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Sci. Signal., 18 December 2012
Vol. 5, Issue 255, p. ra92
[DOI: 10.1126/scisignal.2003184]

RESEARCH ARTICLES

IGFBP7 Binds to the IGF-1 Receptor and Blocks Its Activation by Insulin-Like Growth Factors

Valentina Evdokimova1,2, Cristina E. Tognon3, Tania Benatar1, Wenyi Yang1, Konstantin Krutikov1, Michael Pollak4, Poul H. B. Sorensen3,5, and Arun Seth1*

1 Biological Sciences Platform, Sunnybrook Research Institute and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M4N 3M5, Canada.
2 Institute of Protein Research, Pushchino, Moscow Region 142290, Russian Federation.
3 Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia V5Z 1L3, Canada.
4 Departments of Medicine and Oncology, McGill University and Jewish General Hospital, Montreal, Quebec H3T 1E2, Canada.
5 Department of Pathology, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada.

Abstract: Insulin-like growth factor–binding protein 7 (IGFBP7) is a secreted factor that suppresses growth, and the abundance of IGFBP7 inversely correlates with tumor progression. Here, we showed that pretreatment of normal and breast cancer cells with IGFBP7 interfered with the activation and internalization of insulin-like growth factor 1 receptor (IGF1R) in response to insulin-like growth factors 1 and 2 (IGF-1/2), resulting in the accumulation of inactive IGF1R on the cell surface and blockade of downstream phosphatidylinositol 3-kinase (PI3K)–AKT signaling. Binding of IGFBP7 and IGF-1 to IGF1R was mutually exclusive, and the N-terminal 97 amino acids of IGFBP7 were important for binding to the extracellular portion of IGF1R and for preventing its activation. Prolonged exposure to IGFBP7 resulted in activation of the translational repressor 4E-binding protein 1 (4E-BP1) and enhanced sensitivity to apoptosis in IGF1R-positive cells. These results support a model whereby IGFBP7 binds to unoccupied IGF1R and suppresses downstream signaling, thereby inhibiting protein synthesis, cell growth, and survival.

* To whom correspondence should be addressed. E-mail: arun.seth{at}utoronto.ca

Citation: V. Evdokimova, C. E. Tognon, T. Benatar, W. Yang, K. Krutikov, M. Pollak, P. H. B. Sorensen, A. Seth, IGFBP7 Binds to the IGF-1 Receptor and Blocks Its Activation by Insulin-Like Growth Factors. Sci. Signal. 5, ra92 (2012).

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