Precise Mapping of an Igf-i-binding Site on the Igf-1r.
From: School of Molecular and Biomedical Science, The University of Adelaide, Adelaide 5005, South Australia, Australia.
The Biochemical journal
- Publish Date: Jan 2007
- ISSN: 1470-8728
- Volume: 401
- Issue: 1
- Pages: 269-77
- Medium: Internet
- Language: English
- Citation (JAMA): Keyhanfar Mehrnaz, Booker Grant W, Whittaker Jonathan, et al. Precise Mapping of an Igf-i-binding Site on the Igf-1r.. Biochem. J. Jan 2007;401:269-77
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.
Mesh Headings (Keywords): Animals, Antibodies, Monoclonal, Binding Sites, Breast Neoplasms, Cell Line, Cell Line, Tumor, Cricetinae, Female, Humans, Insulin-Like Growth Factor I, Kidney, Mice, Peptide Mapping, Point Mutation, Protein Conformation, Receptor, IGF Type 1, Receptor, Insulin
Check for Full Text / PubMed Unique Identifier (PMID): 16981855
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