title: Insulin-like growth factor-I receptor mediates the prosurvival effect of fibronectin.
abstract: We recently showed that extracellular matrix (ECM) proteins, which are abundant in desmoplastic pancreatic tumor, are as potent as growth factors in inhibiting apoptosis in pancreatic cancer (PaCa) cells. Here we show that fibronectin, a major ECM component, engages insulin-like growth factor-I receptor (IGF-IR) to inhibit PaCa cell death. We found that fibronectin-induced protection from apoptosis is fully mediated by IGF-IR and is independent of IGF-I. Pharmacologic and molecular inhibitions of IGF-IR stimulated apoptosis and prevented the prosurvival effect of fibronectin in PaCa cells. Our data indicate that fibronectin protects from apoptosis through trans-activation of IGF-IR. We showed that fibronectin stimulated complex formation between its receptor beta3 integrin and protein-tyrosine phosphatase SHP-2. This process of complex formation, in turn, prevents SHP-2 from dephosphorylating IGF-IR resulting in sustained phosphorylation of IGF-IR and leading to the downstream activation of Akt kinase, up-regulation of antiapoptotic Bcl(xL), and inhibition of apoptosis. Among ECM proteins tested only fibronectin and laminin but not vitronectin and collagen I stimulated trans-activation of IGF-IR. Interaction of fibronectin with beta3 but not beta1 integrin receptors mediates the survival pathway. In contrast, fibronectin-induced adhesion is mediated through beta1 integrin receptor and is IGF-IR-independent. Thus, our results indicate that the prosurvival effect of fibronectin in PaCa cells is mediated by trans-activation of IGF-IR induced by the beta3 integrin receptor. The data suggest IGF-IR as a key target for prevention of the prosurvival effects of ECM proteins and growth factors in pancreatic cancer.
authors.affiliation: Department of Medicine, Veterans Affairs Greater Los Angeles Healthcare System and University of California, Los Angeles, California 90073.
authors.forename: Mouad
authors.initials: M
authors.lastname: Edderkaoui
authors.affiliation: Department of Medicine, Veterans Affairs Greater Los Angeles Healthcare System and University of California, Los Angeles, California 90073.
authors.forename: Peggy
authors.initials: P
authors.lastname: Hong
authors.affiliation: School of Medicine, Sungkyunkwan University, Seoul 135-710, Korea.
authors.forename: Jong K
authors.initials: JK
authors.lastname: Lee
authors.affiliation: Department of Medicine, Veterans Affairs Greater Los Angeles Healthcare System and University of California, Los Angeles, California 90073.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Pandol
authors.affiliation: Department of Medicine, Veterans Affairs Greater Los Angeles Healthcare System and University of California, Los Angeles, California 90073. Electronic address: agukovsk@ucla.edu.
authors.forename: Anna S
authors.initials: AS
authors.lastname: Gukovskaya
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005353:Fibronectins / Q000494:pharmacology*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000502:physiology; D019012:Integrin beta1 / Q000502:physiology; D039661:Integrin beta3 / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology; D010190:Pancreatic Neoplasms / Q000473:pathology*; D010766:Phosphorylation; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases / Q000502:physiology; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: D005353:Fibronectins; D019012:Integrin beta1; D039661:Integrin beta3; D047908:Intracellular Signaling Peptides and Proteins; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; C516724:PTPN11 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases