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

Masaaki Fujita, Katsuaki Ieguchi, Dora M. Cedano-Prieto, Andrew Fong, Charles Wilkerson, Jane Q. Chen, Mac Wu, Su Hao Lo, Anthony T W Cheung, MacHelle D. Wilson, Robert D. Cardiff, Alexander D. Borowsky, Yoko K. Takada, Yoshikazu Takada

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20 Citations (Scopus)

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. Wedid not detect an effect ofWTIGF1 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 byWTIGF1 under anchorage-independent conditions. Using cancer cells stably expressingWTIGF1 or R36E/R37E, we determined that R36E/R37E suppressed tumorigenesis in vivo, whereas WT IGF1 markedly enhanced it. R36E/R37E suppressed the binding ofWTIGF1 to the cell surface and the subsequent ternary complex formation induced byWTIGF1. 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.

Original languageEnglish
Pages (from-to)19593-19603
Number of pages11
JournalJournal of Biological Chemistry
Volume288
Issue number27
DOIs
Publication statusPublished - Jul 5 2013
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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    Fujita, M., Ieguchi, K., Cedano-Prieto, D. M., Fong, A., Wilkerson, C., Chen, J. Q., Wu, M., Lo, S. H., Cheung, A. T. W., Wilson, M. D., Cardiff, R. D., Borowsky, A. D., Takada, Y. K., & Takada, Y. (2013). 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. Journal of Biological Chemistry, 288(27), 19593-19603. https://doi.org/10.1074/jbc.M113.470872