title: An integrin binding-defective mutant of insulin-like growth factor-1 (R36E/R37E IGF1) acts as a dominant-negative antagonist of the IGF1 receptor (IGF1R) and suppresses tumorigenesis but still binds to IGF1R.
abstract: Insulin-like growth factor-1 (IGF1) is a major therapeutic target for cancer. We recently reported that IGF1 directly binds to integrins (αvβ3 and α6β4) and induces ternary complex formation (integrin-IGF1-IGF1 receptor (IGF1R)) and that the integrin binding-defective mutant of IGF1 (R36E/R37E) is defective in signaling and ternary complex formation. These findings predict that R36E/R37E competes with WT IGF1 for binding to IGF1R and inhibits IGF signaling. Here, we described that excess R36E/R37E suppressed cell viability increased by WT IGF1 in vitro in non-transformed cells. We studied the effect of R36E/R37E on viability and tumorigenesis in cancer cell lines. We did not detect an effect of WT IGF1 or R36E/R37E in cancer cells under anchorage-dependent conditions. However, under anchorage-independent conditions, WT IGF1 enhanced cell viability and induced signals, whereas R36E/R37E did not. Notably, excess R36E/R37E suppressed cell viability and signaling induced by WT IGF1 under anchorage-independent conditions. Using cancer cells stably expressing WT IGF1 or R36E/R37E, we determined that R36E/R37E suppressed tumorigenesis in vivo, whereas WT IGF1 markedly enhanced it. R36E/R37E suppressed the binding of WT IGF1 to the cell surface and the subsequent ternary complex formation induced by WT IGF1. R36E/R37E suppressed activation of IGF1R by insulin. WT IGF1, but not R36E/R37E, induced ternary complex formation with the IGF1R/insulin receptor hybrid. These findings suggest that 1) IGF1 induces signals under anchorage-independent conditions and that 2) R36E/R37E acts as a dominant-negative inhibitor of IGF1R (IGF1 decoy). Our results are consistent with a model in which ternary complex formation is critical for IGF signaling.
authors.affiliation: Department of Dermatology, University of California Davis School of Medicine, Sacramento, California 95817, USA.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Fujita
authors.forename: Katsuaki
authors.initials: K
authors.lastname: Ieguchi
authors.forename: Dora M
authors.initials: DM
authors.lastname: Cedano-Prieto
authors.forename: Andrew
authors.initials: A
authors.lastname: Fong
authors.forename: Charles
authors.initials: C
authors.lastname: Wilkerson
authors.forename: Jane Q
authors.initials: JQ
authors.lastname: Chen
authors.forename: Mac
authors.initials: M
authors.lastname: Wu
authors.forename: Su-Hao
authors.initials: SH
authors.lastname: Lo
authors.forename: Anthony T W
authors.initials: AT
authors.lastname: Cheung
authors.forename: Machelle D
authors.initials: MD
authors.lastname: Wilson
authors.forename: Robert D
authors.initials: RD
authors.lastname: Cardiff
authors.forename: Alexander D
authors.initials: AD
authors.lastname: Borowsky
authors.forename: Yoko K
authors.initials: YK
authors.lastname: Takada
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Takada
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D016023:Integrins; D051379:Mice; D008954:Models, Biological; D020125:Mutation, Missense; D041681:NIH 3T3 Cells; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics
chemical_list: D007328:Insulin; D016023:Integrins; C519530:insulin-like growth factor-1, mouse; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1
keywords: Cancer; Drug Discovery; Extracellular Matrix; Growth Factors; Insulin-like Growth Factor (IGF); Integrins; Mutant; Signal Transduction