Insulin receptor protein kinase

Tyr insulin receptor, protein kinase C, protein kinase G, protein kinase A... 

F. 11.14. The insulin receptor-protein kinase B signaling pathway. Abbreviations Ins, insulin IRS, insulin receptor substrate PH domains, pleckstrin homology domains PDKl, phosphoinositide-dependent protein kinase 1 PKB, protein kinase B. The final phosphorylation step that activates PKB is shown in blue. 

The insulin receptor protein represents a ligand-operated enzyme (C), a catalytic receptor. When insulin binds to the extracellular attachment site, a tyrosine kinase activity is "switched on at the intracellular portion. Protein phosphorylation leads to altered cell function via the assembly of other signal proteins. Receptors for growth hormones also belong to the catalytic receptor class. 

Wilden, P.A. Kahn, C.R. The level of insulin receptor tyrosine kinase activity modulates the activities of phosphatidylinositol 3-kinase, microtubule-associated protein, and S6 kinases. Mol. Endocrinol., 8, 558-567 (1994)... 

Fig. 3. Artificial substrates for the insulin receptor tyrosyl kinase. Shows the Km values exhibited by basal and insulin-stimulated kinase activities together with the insulin-stimulated increase in Vmax for a variety of substrates. These include angiotensin and its modified derivative (VAL-5), also synthetic peptides of Glu Tyr and the so-called sarc -peptide, which bears the sequence around the tyrosyl autophosphorylation site of the sarc protein. Data are also given for a G-protein mixture of Gj/G0. These studies (referred to in the text) all employed soluble, purified insulin receptor preparations. No evidence has yet been presented for tyrosyl phosphorylation of substrates using isolated membrane preparations containing insulin receptors.

It remains to be seen whether the insulin receptor can activate Gins either directly or indirectly and whether the tyrosyl kinase activity of the receptor is involved. However, it is of interest that recently purified G and Gj have been shown to be capable of being phosphorylated by the insulin receptor tyrosyl kinase [113]. Such phosphorylation occurred on both the a and the /3 subunits. However, phosphorylation only occurred using the intact holomeric form of these G-proteins and not the activated, dissociated subunits. Other G-proteins may also be phosphorylated. However, whether any functional changes ensue and whether such reactions can occur in vivo. will have to be determined. 

PHOSPHORYLA TWN chronic myelongenous leukemia-associated KIO BCR-ABL Drosophila Kr protein hepatitis B virus core and precore antigens human c-fos protein human c-myc protein human EGF receptor human epidermal growth factor receptor (tyrosine kinase domain) human immunodeficiency virus p24 human immunodeficiency virus tat protein human insulin receptor 6-subunit human insulin receptor - tyrosine kinase domain... 

Figure 21.20. Insulin Activates Protein Phosphatase 1. Insulin triggers a cascade leading to the activation of protein phosphatase 1, which results in the stimulation of glycogen synthesis and inhibition of its breakdovm. The activated receptor tyrosine kinase switches on a putative master kinase that phosphorylates the insulin-sensitive protein kinase. In turn, the glycogen-targeting suhunit (Rgj suhunit) of the phosphatase is phosphorylated, which activates the enzyme. [After P. Dent, A. Lavoirme, S. Nakielny, F. B. Caudwell, P. Watt, and P. Cohen. Nature 348(1990) 306.]...

In Xenopus o(x es (126,134), treatment with metformin has been shown to increase insulin receptor tyrosine kinase activity associated with activation of phospholipase C and increased levels of IPg and intracellular Ca. Thus metformin, through increasing receptor tyrosine kinase activity, may facilitate IRS protein phosphorylation and activation of phosphatidylinositol-3-kinase, leading to increased glucose uptake. 

On phosphorylation, the insulin receptor tyrosine kinase is activated. Because the two units of the receptor are held in close proximity to one another, additional sites within the receptor also are phosphorylated. These phosphorylatcd sites act as docking sites for other substrates, including a class of molecules referred to as insulin-receptor substrates (IJ S). From the IRS protein, the signal is conveyed through a series of membrane-anchored molecules to a protein kinase that finally leaves the membrane (Figure 14,20), lRS-1 and IRS-2 are two homologous proteins with a common... 

Figure 14.21 The modular structure of Insulin receptor substrates IRS-1 and IRS-2 This schematic view represents the amino acid sequence common to IRS-1 and lRS-2. Each protein contains a pleckstrin homology domain (which binds phosphoinositide lipids), a phospbotyrosine-binding domain, and four sequences that approximate Tyr-X-X-Met (YXXM). The latter are phosphorylated by the insulin receptor tyrosine kinase.

The favorable results in the case of the insulin receptor tyrosine kinase prompted the application of the bisubstrate analog approach to a serine/ threonine kinase [44]. Protein kinase A was selected because it had been... 

Inhibition of EGF-R tyrosine kinase by hypericin 1 was shown to be irreversible, non-competitive and time as well as temperature dependent. The IC50 increased from 0.75 pM in the dark to 44 nM with light illumination for 30 min. This effect was presumably due to a type I photosensitization mechanism since exclusion of oxygen did not alter the inhibition curve. Some Ser/Thr protein kinases (e.g., protein kinase A, casein kinase 1 and 2) and the enzyme 5 -nucleotidase were not inhibited even at concentrations > 100 pM [144]. However, the same authors recently reported that hypericin 1 in addition to protein kinase C also caused the light-dependent inhibition of certain other Ser/Thr kinases (e.g. protein kinase CK-2, mitogen-activated kinase) and the insulin receptor tyrosine kinase, while it was ineffective towards the cytosolic tyrosine kinases Lyn, Fgr, TPK-IIB and CSK. These results suggest that distantly related protein kinases could still share common reactive domains for the interaction with hypericin 1 [156]. In contrast to the above mentioned studies, Richter and Davies [157] observed no inhibition of EGF-induced tyrosine phosphorylation of the EGF-R in HN5 squamous carcinoma... 

Taylor, S.S. Radzio-Andzelm, E. Hunter, T. How do protein kinases discriminate between serine/threonine and tyrosine Structural insights from the insulin receptor protein-tyrosine kinase. FASEB J., 9, 1255-1267 (1995)... 

Ellis, L. Levine, B.A. Use of recombinant baculoviruses and IH nuclear magnetic resonance to study tyrosine phosphorylation by a soluble insulin receptor protein-tyrosine kinase. Methods EnzymoL, 200, 660-670 (1991)... 

The disturbances in protein phosphorylation patterns in Cr(VI) treated cells are considered among the possible reasons for Cr(VI) toxicity and carcinogenicity (295, 626). The question then arises, as to whether the proposed beneficial action of Cr(III) in activation of insulin receptor tyrosine kinase (496,497) is, in fact, a sign of Cr(III) toxicity (5). Unpredictable changes in the concentrations of phosphorylated proteins in the presence of excess Cr(III) may lead to abnormalities in the cell signaling pathways and ultimately to cancer (5). An answer to this dilemma may lie in selectivity studies (which are yet to be performed) of different types of Cr(III) complexes toward various kinases or phosphatases. Clearly, the Cr(III) complexes of potential use as anti-diabetics should be highly selective in the activation of protein tyrosine kinase of the p-subunit of the insulin receptor (496, 497). On the other hand, the potential ability of some Cr(III) complexes to selectively activate non-insulin dependent protein kinases may lead to beneficial effects, such as stimulation of immune responses or antitumor activity (627, 628). 

Binding of insulin to its receptor, and of IGF-I to IGF-I receptors, leads to activation of insulin receptor tyrosine kinase and autophosphorylation of the receptor, followed by tyrosine phosphorylation of the insulin receptor substrate (IRS) protein (Shpakov and Pertseva, 2000). This then activates downstream pathways such as phospholipase Cy (PLC-y, Gasparini et al., 2002), phosphoinositide 3-kinase (PI3K Sun et al., 1993a), and MAPK (Giovannone et al., 2000 see Plum et al., 2005 for review). The activities of tyrosine kinases are lower in late-onset AD brains than in age-matched controls (Frolich et al., 1998, 1999). 

A different mode of interference of ascorbate with growth factor receptors was suggested by Monteiro et al. (1993). In HER 14 cells, physiological concentrations of ascorbate inhibited a protein tyrosine phosphatase acting on the EGF receptor. The effect could be prevented by EGF. Interestingly, the inhibitory effect of ascorbate on the phosphatase was more pronounced at low concentrations of ascorbate and low cell density, which was interpreted by the authors as indicating a prooxidant action of ascorbate. Activation of signal transduction pathways has been described for the insulin receptor tyrosine kinase (Koshio et al., 1988) and a protein tyrosine kinase in the rat liver plasma membrane (Chan et al., 1986). 

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