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

Research output: Contribution to journalArticle

19 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

Fingerprint

Somatomedin Receptors
Somatomedins
Integrins
Carcinogenesis
Cells
Cell Survival
Insulin Receptor
Neoplasms
Chemical activation

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

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

In: Journal of Biological Chemistry, Vol. 288, No. 27, 05.07.2013, p. 19593-19603.

Research output: Contribution to journalArticle

Fujita, M, Ieguchi, K, Cedano-Prieto, DM, Fong, A, Wilkerson, C, Chen, JQ, Wu, M, Lo, SH, Cheung, ATW, Wilson, MD, Cardiff, RD, Borowsky, AD, Takada, YK & 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, vol. 288, no. 27, pp. 19593-19603. https://doi.org/10.1074/jbc.M113.470872
Fujita, Masaaki ; Ieguchi, Katsuaki ; Cedano-Prieto, Dora M. ; Fong, Andrew ; Wilkerson, Charles ; Chen, Jane Q. ; Wu, Mac ; Lo, Su Hao ; Cheung, Anthony T W ; Wilson, MacHelle D. ; Cardiff, Robert D. ; Borowsky, Alexander D. ; Takada, Yoko K. ; Takada, Yoshikazu. / 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. In: Journal of Biological Chemistry. 2013 ; Vol. 288, No. 27. pp. 19593-19603.
@article{76b258494e1d419a9bab5e5c09741f42,
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. 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.",
author = "Masaaki Fujita and Katsuaki Ieguchi and Cedano-Prieto, {Dora M.} and Andrew Fong and Charles Wilkerson and Chen, {Jane Q.} and Mac Wu and Lo, {Su Hao} and Cheung, {Anthony T W} and Wilson, {MacHelle D.} and Cardiff, {Robert D.} and Borowsky, {Alexander D.} and Takada, {Yoko K.} and Yoshikazu Takada",
year = "2013",
month = "7",
day = "5",
doi = "10.1074/jbc.M113.470872",
language = "English",
volume = "288",
pages = "19593--19603",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "27",

}

TY - JOUR

T1 - 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

AU - Fujita, Masaaki

AU - Ieguchi, Katsuaki

AU - Cedano-Prieto, Dora M.

AU - Fong, Andrew

AU - Wilkerson, Charles

AU - Chen, Jane Q.

AU - Wu, Mac

AU - Lo, Su Hao

AU - Cheung, Anthony T W

AU - Wilson, MacHelle D.

AU - Cardiff, Robert D.

AU - Borowsky, Alexander D.

AU - Takada, Yoko K.

AU - Takada, Yoshikazu

PY - 2013/7/5

Y1 - 2013/7/5

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84880047955&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84880047955&partnerID=8YFLogxK

U2 - 10.1074/jbc.M113.470872

DO - 10.1074/jbc.M113.470872

M3 - Article

C2 - 23696648

AN - SCOPUS:84880047955

VL - 288

SP - 19593

EP - 19603

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 27

ER -