title: Crosstalk between insulin-like growth factor (IGF) receptor and integrins through direct integrin binding to IGF1.
abstract: It has been generally accepted that integrin cell adhesion receptors are involved in growth factor signaling (integrin-growth factor crosstalk), since antagonists to integrins often suppress growth factor signaling. Partly because integrins have been originally identified as cell adhesion receptors to extracellular matrix (ECM) proteins, current models of the crosstalk between IGF1 and integrins propose that ECM ligands (e.g., vitronectin) bind to integrins and IGF1 binds to IGF receptor type 1 (IGF1R), and two separate signals merge inside the cells. Our research proves otherwise. We discovered that IGF1 interacts directly with integrins, and induces integrin-IGF-IGF1R complex formation on the cell surface. IGF1 signaling can be detected in the absence of ECM (anchorage-independent conditions). Integrin antagonists block both ECM-integrin interaction and IGF-integrin interaction, and do not distinguish the two. This is one possible reason why integrin-IGF1 interaction has not been detected. With these new discoveries, we believe that the direct IGF-integrin interaction should be incorporated into models of IGF1 signaling. The integrin-binding defective mutant of IGF1 is defective in inducing IGF signaling, although the mutant still binds to IGF1R. Notably, the IGF1 mutant is dominant-negative and suppresses cell proliferation induced by wt IGF1, and suppresses tumorigenesis in vivo, and thus the IGF1 mutant has potential as a therapeutic.
authors.affiliation: Departments of Dermatology, Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Sacramento, CA 95817, United States; Graduate Institute of Translational Medicine, College of Medical Science and Technology, Taipei Medical University, 250 Wu-Hsing Street, Taipei 11031, Taiwan, ROC. Electronic address: ytakada@ucdavis.edu.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Takada
authors.affiliation: Departments of Dermatology, Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Sacramento, CA 95817, United States; Graduate Institute of Translational Medicine, College of Medical Science and Technology, Taipei Medical University, 250 Wu-Hsing Street, Taipei 11031, Taiwan, ROC.
authors.forename: Yoko K
authors.initials: YK
authors.lastname: Takada
authors.affiliation: Department of Clinical Immunology and Rheumatology, The Tazuke-Kofukai Medical Research Institute, Kitano Hospital, Osaka, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Fujita
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D016023:Integrins / Q000378:metabolism*; D051379:Mice; D011485:Protein Binding; D021381:Protein Transport; D020239:Receptor Cross-Talk; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D017451:Receptors, Somatomedin; D015398:Signal Transduction
chemical_list: C583557:IGF1 protein, human; C000597236:IGF1R protein, human; D016023:Integrins; D017451:Receptors, Somatomedin; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1
keywords: Crosstalk; Dominant-negative antagonist; IGF1; Integrin; Signaling