Protein-tyrosine phosphatases

The extent of tyrosine phosphorylation of signal proteins is determined both by the activity of the tyrosine kinases and also the activity of tyrosine-specific protein phosphatases. If the total activity of both enzymes in the cell is considered, it is found that there is a preponderance of protein tyrosine phosphatase activity compared to tyrosine kinase activity. In contrast, the activities of the Ser/Thr-specific protein kinases and protein phosphatases are approximately balanced. It is estimated that the activity of the protein tyrosine phosphatases is about 3-4 orders of magnitude higher than the activity of the protein tyrosine kinases. With this relationship between the activities, it is not surprising that the net level of tyrosine phosphorylation in the cell is very low and that tyrosine phosphorylation is often only transient. Consequently, it took a relatively long time until the importance of tyrosine phosphorylation for signal transduction was assessed correctly. 

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Zhang, Z.-Y., Dixon, J. E. Active site labeling of the yersinia protein tyrosine phosphatase The determination of the pKa of active site cysteine and the function of the conserved histidine 402. Biochem. 32 (1993) 9340-9345. 

Figure 4 Schematic diagram of the first step of the reaction catalyzed hy bovine protein tyrosine phosphatase (BPTP) formation of the cysteinyl phosophate intermediate.

Hydrogen peroxide (H202) exhibits insulin-like activity in isolated cells. Like that of vanadate, this effect is thought to be mediated by inhibition of protein-tyrosine phosphatases. 

Protein Phosphatases. Figure 3 Classification of protein tyrosine phosphatases. See text for details. Common names for selected PTPs are used according to Ref. [2]. 

Tonks NK (2006) Protein tyrosine phosphatases from genes, to function, to disease. Nat Rev Mol Cell Biol 7 833-846... 

When considering the role of phosphorylation in the regulation of the HS response, it is indeed curious that oxidative stress and heat induce a protein tyrosine phosphatase at the transcriptional level (Keyse and Emslie, 1992). Whether this phosphatase has any role in the regulation of HSF phosphorylation is not known, but it does indicate that both transcriptional and translational regulation of signaling... 

Keyse, S.M. Emslie, E.A. (1992). Oxidative stress and heat shock induce a human gene encoding a protein-tyrosine phosphatase. Nature 359, 644-647. 

IL-10 inhibits CD28 and ICOS costimulations of T 127 cells via Src homology 2 domain-containing protein tyrosine phosphatase 1. J Allergy Chn Immunol 2007 120 76-83. 

Perret D, Shields M, Saxon A, Kehry MR A mouse Fey Fee protein that inhibits mast cells through activation of FcyRIIB, SH2 domain-containing inositol SS phosphatase 1, and SH2 domain-containing protein tyrosine phosphatases. J Allergy Chn Immunol 2008 121 441-447. 

AmpC P-Lactamase Phosphodiesterase 4 Protein Tyrosine Phosphatase IB... 

Protein tyrosine phosphatase IB (PTP1B) inhibitor. IC5o = 4.1 pM... 

Doman TN, McGovern SL, Witherbee BJ, Kasten TP, Kurumbail R, Stallings WC, Connolly DT, Shoichet BK. Molecular docking and high throughput screening for novel inhibitors of protein tyrosine phosphatase IB. J Med Chem 2002 45 2213-21. 

Walton KM, Dixon JE Protein tyrosine phosphatases. Annu Rev Biochem 1993 62 101. 

GAO Y H and YAMAGUCHI M (2000) Suppressive effect of genistein on rat bone osteoclasts Involvement of protein kinase inhibition and protein tyrosine phosphatase activation. Int J Mol Med 5, 261-7. 

JOHNSON T o, ERMOLIEFF J and JiROUSEK M R (2002) Protein tyrosine phosphatase 1B inhibitors for diabetes. Nat Rev Drug Discov. 1 (9) 696-709. 

Bennett MS, Z Guan, M Laurberg, X-D Su (2001) Bacillus subtilis arsenate reductase is structurally and functionally similar to low molecular weight protein tyrosine phosphatases. Proc Natl Acad Sci USA 98 13577-13582. 

A machine-learning method was proposed by Klon et al. [104] as an alternative form of consensus scoring. The method proved unsuccessful for PKB, but showed promise for the phosphatase PTPIB (protein tyrosine phosphatase IB). In this approach, compounds were first docked into the receptor and scored using conventional means. The top scoring compounds were then assumed to be active and used to build a naive Bayes classification model, all compounds were subsequently re-scored and ranked using the model. The method is heavily dependent upon predicting accurate binding... 

Kim CH, Qu CK, Hangoc G, et al. Abnormal chemokine-induced responses of immature and mature hematopoietic cells from motheaten mice implicate the protein tyrosine phosphatase SHP-1 in chemokine responses. J Exp Med 1999 190(5) 681-690. 

Gould, K. L Moreno, S., Tonks, N. K., and Nurse, P. (1990). Complementation of the mitotic activator, p80c r25, by a human protein-tyrosine phosphatase. Science 250 1573-1576. 

Zhang X-Y, Bishop AC (2007) Site-specific incorporation of allosteric-inhibition sites in a protein tyrosine phosphatase. J Am Chem Soc 129 3812-3813... 

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... 

Insulin binding to the extracellular side of cell membranes initiates the insulin cascade , a series of phosphorylation/dephosphorylation steps. A postulated mechanism for vanadium is substitution of vanadate for phosphate in the transition state structure of protein tyrosine phosphatases (PTP).267,268 In normal physiological conditions, the attainable oxidation states of vanadium are V111, Viv and Vv. Relevant species in solution are vanadate, (a mixture of HV042-/ H2VOO and vanadyl V02+. Vanadyl is not a strong inhibitor of PTPs, suggesting other potential mechanisms for insulin mimesis for this cation. 

Useful serine/threonine protein phosphatase inhibitors include microcystin-LR (which inhibits protein phosphatases 1, 2A, and 2C, and related enzymes) and /1-glycerophosphate. Sodium fluoride may also be employed. Sodium orthovanadate inhibits protein tyrosine phosphatases. 

Tertoolen, L. G., Blanchetot, C., Jiang, G., Overvoorde, J., Gadella, T. W., Jr., Hunter, T. and den Hertog, J. (2001). Dimerization of receptor protein-tyrosine phosphatase alpha in living cells. BMC Cell Biol. 2, 8. 

Majeti, R. and Weiss, A. (2001). Regulatory mechanisms for receptor protein tyrosine phosphatases. Chem. Rev. 101, 2441-2448. 

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