ErbB2 is necessary for induction of carcinoma cell invasion by ErbB family receptor tyrosine kinases.
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.
Spencer
K S
KS
Department of Immunology, The Scripps Research Institute, La Jolla, California 92037, USA.
Graus-Porta
D
D
Leng
J
J
Hynes
N E
NE
Klemke
R L
RL
D000230:Adenocarcinoma / Q000503:physiopathology*; D001943:Breast Neoplasms / Q000503:physiopathology*; D002465:Cell Movement; D050719:Crk-Associated Substrate Protein; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000378:metabolism; D005260:Female; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009361:Neoplasm Invasiveness; D010446:Peptide Fragments / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D011506:Proteins; D011518:Proto-Oncogene Proteins; D050737:Proto-Oncogene Proteins c-crk; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D017978:Receptors, Growth Factor / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D050717:Retinoblastoma-Like Protein p130; D015398:Signal Transduction
D050719:Crk-Associated Substrate Protein; D004815:Epidermal Growth Factor; D020928:Mitogen-Activated Protein Kinases; D010446:Peptide Fragments; D010750:Phosphoproteins; D011494:Protein Kinases; D011506:Proteins; D011518:Proto-Oncogene Proteins; D050737:Proto-Oncogene Proteins c-crk; D020794:Receptor Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D017978:Receptors, Growth Factor; D011994:Recombinant Proteins; D050717:Retinoblastoma-Like Protein p130; C493841:BCAR1 protein, human