Insulin receptor kinase

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... 

Figure 7.5 Schematic diagram illustrating proposed mechanism for chromodulin-activated insulin receptor kinase activity. (Adapted with permission from Figure 1 of Vincent, J. B. J. Nutr., 2000, 130, 715-718.)...

Design concepts are now being applied more effectively to mineral supplements. For example, by controlling the redox potential of iron, toxic effects associated with excess Fe(II) during parental supplementation can be avoided. Peroxovanadate complexes can inhibit insulin-receptor-associated phosphotyrosine phosphatase and activate insulin receptor kinase, and both V(IV) and V(V) offer promise as potential insulin mimics. 

It is not clear whether V(V) or V(IV) (or both) is the active insulin-mimetic redox state of vanadium. In the body, endogenous reducing agents such as glutathione and ascorbic acid may inhibit the oxidation of V(IV). The mechanism of action of insulin mimetics is unclear. Insulin receptors are membrane-spanning tyrosine-specific protein kinases activated by insulin on the extracellular side to catalyze intracellular protein tyrosine phosphorylation. Vanadates can act as phosphate analogs, and there is evidence for potent inhibition of phosphotyrosine phosphatases (526). Peroxovanadate complexes, for example, can induce autophosphorylation at tyrosine residues and inhibit the insulin-receptor-associated phosphotyrosine phosphatase, and these in turn activate insulin-receptor kinase. 

Adipocyte lipid-binding protein (ALBP) is the adipocyte member of an intracellular hydrophobic ligand-binding protein family. ALBP is phosphorylated by the insulin receptor kinase upon insulin stimulation. The crystal structure of recombinant murine ALBP has been determined and refined to 2.5 A. The final R-factorfor the model is 0.18 with good canonical properties. 

Breum L, Bjerre U, Bak JF, Jacobsen S, Astrup A (1995) Long-term effects of fluoxetine on glycemic control in obese patients with non-insulin-dependent diabetes mellitus or glucose intolerance influence on muscle glycogen synthase and insulin receptor kinase activity. Metabolism 44 1570-1576... 

There is recent data to suggest that there may in fact be a biological role for the internalized insulin and EGF receptors (both of which are themselves tyrosine kinases). Thus, microinjection of insulin-occupied insulin receptors into Xenopus oocytes causes the increased phosphorylation of ribosomal protein S6 (a known substrate for the insulin receptor/kinase) [62] and the EGF receptor in endocytic vesicles has been shown to retain its kinase activity [63]. Whether the internalized insulin receptor/kinase or EGF receptor/kinase has a physiological role or not is as yet unknown. Clearly, though, these data suggest that there is much more to be learned about the role of internalized hormone-receptor complexes, especially those where the receptor possesses intrinsic enzymatic activity. 

The insulin-receptor kinase was also shown to be capable of phosphorylating the... 

Kobayashi et al. (1992) found an increase of insulin sensitivity by activating insulin receptor kinase in genetically obese Wistar fatty rats treated with various doses of pioglitazone. 

Kobayashi M, Iwanshi M, Egawa K, Shigeta Y (1992) Pioglitazone increases insulin sensitivity by activating insulin receptor kinase. Diabetes 41 476-483... 

A process by which a substrate protein, usually a receptor, catalyzes selfphosphorylation, usually at a tyrosine residue. The mechanism can be either intramolecular (cis) or intermolecular (trans) although at least one system has been described with both cis and trans processes. See Cobb, M.H., Sang, B.-C., Gonzalez, R., Goldsmith, E., and Ellis, L., Autophosphorylation activates the soluble cytoplasmic domain of the insulin receptor in an intermolecular reaction, J. Biol. Chem. 264, 18701-18706, 1989 Frattali, A.L., Treadway, J.L., and Pessin, J.E., Transmembrane signaling by the human insulin receptor kinase. Relationship between intramolecular subunit trans- and c A-autophosphorylation and substrate kinase activation, J. Biol. Chem. 267, 19521-19528, 1992 Rim, J., Faurobert, E., Hurley,... 

J. B., and Oprian, D.D., In vitro assay for fran -phosphorylation of rhodopsin by rhodopsin kinase. Biochemistry 36, 7064-7070, 1997 Cann, A.D., Bishop, S.M., Ablooglu, A.J., and Kobanski, R.A., Partial activation of the insulin receptor kinase domain by juxtamembrane autophosphorylation. Biochemistry 37,11289-11300,1998 Iwasaki, Y., Nishiyama, H., Suzuki,... 

Contrasting with this troublesome aspect, the lack of conservation of the wrapping (dehydron) pattern across kinases has paramount potential to promote drug specificity, as illustrated in Fig. 7.1c, d. Thus, the structural alignment of the focal adhesion kinase (FAK, PDB.2J0L) and the insulin receptor kinase (PDB.1GAG)... 

Focal adhesion kinase Insulin receptor kinase... 

BASIC CHARACTERISTICS OF TRANSMEMBRANE SIGNALLING THROUGH THE INSULIN RECEPTOR KINASE... 

For a long time the search for tyrosine-phosphorylated proteins which might serve as a substrate for the insulin receptor kinase was unsuccessful. White... 

The first evidence of a cellular substrate of the insulin receptor kinase came from White et al. (1985b) who described a 185 kDa phosphoprotein in Fao hepatoma cells which was rapidly phosphorylated upon insulin stimulation. ppl85, recently renamed IRS-1, is a cytosolic protein with at least 30 potential serine/threonine- and 10 potential tyrosine-phosphorylation sites (Sun et al., 1991). Six of these tyrosine-phosphorylation sites lie in the amino acid sequence motif Tyr-Met-Xaa-Met which is recognized in its phosphorylated form by the SH2 (src homology 2) domain of the phosphatidylinositol 3-kinase (PI 3-kinase) (Sun et al., 1991). 

IRS-1 is highly phosphorylated on serine residues in the basal state insulin stimulation leads to additional tyrosine phosphorylation and an increase in serine phosphorylation (Sun et al., 1991, 1992). Mutated kinase-negative insulin receptors that cannot be autophosphorylated after ligand binding are completely unable to phosphorylate IRS-1 (Chou et al., 1987). Thus phosphorylation of the insulin receptor kinase seems to be a prerequisite for IRS-1 phosphorylation at tyrosine residues (White et al., 1988a Wilden et al., 1990 Backer et al., 1991b). After insulin stimulation, IRS-1 is rapidly tyrosine phosphorylated and thereby associated with PI 3-kinase (Backer et al., 1991b). It is believed that this association leads to activation of PI 3-kinase which results in phosphorylation of phosphatidylinositol molecules (Cantley et al., 1991). 

It has been known for a long time that a number of enzymes are regulated by insulin through phosphorylation and dephosphorylation at serine residues (Kahn, 1985). Therefore, a signal transduction from the tyrosine-specific insulin receptor kinase to a serine-specific kinase must occur. The serine kinase that might fulfil both functions in the insulin signal-transduction chain has not yet been identified however, there are several possible candidates for these so called switch kinases (Fig. 10). 

The above may be of pathophysiological relevance as a decreased basal and insulin-stimulated glycogen phosphatase activity and phosphorylase phosphatase activity (Type-1 protein phosphatase, PP-1) in the skeletal muscle of insulin-resistant individuals has been found (Freymond era/., 1988 Kida era/., 1990, 1992 Damsbo et al., 1991). Other studies suggest increased phosphotyrosine phosphatase activity in patients with NIDDM who show decreased autoactivation of the insulin receptor kinase (McGuire et al., 1991). 

It is believed that the insulin receptor kinase might activate other serine-specific kinases which have a dual function, i.e. further transduction of the... 

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