The direct binding of insulin-like growth factor-1 (IGF-1) to integrin αvβ3 is involved in IGF-1 signaling

Jun Saegusa, Satoshi Yamaji, Katsuaki Ieguchi, Chun Yi Wu, Kit S. Lam, Fun Tong Liu, Yoko K. Takada, Yoshikazu Takada

Research output: Contribution to journalArticle

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Abstract

It has been proposed that ligand occupancy of integrin αvβ3 with extracellular matrix ligands (e.g. vitronectin) plays a critical role in insulin-like growth factor-1 (IGF-1) signaling. We found that expression of αvβ3 enhanced IGF-1-induced proliferation of Chinese hamster ovary cells in serum-free conditions (in the absence of vitronectin). We hypothesized that the direct integrin binding to IGF-1 may play a role in IGF-1 signaling. We demonstrated that αvβ3 specifically and directly bound to IGF-1 in cell adhesion, enzyme-linked immunosorbent assay-type binding, and surface plasmon resonance studies. Welocalized the amino acid residues of IGF-1 that are critical for integrin binding by docking simulation and mutagenesis. We found that mutating two Arg residues at positions 36 and 37 in the C-domain of IGF-1 to Glu (the R36E/R37E mutation) effectively reduced integrin binding. Interestingly, although the mutant still bound to IGF1R, it was defective in inducing IGF1R phosphorylation, AKT and ERK1/2 activation, and cell proliferation. Furthermore wild type IGF-1 mediated co-precipitation of αvβ3 and IGF1R, whereas the R36E/R37E mutant did not, suggesting that IGF-1 mediates the interaction between αvβ3 and IGF1R. These results suggest that the direct binding to IGF-1 to integrin αvβ3 plays a role in IGF-1 signaling through ternary complex formation (αvβ3-IGF-IGF1R), and integrin-IGF-1 interaction is a novel target for drug discovery.

Original languageEnglish
Pages (from-to)24106-24114
Number of pages9
JournalJournal of Biological Chemistry
Volume284
Issue number36
DOIs
Publication statusPublished - Sep 4 2009
Externally publishedYes

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Somatomedins
Integrins
Vitronectin
Ligands
Immunosorbents
Mutagenesis
Phosphorylation
Surface Plasmon Resonance
Cell adhesion
Cell proliferation
Surface plasmon resonance
Drug Discovery
Coprecipitation
Cricetulus
Cell Adhesion
Extracellular Matrix
Ovary
Assays
Chemical activation
Enzyme-Linked Immunosorbent Assay

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Saegusa, J., Yamaji, S., Ieguchi, K., Wu, C. Y., Lam, K. S., Liu, F. T., ... Takada, Y. (2009). The direct binding of insulin-like growth factor-1 (IGF-1) to integrin αvβ3 is involved in IGF-1 signaling. Journal of Biological Chemistry, 284(36), 24106-24114. https://doi.org/10.1074/jbc.M109.013201

The direct binding of insulin-like growth factor-1 (IGF-1) to integrin αvβ3 is involved in IGF-1 signaling. / Saegusa, Jun; Yamaji, Satoshi; Ieguchi, Katsuaki; Wu, Chun Yi; Lam, Kit S.; Liu, Fun Tong; Takada, Yoko K.; Takada, Yoshikazu.

In: Journal of Biological Chemistry, Vol. 284, No. 36, 04.09.2009, p. 24106-24114.

Research output: Contribution to journalArticle

Saegusa, J, Yamaji, S, Ieguchi, K, Wu, CY, Lam, KS, Liu, FT, Takada, YK & Takada, Y 2009, 'The direct binding of insulin-like growth factor-1 (IGF-1) to integrin αvβ3 is involved in IGF-1 signaling', Journal of Biological Chemistry, vol. 284, no. 36, pp. 24106-24114. https://doi.org/10.1074/jbc.M109.013201
Saegusa, Jun ; Yamaji, Satoshi ; Ieguchi, Katsuaki ; Wu, Chun Yi ; Lam, Kit S. ; Liu, Fun Tong ; Takada, Yoko K. ; Takada, Yoshikazu. / The direct binding of insulin-like growth factor-1 (IGF-1) to integrin αvβ3 is involved in IGF-1 signaling. In: Journal of Biological Chemistry. 2009 ; Vol. 284, No. 36. pp. 24106-24114.
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