Receptor tyrosine kinase signaling required for integrin alpha v beta 5-directed cell motility but not adhesion on vitronectin.
FG human pancreatic carcinoma cells adhere to vitronectin using integrin alpha v beta 5 yet are unable to migrate on this ligand whereas they readily migrate on collagen in an alpha 2 beta 1-dependent manner. We report here that epidermal growth factor receptor (EGFR) activation leads to de novo alpha v beta 5-dependent FG cell migration on vitronectin. The EGFR specific tyrosine kinase inhibitor tyrphostin 25 selectively prevents EGFR autophosphorylation thereby preventing the EGF-induced FG cell migration response on vitronectin without affecting constitutive migration on collagen. Protein kinase C (PKC) activation also leads to alpha v beta 5-directed motility on vitronectin; however, this is not blocked by tyrosine kinase inhibitors. In this case, PKC activation appears to be associated with and downstream of EGFR signaling since calphostin C, an inhibitor of PKC, blocks FG cell migration on vitronectin induced by either PKC or EGF. These findings represent the first report implicating a receptor tyrosine kinase in a specific integrin mediated cell motility event independent of adhesion.
Klemke
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RL
Scripps Research Institute, Department of Immunology, La Jolla, California 92037.
Yebra
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Bayna
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EM
Cheresh
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DA
D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005434:Flow Cytometry; D019833:Genistein; D006023:Glycoproteins; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D016023:Integrins / Q000502:physiology*; D007529:Isoflavones / Q000494:pharmacology; D007700:Kinetics; D009281:Naphthalenes; D009570:Nitriles / Q000494:pharmacology*; D010190:Pancreatic Neoplasms; D019000:Phosphotyrosine; D011083:Polycyclic Compounds / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D019030:Receptors, Vitronectin; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000031:analogs & derivatives / Q000032:analysis; D020032:Tyrphostins; D019096:Vitronectin
D006023:Glycoproteins; D016023:Integrins; D007529:Isoflavones; D009281:Naphthalenes; D009570:Nitriles; D011083:Polycyclic Compounds; D019030:Receptors, Vitronectin; D020032:Tyrphostins; D019096:Vitronectin; C064660:integrin alphaVbeta5; C079836:tyrphostin 25; D019000:Phosphotyrosine; D014443:Tyrosine; D004815:Epidermal Growth Factor; D007334:Insulin-Like Growth Factor I; D019833:Genistein; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases; D017526:Receptor, IGF Type 1; D011493:Protein Kinase C; C058819:calphostin C; D013755:Tetradecanoylphorbol Acetate