Insulin receptor of human cerebral gliomas. Structure and function.

Abstract

The insulin receptor from human brain tumors of glial origin was examined for the first time using intact cells (from an established cultured human glioblastoma cell line) and partially purified solubilized membranes (from cultured cells and freshly isolated human brain tumors). The structure of the glial insulin receptor subunits was assessed by affinity cross-linking of 125I-insulin with the a-subunit of the receptor, neuraminidase treatment of the cross-linked receptor, behavior of the receptor on lectin columns, and electrophoretic mobility of the phosphorylated ,8-subunit. The functions of the insulin receptor were examined by measuring specific "SI-insulin binding (receptor concentration, affinity, specificity, pH-, time-, and temperature dependence), insulin-induced down-regulation of the receptor, insulin-stimulated autophosphorylation of the 13-subunit, and phosphorylation of exogenous substrates as well as insulin-stimulated glucose uptake in glioblastoma cells. All of these properties were typical for the insulin receptor from target tissues for insulin action. The insulin receptor of the normal human brain showed the altered electrophoretic mobility and lack of neuraminidase sensitivity of its a-subunit previously reported for the rat brain receptor. There was no difference, however, in the functions of the receptor subunits (binding, phosphorylation) from the normal brain tissue and the eight human gliomal tumors. Since the glial elements compose a majority of the brain cells, the "normal" structure and function of their insulin receptor might provide a key to understanding the role of insulin in the carbohydrate metabolism of the human central nervous system.

Akt-Dependent Proapoptotic Effects of Dietary Restriction on Late-Stage Management of a Phosphatase and Tensin Homologue/Tuberous Sclerosis Complex 2–Deficient Mouse Astrocytoma

“…The observation that glucose stimulates IGF-I transcription and IGF-IR/IR tyrosine phosphorylation in a dose-dependent manner in CT-2A cells in vitro lends additional support to the contention that IGF-I may act as an autocrine/paracrine growth factor in this experimental astrocytoma model. Although the IR is expressed in several regions of the adult brain and can be expressed in human gliomas (50,51), the insulin molecule itself is not produced in the central nervous system or in the central nervous system tumors and must cross the blood-brain barrier to reach the receptor. Furthermore, a recent study showed that less than 1% of peripherally given insulin enters the brain from the circulation in rodents (51).…”

Immunohistochemical Localization of Insulin-Like Growth Factor 1 Receptors in Benign and Malignant Tissues of the Female Genital Tract

“…The a-subunits contain the extracellular li gand binding site whereas the P-subunits con tain a transmembrane domain which induces intracellular tryosine kinase activity [29,30], Recent studies have suggested furthermore that the IGF-1 receptor can be a hybrid com posed of an insulin a/p-heterodimer, forming a heterotetrameric holoreceptor complex [29][30][31][32][33][34][35][36]. Despite the fact that insulin receptors and IGF-1 receptors are encoded from different genes they are structurally homologous [37], It is believed that this homology allows insulin to bind to the IGF-1 receptor -although with less affinity than IGF-1 [6,29,38,39], Binding of insulin and IGF-1 with the receptor's a-subunit initiates a receptor-me diated signaling process on tyrosine residues by autophosphorylation of the P-subunit [28,31,[40][41][42]. This leads to a series of biological effects e.g.…”

Acute food deprivation reduces expression of diazepam-binding inhibitor, the precursor of the anorexigenic octadecaneuropeptide ODN, in mouse glial cells

“…Although insulin receptors are expressed by cultured rat astrocytes (Schechter & Yanovitch 1999), the presence of this receptor in glial cells in situ has never been reported. Insulin binding sites have only been described in freshly isolated human brain tumors of glial origin (Grunberger et al 1986). Here, we have shown by an immunohistochemical approach that insulin receptors are present in numerous cells in the area bordering the third ventricle ( Fig.…”