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Type: Journal article
Title: Precise mapping of an IGF-I-binding site on the IGF-1R
Author: Keyhanfar, M.
Booker, G.
Whittaker, J.
Wallace, J.
Forbes, B.
Citation: Biochemical Journal, 2007; 401 Part 1(1):269-277
Publisher: Portland Press
Issue Date: 2007
ISSN: 0264-6021
Statement of
Mehrnaz Keyhanfar, Grant W. Booker, Jonathan Whittaker, John C. Wallace and Briony E. Forbes
Abstract: The IGF-1R [type 1 IGF (insulin-like growth factor) receptor] is activated upon binding to IGF-I and IGF-II leading to cell growth, survival and migration of both normal and cancerous cells. We have characterized the binding interaction between the IGF-1R and its ligands using two high-affinity mouse anti-IGF-1R mAbs (monoclonal antibodies), 7C2 and 9E11. These mAbs both block IGF-I binding to the IGF-1R but have no effect on IGF-II binding. Epitope mapping using chimaeras of the IGF-1R and insulin receptor revealed that the mAbs bind to the CR (cysteine-rich) domain of IGF-1R. The epitope was finely mapped using single point mutations in the IGF-1R. Mutation of Phe241, Phe251 or Phe266 completely abolished 7C2 and 9E11 binding. The three-dimensional structure showed that these residues cluster on the surface of the CR-domain. BIAcore analyses revealed that IGF-I and a chimaeric IGF-II with the IGF-I C-domain competed for the binding of both mAbs with the IGF-1R, whereas neither IGF-II nor a chimaeric IGF-I with the IGF-II C-domain affected antibody binding. We therefore conclude the IGF-I C-domain interacts with the CR (cysteine-rich) domain of the receptor at the cluster of residues Phe241, Phe251 and Phe266. These results allow precise orientation of IGF-I within the IGF-I–IGF-1R complex involving the IGF-I C-domain binding to the IGF-1R CR domain. In addition, mAbs 7C2 and 9E11 inhibited both IGF-I- and IGF-II-induced cancer cell proliferation, migration and IGF-1R down-regulation, demonstrating that targeting the IGF-1R is an effective strategy for inhibition of cancer cell growth.
Keywords: binding epitope
insulin-like growth factor (IGF)
type 1 insulin-like growth factor receptor (IGF-1R)
mono-clonal antibody
Description: Copyright © 2007 The Biochemical Society, London
DOI: 10.1042/BJ20060890
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Molecular and Biomedical Science publications

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