Endocrinology, Vol 135, 472-475, Copyright © 1994 by Endocrine Society

ARTICLES

Negative cooperativity in the insulin-like growth factor-I receptor and a chimeric IGF-I/insulin receptor

CT Christoffersen, KE Bornfeldt, CM Rotella, N Gonzales, H Vissing, RM Shymko, J ten Hoeve, J Groffen, N Heisterkamp and P De Meyts
Hagedorn Research Institute, Gentofte, Denmark.

Insulin and insulin-like growth factor-I (IGF-I) share a spectrum of metabolic and growth-promoting effects, mediated through homologous receptors that belong to the tyrosine kinase family. The dissociation rate of insulin from its receptor is affected by negative cooperativity, i.e. accelerates with increased receptor occupancy. The dose-response curve for the acceleration of tracer dissociation by unlabeled insulin has a distinct bell-shaped curve, with a progressive slowing down at insulin concentrations greater than 100 nM. The kinetics of the IGF-I interaction with its receptor has not been studied in such detail. In the present work, we report that while the IGF-I receptor exhibits negative cooperativity like the insulin receptor, the concentration dependence of the dissociation kinetics is distinct from that of native human insulin by not being bell-shaped, but monophasic like that of insulin analogues mutated at the hexamer- forming surface; it is changed to an insulin-type curve by substitution of IGF-I receptor's sequence including residues 382-565 with the homologous insulin receptor domain. The data suggest that like insulin, IGF-I has a bivalent binding mode and crosslinks two distinct areas of the two alpha subunits that are close, but distinct from the equivalent insulin receptor binding sites.

This article has been cited by other articles:

				L. Gauguin, C. Delaine, C. L. Alvino, K. A. McNeil, J. C. Wallace, B. E. Forbes, and P. De Meyts Alanine Scanning of a Putative Receptor Binding Surface of Insulin-like Growth Factor-I J. Biol. Chem., July 25, 2008; 283(30): 20821 - 20829. [Abstract] [Full Text] [PDF]

				K. H. Surinya, B. E. Forbes, F. Occhiodoro, G. W. Booker, G. L. Francis, K. Siddle, J. C. Wallace, and L. J. Cosgrove An Investigation of the Ligand Binding Properties and Negative Cooperativity of Soluble Insulin-like Growth Factor Receptors J. Biol. Chem., February 29, 2008; 283(9): 5355 - 5363. [Abstract] [Full Text] [PDF]

				J. Whittaker and L. Whittaker Characterization of the Functional Insulin Binding Epitopes of the Full-length Insulin Receptor J. Biol. Chem., June 3, 2005; 280(22): 20932 - 20936. [Abstract] [Full Text] [PDF]

				J. C. Opazo, R. E. Palma, F. Melo, and E. P. Lessa Adaptive Evolution of the Insulin Gene in Caviomorph Rodents Mol. Biol. Evol., May 1, 2005; 22(5): 1290 - 1298. [Abstract] [Full Text] [PDF]

				R. M. Stroud and J. A. Wells Mechanistic Diversity of Cytokine Receptor Signaling Across Cell Membranes Sci. Signal., May 4, 2004; 2004(231): re7 - re7. [Abstract] [Full Text] [PDF]

				V. A. Patel, A. Logan, J. C. Watkinson, S. Uz-Zaman, M. C. Sheppard, J. D. Ramsden, and M. C. Eggo Isolation and characterization of human thyroid endothelial cells Am J Physiol Endocrinol Metab, January 1, 2003; 284(1): E168 - E176. [Abstract] [Full Text] [PDF]

				J. Whittaker, A. V. Groth, D. C. Mynarcik, L. Pluzek, V. L. Gadsboll, and L. J. Whittaker Alanine Scanning Mutagenesis of a Type 1 Insulin-like Growth Factor Receptor Ligand Binding Site J. Biol. Chem., November 16, 2001; 276(47): 43980 - 43986. [Abstract] [Full Text] [PDF]

				S. Geddes, P. Holst, J. Grotzinger, R. Gill, P. Nugent, P. De Meyts, A. Wollmer, S. Wood, and J. Pitts Structure-function studies of an IGF-I analogue that can be chemically cleaved to a two-chain mini-IGF-I Protein Eng. Des. Sel., January 1, 2001; 14(1): 61 - 65. [Abstract] [Full Text] [PDF]

				J. M. Pell, R. A. Hill, C. E. H. Stewart, C. R. Weston, and H. C. Flick-Smith Enhancement of Insulin-Like Growth Factor I Activity by Novel Antisera: Potential Structure/Function Interactions Endocrinology, February 1, 2000; 141(2): 741 - 751. [Abstract] [Full Text] [PDF]

				R. Gill, C. Verma, B. Wallach, B. Urso, J. Pitts, A. Wollmer, P. De Meyts, and S. Wood Modelling of the disulphide-swapped isomer of human insulin-like growth factor-1: implications for receptor binding Protein Eng. Des. Sel., April 1, 1999; 12(4): 297 - 303. [Abstract] [Full Text] [PDF]

				A. Pizard, J. Marchetti, J. Allegrini, F. Alhenc-Gelas, and R. M. Rajerison Negative Cooperativity in the Human Bradykinin B2 Receptor J. Biol. Chem., January 16, 1998; 273(3): 1309 - 1315. [Abstract] [Full Text] [PDF]

				S. Manes, L. Kremer, J. P. Albar, C. Mark, R. Llopis, and C. Martinez-A Functional Epitope Mapping of Insulin-Like Growth Factor I (IGF-I) by Anti-IGF-I Monoclonal Antibodies Endocrinology, March 1, 1997; 138(3): 905 - 915. [Abstract] [Full Text] [PDF]