Protein tyrosine phosphatase Regulation

Li, D.M., and Sun H., 1997, TEPl, encoded by a candidate tumor suppressor locus, is a novel protein tyrosine phosphatase regulated by transforming growth factor. Cancer Res. 57 2124-2129. 

Bourdeau A, Dube N, Tremblay ML (2005) Cytoplasmic protein tyrosine phosphatases, regulation and function the roles of PTPIB and TC-PTP. Curr Opin Cell Biol 17 203-209... 

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... 

Since then, a plethora of tyrosine-phosphorylated proteins has been discovered. Originally, tyrosine phosphorylation was believed to be involved primarily in regulating cell proliferation, since many oncogene products and growth factor receptors are protein tyrosine kinases (PTKs). However, it has become clear that tyrosine phosphorylation is involved in regulating a variety of cellular processes. In fact, the nervous system contains a large variety of PTKs and protein tyrosine phosphatases (PTPs), and some of these are exclusively expressed in neuronal tissues. Figure 24-1 shows the... 

Other molecules are known to bind the intracellular portion of CD95 and regulate both positively or negatively the cell death signal. EAP-1 is a protein tyrosine phosphatase, which is highly expressed in CD95-resistant... 

Sattler, M., Salgja, R., Shrikhande, G., Verma, S., Choi, J.L., Rohrschneider, L.R., and Griffin, J.D., 1997, The phosphatidyhnositol polyphosphate 5-phosphatase SHIP and the protein tyrosine phosphatase SHP-2 form a complex in hematopoietic cells which can be regulated by BCR/ABL and growth factors. Oncogene, 15 2379-2384. 

The fact that cellular activity of protein tyrosine phosphatases by far exceeds that of protein tyrosine kinases suggests that there is strict control of the dephosphorylation rate in a cell. The mechanisms are those already highlighted in previous chapters as central elements of regulation of activity of signal molecules. 

Another mechanism of regulation of protein tyrosine phosphatases is via Ser/Thr phosphorylation. Specific phosphorylation of protein tyrosine phosphatases by Ser/ Thr-specific protein kinases of types A and C has been reported (see Neel and Tonks, 1997). This observation indicates the possibility that signal transductions via Ser/Thr kinases and via Tyr kinases/phosphatases may cooperate and that different signal pathways may be crosslinked in this way. 

Down-regulation of T-cell protein tyrosine phosphatase in IM-resistant cells may represent a novel mechanism for IM resistance (40). A recently published analysis of data from the IRIS trial demonstrated that trough blood levels of IM and its active major metabolite, CGP74588, correlated with achievement of CCR and MMR (41). 

Ahmad, E Li, P.-M. Meyerovitch, J. Goldstein, B.J. Osmotic loading of neutrahzing antibodies demonstrates a role of protein-tyrosine phosphatase IB in negative regulation of the insulin action pathway. J. Biol. Chem., 270, 20503-20508 (1995)... 

Many peroxovanadates have potent insulin-mimetic properties [1,2]. Apparently, this functionality derives from the ability of these compounds to rapidly oxidize the active site thiols found in the group of protein tyrosine phosphatases that are involved in regulating the insulin receptor function [3], The discovery of vanadium-dependent haloperoxidases in marine algae and terrestrial lichens provided an additional stimulus in research toward obtaining functional models of peroxidase activity, and there is great interest in duplicating the function of these enzymes (see Section 10.4.2). 

Studies of the oxidation of organic sulfides with amino acid-derived ligands in acetonitrile revealed very little difference between the mechanism of their oxidation and that of halides, except for one major exception. Despite the fact that acid conditions are still required for the catalytic cycle, hydroxide or an equivalent is not produced in the catalytic cycle, so no proton is consumed [48], As a consequence, there is no requirement for maintenance of acid levels during a catalyzed reaction. Peroxo complexes of vanadium are well known to be potent insulin-mimetic compounds [49,50], Their efficacy arises, at least in part, from an oxidative mechanism that enhances insulin receptor activity, and possibly the activity of other protein tyrosine kinases activity [51]. With peroxovanadates, this is an irreversible function. Apparently, there is no direct effect on the function of the kinase, but rather there is inhibition of protein tyrosine phosphatase activity. The phosphatase regulates kinase activity by dephosphorylating the kinase. Oxidation of an active site thiol in the phosphatase prevents this down-regulation of kinase activity. Presumably, this sulfide oxidation proceeds by the process outlined above. 

Salmeen, A., J.N. Andersen, M.P. Myers, T.C. Meng, J.A. Hinks, N.K. Tonks, and D. Barford. 2003. Redox regulation of protein tyrosine phosphatase IB involves a sulphenyl-amide intermediate. Nature. 423 769-73. 

Qiu, W., R.K. Avramoglu, N. Dube, T.M. Chong, M. Naples, A. C., K.G. Sidiropoulos, G.F. Lewis, J.S. Cohn, M.L. Tremblay, and K. Adeh 2004. Hepatic TRP-1B expression regulates the assembly and secretion of apolipoprotein B-containing lipoproteins. Evidence from protein tyrosine phosphatase-IB overexpression knockout and RNAi studies. Diabetes 53 3057-3066. 

Although these neurotrophic factors stimulate neurogenesis after brain ischemia, chronic intraventricular administration of peptides or proteins is inappropriate for human therapies because of insufficient penetration into brain tissue. Since various receptor tyrosine kinases, including EGF, FGF-2, BDNF, and VEGF receptors, are negatively regulated by protein tyrosine phosphatases (Ostman and Bohmer, 2001), inhibitors for protein tyrosine phosphatases possibly promote... 

Ostman, A., and Bohmer, F. D. (2001). Regulation of receptor tyrosine kinase signaling by protein tyrosine phosphatases. Trends Cell Biol 11, 258—266. 

B. P., and Tremblay, M. L. 2002. Attenuation of leptin action and regulation of obesity by protein tyrosine phosphatase IB. Dev. Cell 2 497-503. 

Sivaramakrishnan S, Keerthi K, Gates KS (2005) A chemical model for redox regulation of protein tyrosine phosphatase IB (PTP1B) Activity. J Am Chem Soc 127 10830-10831... 

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