Specific cross-talk between epidermal growth factor receptor and integrin alphavbeta5 promotes carcinoma cell invasion and metastasis.
Tyrosine kinase receptors and integrins play essential roles in tumor cell invasion and metastasis. Previously, we showed that epidermal growth factor (EGF) stimulation of pancreatic carcinoma cells led to invasion and metastasis that was blocked by antagonists of integrin alpha(v)beta(5). Here, we show that EGF stimulates metastasis of carcinoma cells via a Src-dependent phosphorylation of p130 CAS leading to activation of Rap1, a small GTPase involved in integrin activation. Specifically, EGF receptor (EGFR)-induced Src activity leads to phosphorylation of a region within the CAS substrate domain, which is essential for Rap1 and alpha(v)beta(5) activation. This pathway induces alpha(v)beta(5)-mediated invasion and metastasis in vivo yet does not influence primary tumor growth or activation of other integrins on these cells. These findings show cross-talk between a tyrosine kinase receptor and an integrin involved in carcinoma cell invasion and metastasis and may explain in part how inhibitors of EGFR affect malignant disease.
Ricono
Jill M
JM
Department of Pathology, Moores UCSD Cancer Center, University of California, San Diego, La Jolla, California 92093-0803, USA.
Huang
Miller
M
Barnes
Leo A
LA
Lau
Steven K
SK
Weis
Sara M
SM
Schlaepfer
David D
DD
Hanks
Steven K
SK
Cheresh
David A
DA
D000818:Animals; D002277:Carcinoma / Q000235:genetics / Q000473:pathology*; D002465:Cell Movement; D002642:Chick Embryo; D017931:DNA Primers; D004815:Epidermal Growth Factor / Q000502:physiology; D066246:ErbB Receptors / Q000502:physiology*; D055785:Gene Knockdown Techniques; D006801:Humans; D055029:Inverted Repeat Sequences / Q000235:genetics; D008168:Lung / Q000196:embryology; D008175:Lung Neoplasms / Q000473:pathology / Q000556:secondary; D009154:Mutation; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000473:pathology*; D016133:Polymerase Chain Reaction; D012334:RNA, Neoplasm / Q000235:genetics; D020239:Receptor Cross-Talk / Q000502:physiology*; D019030:Receptors, Vitronectin / Q000235:genetics / Q000502:physiology*; D014407:Tumor Cells, Cultured
D017931:DNA Primers; D012334:RNA, Neoplasm; D019030:Receptors, Vitronectin; C064660:integrin alphaVbeta5; D004815:Epidermal Growth Factor; D066246:ErbB Receptors