The Insulin Receptor

Loss of the cell s responsiveness to the hormone insulin caused by pathological alterations in the insulin receptor signal transduction pathway, and often leading... 

The insulin receptor is a transmembrane receptor tyrosine kinase located in the plasma membrane of insulin-sensitive cells (e.g., adipocytes, myocytes, hepatocytes). It mediates the effect of insulin on specific cellular responses (e.g., glucose transport, glycogen synthesis, lipid synthesis, protein synthesis). 

Insulin Receptor. Figure 1 Structure and function of the insulin receptor. Binding of insulin to the a-subunits (yellow) leads to activation of the intracellular tyrosine kinase ((3-subunit) by autophosphorylation. The insulin receptor substrates (IRS) bind via a phospho-tyrosine binding domain to phosphorylated tyrosine residues in the juxtamembrane domain of the (3-subunit. The receptor tyrosine kinase then phosphorylates specific tyrosine motifs (YMxM) within the IRS. These tyrosine phosphorylated motifs serve as docking sites for some adaptor proteins with SRC homology 2 (SH2) domains like the regulatory subunit of PI 3-kinase. 

Stimulation of the insulin receptor results in the activation of two major pathways [3] (i) the mitogen-activated protein (MAP) kinase cascade (discussed in chapter MAP kinase cascade) and (ii) the phospha-tidylinositol 3-kinase (PI 3-kinase) pathway which has been extensively studied in the context of the metabolic responses to insulin (summarized in Table 1 and Fig. 2). 

Insulin Analogs. At present, the only known ligands of the insulin receptors are insulin isotypes from different species and a number of synthetic analogs... 

Concanavalin A is a plant lectin from the jack bean (Canavalia ensiformis) which binds with high affinity to mannose residues of glycoproteins. Concanavalin A is known to stimulate the tyrosine kinase activity of the INSR (3-subunit with consecutive activation of kinases downstream the insulin receptor (IRS, PI 3-kinase). It is believed that Concanavalin A stimulates the activation and autophosphorylation of the INSR kinase through aggregation of the receptor, although the precise mechanism of action is unclear. 

Kido Y, Nakae J, Accili D (2001) Clinical review 125 the insulin receptor and its cellular targets. J Clin Endocrinol Metab 86 972-979... 

The insulin-like growth factor I receptor is closely related to the insulin receptor. The RTK activity of the IGF-I receptor is regulated by intermolecular autophosphorylation at three sites within the activation loop. The crystal structure of the trisphosphorylated form of IGF-I RTK domain with an ATP analog and a specific peptide substrate showed that autophosphorylation stabilizes the activation loop in a conformation that facilitates catalysis. Furthermore, the structure revealed how... 

Like other growth factors, the IDGFs presumably activate a signal transduction pathway that ultimately controls transcription and replication. One possibility is that they interact in some way with the insulin receptor (InsR) pathway, which has... 

An intriguing possibility is that the IDGFs could interact as lectins with the insulin receptor itself, which is already known to bind other lectins. Wheat germ... 

Raff I have a question about the insulin receptor glycosylation. Is it needed for function, or is it just needed to get the receptor to the plasma membrane in a stable form ... 

Nadiv O, Shinitzky M, Manu H, Hecht D, Roberts CT Jr, LeRoith D, Zick Y (1994) Elevated protein tyrosine phosphatase activity and increased membrane viscosity are associated with impaired activation of the insulin receptor kinase in old rats. Biochem J 298(Pt 2) 443 150... 

Waugh, S.M., DiBella, E.E., and Pilch, P.F. (1989) Isolation of a proteolitically derived domain of the insulin receptor containing the major site of cross-linking/binding. Biochemistry 28, 3448-3455. 

Wedekind, F., Baer-Pontzen, K., Bala-Mohan, S., Choli, D., Zahn, H., and Brandenburg, D. (1989) Hormone binding site of the insulin receptor Analysis using photoaffinity-mediated avidin complexing. Biol. Chem. Hoppe-Seyler 370, 251-258. 

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