Serine-threonine phosphatases

Cohen PTW (1997) Novel protein serine/threonine phosphatases variety ist he spice of life. Trends Biochem Sci 22 245-251... 

The brain contains multiple forms of protein serine-threonine phosphatases 399... 

Protein serine-threonine phosphatases play a critical role in the control of cell function 400... 

Protein dephosphorylation is catalyzed by phospho-hydrolases called protein phosphatases. While the number of protein tyrosine kinases is roughly comparable to the number of protein tyrosine phosphatases, protein serine-threonine kinases vastly outnumber the protein serine-threonine phosphatases, of which about 25 different species are known to exist. This relative under-representation may be accounted for by the alternative diversification... 

These enzymes are more closely related, in terms of their amino acid sequences, to protein tyrosine phosphatases than to protein serine-threonine phosphatases. 

Price, N. E. and Mumby, M. C. Brain protein serine/ threonine phosphatases. Curr. Opin. Neurobiol. 9 336-342, 1999. 

Goldberg, J., Huang, H. B., Kwon,Y. G., Greengard, P., Nairn, A. C. and Kuriyan, J. Three-dimensional structure of the catalytic subunit of protein serine/threonine phosphatase-1. Nature 376 745-753,1995. 

Nonreceptor protein tyrosine phosphatases are structurally different from serine-threonine phosphatases and contain a cysteine residue in their... 

PP2Cc Serine/threonine phosphatases, family 2C, catalytic domain E(MFP)B 8(8) 11(11) 1A6Q... 

The serine/threonine phosphatase inhibitor okadaic acid (incubation time and concentration vary from 10 nM, 30 minutes to 1 pM, 1 hour at 37°C) leads to selective stimulation of caveolae uptake (18,64). 

Phosphorylation of serine, threonine, and tyrosine side-chain OH groups of proteins by kinases and their dephosphorylation by protein phosphatases provides an important mechanism for biological regulation. Tyrosine phosphatases are not metalloenzymes but the serine/threonine phosphatases contain a bimetallic site. 

The cytotoxicities of okadaic acid as EC50 against the P388 and L1210 cell lines are 1.7 nano-molar and 17 nano-molar, respectively. Additionally, okadaic acid strongly inhibits protein serine/threonine phosphatase 1,2A,... 

Tacrolimus (previously known as FK506) is a macrolide antibiotic which is obtained from the fungus Streptomyces tsukubaensis. Tacrolimus binds in-tracellularly to the protein FKBP (FK binding protein) which is distinct from the protein that binds cyclosporine. However both drug-protein complexes associate in a similar way with calcineurin and inhibits its serine/threonine phosphatase activity, although the immunosuppressive potency of tacrolimus is approximately 100 fold higher than that of cyclosporine. 

Fig. 10. A possible mechanism for phosphomonoester hydrolysis at the catalytic site of serine/threonine phosphatase-1 active site.

Dragmacidins D and E (199) from the Australian sponge Spongosorites sp. inhibit serine-threonine phosphatases [158]. 

Fig. 4.1 Mechanism of action of cyclosporine. Cyclosporine readily diffuses into the cytoplasm of the target cells where it binds to cyclophilins. The cyclosporine-cyclophilin complex stably associates with calcineurin and inhibits calcineurin activity. Calcineurin is a Ca2+-dependent enzyme— serine/threonine phosphatase— which after activation by Ca2+, dephosphorylates a cytosolic component of NFAT (NFATc, cytosolic factor of activated T cells). After dephosphorylation, NFATc migrates from the cytoplasm to the nucleus where it associates with NFATn and induces transcription of several cytokine genes including IL-2. Cyclosporine inhibits calcineurin activity after associating with cyclophilins, resulting in the inhibition of IL-2 production and other cytokines (see Color Insert)...

Fostriecin (20, CI-920) is a novel metabolite of Streptomyces pulveraceus that was first isolated in 1983 by a research group at Warner Lambert-Parke Davis.22 It displays antitumor activity against a broad range of cancerous cell lines in vitro. This activity is suggested to be intimately related to the potent and highly selective inhibitory activity against serine/threonine phosphatase PP2A.23 In fact, fostriecin is the most selective protein phosphatase inhibitor reported to date, and it... 

Barford, D. 1996. Molecular mechanisms of the protein serine/threonine phosphatases. Tr. Biochem. Sci. 21 407 412. 

While protein kinases are responsible for the phosphorylation of their substrates, protein phosphatases perform the opposite duty, removing phosphate groups from their substrates, thus countering the functional impact of the kinases. The two major types of protein phosphatases are the serine/threonine phosphatases and tyrosine phosphatases. Several natural compounds with potent serine/threonine phosphatase inhibitory activity have been identified, including the cyanobacterial metabolite microcystin [105,106]. This compound labels its targets via a Michael addition of a noncatalytic active site cysteine residue with an acceptor in the macrocyclic peptide backbone [107]. A fluorescent probe based on microcystin was synthesized by Shreder et al., and its use in Jurkat lysates identified two previously undescribed phosphatase targets of microcystin, PP-4 and PP-5 [108]. Whereas serine/threonine... 

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