbB2 receptors do not. ErbB2 facilitates cell invasion through extracellular regulated kinase (ERK) activation and coupling of the adaptor proteins, p130CAS and c-CrkII, which regulate the actin-myosin cytoskeleton of migratory cells. Overexpression of ErbB2 in cells devoid of other ErbB receptor members is sufficient to promote ERK activation 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.

Key Words: epidermal growth factor • ERK • cell • migration • adaptor proteins • signal transduction

© 2000 The Rockefeller University Press

Abbreviations used in this paper: β-gal, β-galactosidase; BTC, β-cellulin; CAS, crk-associated substrate; ECM, extracellular matrix; ERK, extracellular regulated kinase; FBM, fibroblast basal media; MAP, mitogen-activated protein; MBP, myelin basic protein; MEK, MAP kinase kinase; NDF, neu differentiation factor; p130CAS, Crk-associated substrate; SH2, src-homology 2 domain.


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