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Phosphoprotein Phosphatases

Phosphoprotein phosphatases, which hydrolyze phosphoprotein phosphatase P (PPP) family the phosphoester bonds of phosphoserines, includes PP1, PP2A, PP2B, and a few related phosphothreonines or phosphotyrosines, play an enzymes, PP4, PP5, PP6 and PP7, while the essential role in signal transduction and actively phosphoprotein phosphatase M family (PPM) contribute to the regulation of protein includes PP2C and related enzymes. Sequences phosphorylation. On the basis of their substrate of the catalytic domains of PPP family specificity they are usually divided into phosphatases are highly related to one another. phosphoserine and phosphothreonine They have been highly conserved during phosphatases on the one hand, and evolution and are homologous in general aspects phosphotyrosine and dual-specificity of their catalytic mechanism to enzymes found in phosphatases, on the other hand. This division prokaryotes (e.g. phage l phosphatase). PPM corresponds also to different families of enzymes phosphatases are found in prokaryotes and with different catalytic mechanisms. Genes eukaryotes, and are numerous in plants. coding for phosphoserine/threonine Although PPP and PPM families share no phosphatases are less numerous in vertebrate sequence homology, they are both metallo- genomes than those for serine /threonine enzymes and their 3-D structures display some kinases, and the complexity of phosphatases general similarities. function arises in part from the interactions of catalytic subunits with other proteins. The serine/threonine phosphatases of the PPP family are mostly regulated by protein-protein Prior to the knowledge of their sequence, interactions. Both PP1c and PP2Ac are catalytic phosphoserine/threonine phosphatases were subunits that interact with a large number of classified on the basis of their substrate targeting and regulatory subunits. PP1 is preference and inhibitor sensitivity. Type 1 targeted to glycogen particles, myofibrils or protein phosphatases (PP1) dephosphorylate the dendritic spines by specific subunits and β-subunit of phosphorylase kinase and are regulated by small proteins controlled by inhibited by phospho-inhibitor-1 and inhibitor-2, phosphorylation. For example, in basal ganglia whereas type 2 protein phosphatases (PP2) neurons, PP1c is inhibited by the phosphorylated dephosphorylate the α-subunit of phosphorylase form of DARPP-32 (32 kDa dopamine and cAMP- kinase and are resistant to the aforementioned regulated protein) that is regulated by dopamine inhibitors. Type 2 phosphatases were further and several other neurotransmitters. The PP2A divided depending on their divalent cation catalytic subunit forms heterotrimers with two requirements for full activity: phosphatase 2A other subunits and interacts with several (PP2A) does not require such cations, whereas inhibitory proteins. In contrast, PP2B phosphatase 2B (PP2B, also known as (calcineurin) is comprised of an A subunit calcineurin) and phosphatase 2C (PP2C) are including the catalytic domain and a B subunit respectively activated by Ca2+ and Mg2+. structurally related to calmodulin. Calcineurin is activated by direct Ca2+ binding to calcineurin B Molecular cloning revealed that serine/threonine and binding of the Ca2+-calmodulin complex to phosphatases belong to two different families of calcineurin A. PP7 is also activated by Ca2+. about a dozen of genes each in mammals: the

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A number of natural toxins produced by a variety for which regulatory mechanisms or targeting by of microorganisms are powerful inhibitors of PP1, protein-protein interactions are as yet poorly PP2A, and PP4-6, with only relatively small characterized. It includes the classic PP2C differences in affinities. This, combined with the phosphatases, a number of enzymes recently high molar concentrations of these phosphatases discovered and pyruvate dehydrogenase found in some cells, makes it sometimes difficult phosphatases. There are as yet no specific to identify their relative contribution to the inhibitor of PPM phosphatases. dephosphorylation of specific substrates in intact cells through the use of these inhibitors. The Table below contains accepted modulators Calcineurin is the specific target of two and additional information. For more information immunosuppressant drugs, cyclosporin A and and a complete list of the related products, please FK506, complexed with their intracellular click: Aladdin receptors (immunophilins), cyclophilin and FK506-binding protein (FKBP), respectively. PPM family members are monomeric enzymes

Gene Family PPP PPM

Type PP1 PP2A PP2B PP4 PP5 PP6 PP7 PP2C

Alternate PPP1 PPP2 PPP3, calcineurin PPP4, PPX PPP5 PPP6 PPP7, rdgC PPM1A,B Names

Mol Mass Catal. ~37 ~36 ~60 ~35 ~60 35 75 40-60 Subunit (kDa)

Heterotrimer: Associated Heterodimer: 1 catalytic Quat. with A:catalytic + CaM subunit Not Known Not Known Not Know n Not Know n Monomer Structure targeting binding 2 regulatory 2+ subunits B:Ca binding subunit

Activated Effect of 2+ 2+ Not Known Not Known Activated by Ca Not Known Not Known Not Known Ca by high Cations 2+ Mg

Phospho- Inhibitor-1 Phospho- DARPP32 Cain PP2A Endogenous Inhibitor-2 I1 AKAP-79 Not Know PP2A Not Known Not Known Not Known Not Known Inhibitors NIPP I2 DSCR1 n RIPP ZAKI-4 CPI17 Phosphatidi c acid

Okadaic Calyculin A acid >Microcysti Nodularin Microcystin >Microcysti n LR >Microcystin LR n LR >Nodularin LR >Calyculin Resistant to Pharmacolog >Tautomyci >Tautomyci >Calyculin A Cyclosporin A A okadaic acid Not ical n Not Known n ~Okadaic acid FK506 >Okadaic and related Known Inhibitors >Calyculin >Okadaic a >Fostriecin acid inhibitors A cid >Tautomycin >Tautomyci >Fostriecin >Cantharidi >Cantharidin n >Cantharidi n n

Tissue Ubiquitous, high Ubiquitou Ubiquitous Ubiquitous Ubiquitous, Ubiquitous Not Known Retina Expression in brain high in s

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testis

Microtubule Cell growth, Physiologica growth at Cell cycle Many Many Many stress Not Known Many l Function centrosome regulation response s

Target of Disease Not Not Known Not Known immunosuppress Not Known Not Known Not Known Not Known Relevance Known ants

Abbreviations Cohen, P.T.W., Novel protein serine/threonine AKAP-79: A kinase anchor protein 79 phosphatases: Variety is the spice of life., Trends Cain: Calcineurin inhibitor Biochem. Sci., 22, 245-251 (1997). CaM: Calmodulin Forrest, A.R., et al., Phosphoregulators: protein kinases and protein phosphatases of mouse., Genome CPI17: 17 kDa PKC-potentiated inhibitory protein Res., 13, 1443-1454 (2003). of PPI Gehringer, M.M., Microcystin-LR and okadaic acid- DARPP32: Dopamine and cAMP-regulated induced cellular effects: a dualistic response., FEBS phosphoprotein Lett., 557, 1-8 (2004). DSCR1: Down syndrome critical region 1 Honkanen, R.E. and Golden, T., Regulators of FKBP: FK506 binding protein serine/threonine protein phosphatases at the dawn of I1PP2A: Protein inhibitor 1 of protein a clinical era?, Curr. Med. Chem., 9, 2055-2075 phosphatase 2A (2002). I2PP2A: Protein inhibitor 2 of protein Kennelly, P.J., Archaeal protein kinases and protein phosphatases: insights from genomics and phosphatase 2A biochemistry., Biochem. J., 370, 373-389 (2003). Inhibitor-2: Proteon phosphatase inhibitor-2 Millward, T.A., et al., Regulation of protein kinase NIPP: Nuclear inhibitor of protein phosphatase 1 cascades by protein phosphatase 2A., Trends PP: Phosphoprotein phosphatase Biochem. Sci., 24, 186-191 (1999). PP1: Phosphoprotein phosphatase 1 Munton, R.P., et al., The role of protein phosphatase-1 PP2A: Phosphoprotein phosphatase 2A in the modulation of synaptic and structural plasticity., PP2B: Phosphoprotein phosphatase 2B or FEBS Lett., 567, 121-128 (2004). calcineurin Peng, A. and Maller, JL., Serine/threonine phosphatases in the DNA damage response and PP2C: Phosphoprotein phosphatase 2C cancer., Oncogene., 29, 5977-5988 (2010). PPM: Phosphoprotein phosphatase M family Pereira, SR., et al., The phosphoprotein phosphatase PPP: Phosphoprotein phosphatase P family family of Ser/Thr phosphatases as principal targets of RIPP: Ribosomal inhibitor of protein phosphatase naturally occurring toxins., Crit Rev Toxicol., 41, 83- 1 110 (2011). ZAKI-4: Down syndrome critical region 1-like 1 Schweighofer, A., et al., Plant PP2C phosphatases: emerging functions in stress signaling., Trends Plant References Sci., 9, 236-243 (2004). Barford, D., et al., The structure and mechanism of Svenningsson, P., et al., DARPP-32: an integrator of protein phosphatases: insights into catalysis and neurotransmission., Annu. Rev. Pharmacol. Toxicol., regulation., Annu. Rev. Biophys. Biomol. Struct., 27, 44, 269-296 (2004). 133-164 (1998). Wera, S. and Hemmings, B.A., Serine threonine Butler, T., et al., Role of serine-threonine protein phosphatases., Biochem. J., 311, 17-29 phosphoprotein phosphatases in smooth muscle (1995). contractility., Am J Physiol, Cell Physiol., 304, C485- Wurzenberger, C. and Gerlich, DW., Phosphatases: C504 (2013). providing safe passage through mitotic exit., Nat Rev Campbell, BE., et al., Serine/threonine phosphatases Mol Cell Biol., 12, 469-482 (2011). in socioeconomically important parasitic nematodes-- prospects as novel drug targets?., Biotechnol Adv., For more information and a complete list of the 29, 28-39 (2011). related products, please click: Aladdin Cohen, P., Classification of protein-serine/threonine phosphatases: Identification and quantitation in cell extracts., Methods Enzymol., 201, 389-398 (1991).

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