Insulin-like growth factor receptors

Abstract

SUMMARYThere are two types of insulin-like growth factor (IGF) receptors. The type I receptor generally binds IGF-I more tightly than IGF-II and also interacts weakly with insulin. The type II receptor prefers IGF-II over IGF-I and does not recognize insulin. The type I receptor is made up of an alpha binding subunit (Mr 130000) and a beta subunit (Mr 95 000) probably organized as a heterotetramer (Oizfh)■ The type II receptor consists of a single binding unit (Mr 250000). IG F stimulates phosphorylation of the beta subunit of the type I receptor in whole cells and solubilized receptor preparations. Tyrosine kinase activity is associated with the type I receptor, resulting in autophosphorylation of the beta subunit and phosphorylation of exogenous substrates. In contrast, phosphorylation of the type II receptor in whole cells is less IGF-dependent, solubilized receptor preparations are not phosphorylated, and purified type II receptors do not exhibit tyrosine kinase activity toward the artificial substrate poly(Glu,Tyr)4:1. There are many similarities between the type I IG F receptor and the insulin receptor; however, different ligand-binding properties, subtle differences in the size of alpha and beta subunits, and immunoreactivity toward anti-receptor antibodies allow us to distinguish between these two receptors. The presence of both IG F receptors as well as insulin receptors on most cells and cross-reactivity of ligands for binding to these receptors present difficulties in assigning a particular biological response to a specific receptor. The type I receptor is down-regulated by ligand while in several cell types the type II receptor is rapidly up-regulated by insulin; the mechanism of up-regulation appears to be a translocation of type II receptors to the cell surface. There are two classes of serum binding proteins for IG F, a M t 150 000 species found in adult blood and a M x 40 000 species, which predominates in foetal blood. Like the type II receptor, IG F binding proteins do not bind insulin. The binding site on the type II receptor can be distinguished from the binding protein sites by a hybrid molecule AjnsuH n-BiGF-i) which recognizes the binding protein but not the type II receptor. Binding proteins produced by cells in culture may cause confusion in the interpretation of experiments that are designed to study the binding of radiolabelled IG F to cell surface receptors in monolayer culture.

Etiology and pathogenesis of uterine leiomyomas: a review.

“…The IGF-I receptor mediates most of the biologic actions of both IGF-I and IGF-II (Cohick and Clemmons 1993), including the mitogenic, metabolic, and cellsurvival properties of IGFs through tyrosine kinase signaling activity. The IGF-II/mannose 6-phosphate receptor appears to be a bifunctional receptor serving as both a lysosomal enzyme-targeting system and a suppressor of the action of IGF-II by increasing its degradation (Nissley and Lopaczynski 1991;Oates et al 1998). The levels of IGF-I receptors in leiomyomas have been reported to exceed those of the myometrium in three studies (Chandrasekhar et al 1992;Tommola et al 1989; Van der Ven et al 1997), whereas Chandrasekhar et al found no difference in the levels of the IGF-II receptors.…”

Histamine-stimulated expression of insulin-like growth factors in human glioma cells

“…The specific importance of type II IGF receptors for cells of the glial lineage is suggested by the presence of high levels of this receptor, but not of type I IGF receptors, in a human glioblastoma cell line (Laurenzi et al, 1995) and by the preferential endocytosis of IGF-IH by rat neonatal astrocytes (Auletta et al, 1992). In most other systems, the type I IGF receptors mediate the mitogenic effect of both IGF-I and IGF-II (Nissley and Lopaczynski, 1991), and aIR3 generally inhibits IGF-I-stimulated growth (Nissley and Lopaczynski, 1991; Van der Ven et al, 1993b). However, the type H IGF receptor has been implicated as a mediator of IGFinduced growth-stimulatory effects in other models (reviewed in Nissley and Lopaczynski, 1991;additional observations in Mathieu et al, 1990, De Leon et al, 1992and Fournier et al, 1993.…”

“…In most other systems, the type I IGF receptors mediate the mitogenic effect of both IGF-I and IGF-II (Nissley and Lopaczynski, 1991), and aIR3 generally inhibits IGF-I-stimulated growth (Nissley and Lopaczynski, 1991; Van der Ven et al, 1993b). However, the type H IGF receptor has been implicated as a mediator of IGFinduced growth-stimulatory effects in other models (reviewed in Nissley and Lopaczynski, 1991;additional observations in Mathieu et al, 1990, De Leon et al, 1992and Fournier et al, 1993. We found that 3-galactosidase, but not aIR3, completely inhibits IGF-Istimulated growth in G47 cells.…”

Expression of insulin-like growth factors (IGFs), their receptors and IGF binding protein-3 in normal, benign and malignant smooth muscle tissues

“…Both IGFs can bind to the type I IGF receptor with similar affinity, whereas the type II IGF/mannose 6-phosphate receptor preferentially binds IGF-II. The type I IGF receptor mediates the mitogenic action of both IGFs (Nissley and Lopaczynski, 1991), and the type II IGF receptor is mainly associated with differentiation and histomorphogenesis (Nissley and Lopaczynski, 1991). IGF functions are modulated by IGF-binding proteins (IGFBPs), of which six distinct variants have been characterized (Drop et al, 1992).…”