Kinase, kinases mechanism

A/-(2,3-Epoxypropyl)-A/-amidinoglycine [70363-44-9] (21) was shown to be an affinity label of creatine kinase. Its mechanism of covalent bond formation is outlined as follows ... 

Zhou G, Myers R, Li Y et al (2001) Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 108 1167-1174... 

Kinase Inhibitors Mechanism of Action Biological Consequences... 

Khandaker MH, Xu L, Rahimpour R, et al. CXCR1 and CXCR2 are rapidly down-modulated by bacterial endotoxin through a unique agonist-independent, tyrosine kinase-dependent mechanism. J Immunol 1998 161 1930-1938. 

MAPK kinase (MAPKK). MAPK kinase itself is activated by phosphorylation by still another protein kinase, termed MAPK kinase kinase (MAPKKK). MAPK kinase kinase is activated upon interaction with a member of the Ras superfamily of small G proteins, which are bound to the plasma membrane (see Ch. 19). The exact mechanism of activation remains unknown, but it is believed that Ras and related proteins, in the activated GTP-bound form, can bind MAPK kinase kinase and thereby draw the kinase to the plasmalemma, where it is activated by as yet unknown factors, perhaps even an additional kinase, MAPK kinase kinase kinase (MAPKKKK). The mechanism governing the activation of Ras and related proteins by extracellular signals is quite complex and involves numerous Tinker proteins, for example She, Grb and Sos, that couple Ras to a variety of plasmalemma-associated growth factor-protein tyrosine kinase receptors (see Chs 20,24 and 27). 

Two tyrosine kinase-based mechanisms have been described the IR and the JAK/ STAT cascades. It should not be assumed that these are either/or mechanisms as there may be parallel transduction (cross-talk) between the two pathways. For example, leptin, an appetite suppressor described more fully in Chapter 9 is a cytokine-like peptide produced by adipose tissue, which signals in the hypothalamus of the brain via JAK2/STAT3, but also influences the IRS/PI3K pathway. 

Kozawa, O., Tanabe, K., Ito, H., Matsuno, H., Niwa, M., Kato, K. and Uematsu, T., 1999b, Sphingosine 1-phosphate regulates heat shock protein 27 induction by ap38 MAP kinase-dependent mechanism in aortic smooth muscle cells, Exp. Cell Res. 250 376-380. 

The protein kinase mechanism uses aspartate as a general base, weakening the hydrogen—oxygen bond of the hydroxyl-containing residues. This allows the hydroxyl nucleophile of the substrate to attack the 7-phosphate of ATP, producing a phosphorylated peptide product and ADP (Scheme 2). 

Palmer, T. M., Benovic, J. L., and Stiles, G. L. (1995) Agonist-dependent phosphorylation and desensitization of the rat A3 adenosine receptor. Evidence for a G-protein-conpled receptor kinase- mediated mechanism. J. Biol. Chem. 270, 29607-29613. 

Keywords Src Src family kinases Kinase selectivity Structure-based design Mechanism-based design... 

Sirolimus (Rapamune) is structurally related to tacrolimus. It is approved for use as an adjunctive agent in combination with cyclosporine for prevention of acute renal allograft rejection. It blocks IL-2-dependent T-cell proliferation by inhibiting a cytoplasmic serine-threonine kinase. This mechanism of action is different from those of tacrolimus and cyclosporine. This allows sirolimus to augment the immunosuppressive effects of these drugs. 

Pedersen IM, Buhl AM, Klausen P et al. The chimeric anti-CD20 antibody rituximab induces apoptosis in B-cell ehronie lymphoeytie leukemia cells through a p38 mitogen activated protein-kinase-dependent mechanism. B/oo[Pg.226]

Corbett, J. A., Sweetland, M. A., Lancaster, J. R., Jr., and McDaniel, M. L. (1993a). A 1 hour pulse with IL-lb induces the formation of nitric oxide and inhibits insulin secretion by rat islets of Langerhans Evidence for a tyrosine kinase signaling mechanism. FASEBJ. 7, 369-374. 

Yan, H. Tsai, M.-D. Nucleoside monophosphate kinases structure, mechanism, and substrate specificity. Adv. EnzymoL Relat. Areas Mol. Biol., 73, 103-134 (1999)... 

Glucagon decreases cholesterol synthesis in isolated hepatocytes [131,132] apparently because it reduces the fraction of hydroxymethylglutaryl-CoA reductase in the active form [131,132], This is due to an increase in reductase kinase activity [133], However, there is no evidence that cAMP-dependent protein kinase phos-phorylates either the reductase, reductase kinase or reductase kinase kinase [134], It has been proposed that the phosphorylation state of these enzymes is indirectly controlled through changes in the activity of protein phosphatase I [132,134], This phosphatase can dephosphorylate and activate the reductase [134,135] and its activity can be controlled by a heat stable inhibitor (inhibitor 1), the activity of which is increased by cAMP-dependent phosphorylation [136,137], Since the phosphorylated forms of acetyl-CoA carboxylase, ATP-citrate lyase, pyruvate kinase, phos-phorylase, phosphorylase kinase and glycogen synthase are also substrates for protein phosphatase I [135], this mechanism could also contribute to their phosphorylation by glucagon. 

Glucagon affects hepatic lipid metabolism. A major effect is inhibition of fatty acid synthesis, which is mainly due to the phosphorylation and inhibition of acetyl-GoA carboxylase by cAMP-dependent protein kinase. ATP-citrate lyase is also phosphorylated, but it is unclear that this is involved in the inhibition of lipogene-sis. Glucagon also inhibits cholesterol synthesis apparently due to a decrease in the activity of hydroxymethylglutaryl-CoA reductase. This is thought to result from a decrease in the activity of protein phosphatase I due to the increased phosphorylation and activation of a heat stable inhibitor by cAMP-dependent protein kinase. This mechanism could also contribute to the effects of glucagon on other hepatic enzymes. 

Bolan EA, Kivell B, Jaligam V, Oz M, Jayanthi LD, et al. 2007. D2 receptors regulate dopamine transporter function via and extracellular signal-regulated kinases 1 and 2-depen-dent and phosphoinositide 3 kinase-independent mechanism. Mol Pharmacol 71 1222-1232. 

---