The Insulin-Like Growth Factor-I Receptor

Abstract

The nonclassical binding kinetics of IGF-I and insulin to their respective receptors, suggestive of negative cooperativity, can be readily explained by our recently proposed novel binding mechanism whereby the bivalent ligand bridges the two receptor α-subunits alternatively at opposite sites in a symmetrical receptor structure. The bivalent binding mechanism also explains bell-shaped bioactivity curves. The possible role of different binding modes versus differences in downstream signaling by insulin and IGF-I in producing specific mitogenic or metabolic responses is discussed.

Insulin-like growth factor-I signaling in human neuroblastoma cells

“…Shc expression is equal among all the neuroblastoma cell lines tested (Figure 2d). Two of the major downstream signaling pathways that mediate (De Meyts et al, 1994;Cheatham and Kahn, 1995;Miller et al, 1997;Kim and Feldman, 1998;Kim et al, 1998a). All the neuroblastoma cell lines we tested express similar levels of Akt and p42/p44 MAPK (Figure 2e and f).…”

“…Upon ligand binding of the IGF-IR, autophosphorylation of its b-subunits occurs, resulting in binding of the major IGF-IR substrates, insulin receptor substrate (IRS)-1, -2 and Shc (Pronk et al, 1993;Giorgetti et al, 1994;Myers and White, 1996). The signaling pathways mediated by Shc and IRS proteins, including the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3 kinase (PI 3-K) pathways, are implicated in the effects of IGF-I on cell survival, mitogenesis, differentiation and cytoskeletal changes (De Meyts et al, 1994;Cheatham and Kahn, 1995;Miller et al, 1997;Kim and Feldman, 1998;Kim et al, 1998a). Targeted disruption of IGF-IR signaling by antisense mRNA or dominant-negative mutants results in inhibition of tumorigenesis in vivo and in vitro by allowing apoptosis to occur (Liu et al, 1998;Reiss et al, 1998).…”

Logical analysis of timing-dependent receptor signalling specificity: application to the insulin receptor metabolic and mitogenic signalling pathways

“…For example, insulin, acting through its receptor, triggers a number of biological responses which can be divided into two broad categories. Metabolic processes, associated with uptake and subsequent storage of glucose, are generally taken to be the primary target of insulin receptor signalling, but mitogenic processes associated with DNA replication, cell growth and division are also activated to a lesser or greater degree (for reviews, see [1][2][3]). Both kinds of signalling begin with hormone binding, which results in receptor autophosphorylation and activation of the receptor tyrosine kinase, followed by a cascade of activation of intracellular signalling molecules (Scheme 1) [4,5].…”

Peptides Identify the Critical Hotspots Involved in the Biological Activation of the Insulin Receptor

“…However, both insulin and IGF-1 can induce mitogenic and metabolic effects in normal cells. It is unclear whether each ligand elicits these activities via its own receptor, or whether insulin exerts its mitogenic effects through its weak affinity binding to the IGF-1 receptor, and IGF-1 exerts its metabolic effects through the insulin receptor (3,4).…”