phosphoprotein phosphatases


Summary: A group of enzymes removing the SERINE- or THREONINE-bound phosphate groups from a wide range of phosphoproteins, including a number of enzymes which have been phosphorylated under the action of a kinase. (Enzyme Nomenclature, 1992)

Top Publications

  1. Winfree L, Speese S, Logan M. Protein phosphatase 4 coordinates glial membrane recruitment and phagocytic clearance of degenerating axons in Drosophila. Cell Death Dis. 2017;8:e2623 pubmed publisher
  2. Khew Goodall Y, Hemmings B. Tissue-specific expression of mRNAs encoding alpha- and beta-catalytic subunits of protein phosphatase 2A. FEBS Lett. 1988;238:265-8 pubmed
    ..In addition to the 2 kb mRNA generally expressed, rat tissues also express a 2.8 kb mRNA related to 2A alpha and a 1.3 kb mRNA related to 2A beta. ..
  3. Abraham D, Podar K, Pacher M, Kubicek M, Welzel N, Hemmings B, et al. Raf-1-associated protein phosphatase 2A as a positive regulator of kinase activation. J Biol Chem. 2000;275:22300-4 pubmed
    ..The PP2A core heterodimer forms complexes with Raf-1 in vivo and in vitro. These data identify PP2A as a positive regulator of Raf-1 activation and are the first indication that PP2A may support the activation of an associated kinase. ..
  4. Su C, Li Z, Cheng J, Li L, Zhong S, Liu L, et al. The Protein Phosphatase 4 and SMEK1 Complex Dephosphorylates HYL1 to Promote miRNA Biogenesis by Antagonizing the MAPK Cascade in Arabidopsis. Dev Cell. 2017;41:527-539.e5 pubmed publisher
    ..Moreover, the protein level of SMEK1 is increased in response to abscisic acid. Our results provide insights into the delicate balance between a protein kinase and a phosphatase during miRNA biogenesis. ..
  5. Garufi A, D Orazi G. High glucose dephosphorylates serine 46 and inhibits p53 apoptotic activity. J Exp Clin Cancer Res. 2014;33:79 pubmed publisher
    ..These results uncover a new mechanism of p53 inactivation providing an interesting novel molecular link between metabolic diseases such as diabetes or obesity and tumor progression and resistance to therapies. ..
  6. Andjelkovic M, Jakubowicz T, Cron P, Ming X, Han J, Hemmings B. Activation and phosphorylation of a pleckstrin homology domain containing protein kinase (RAC-PK/PKB) promoted by serum and protein phosphatase inhibitors. Proc Natl Acad Sci U S A. 1996;93:5699-704 pubmed
    ..Taken together the results suggest that RAC-PK is a component of a signaling pathway regulated by phosphatidylinositol (PI) 3-kinase, whose action is required for RAC-PK activation by phosphorylation. ..
  7. Bielawska A, Greenberg M, Perry D, Jayadev S, Shayman J, McKay C, et al. (1S,2R)-D-erythro-2-(N-myristoylamino)-1-phenyl-1-propanol as an inhibitor of ceramidase. J Biol Chem. 1996;271:12646-54 pubmed
    ..These studies point to an important role for ceramidases in the regulation of endogenous levels of ceramide. ..
  8. Lu M, MacGregor G, Wang W, Giebisch G. Extracellular ATP inhibits the small-conductance K channel on the apical membrane of the cortical collecting duct from mouse kidney. J Gen Physiol. 2000;116:299-310 pubmed
    ..We conclude that the inhibitory effect of ATP on the apical K channel is mediated by stimulation of P(2)Y(2) receptors and results from increasing dephosphorylation by enhancing PKG-sensitive phosphatase activity. ..
  9. Chen X, Poorey K, Carver M, Müller U, Bekiranov S, Auble D, et al. Transcriptomes of six mutants in the Sen1 pathway reveal combinatorial control of transcription termination across the Saccharomyces cerevisiae genome. PLoS Genet. 2017;13:e1006863 pubmed publisher
    ..In combination with other recent whole-genome studies on termination of non-coding RNAs, our results provide promising directions for further investigation. ..

More Information


  1. Gangula N, Maddika S. Interplay between the phosphatase PHLPP1 and E3 ligase RNF41 stimulates proper kinetochore assembly via the outer-kinetochore protein SGT1. J Biol Chem. 2017;292:13947-13958 pubmed publisher
    ..Taken together, our results suggest that PHLPP1 plays an important role in the assembly of kinetochores by counteracting RNF41-mediated SGT1 degradation. ..
  2. Carling D, Zammit V, Hardie D. A common bicyclic protein kinase cascade inactivates the regulatory enzymes of fatty acid and cholesterol biosynthesis. FEBS Lett. 1987;223:217-22 pubmed
    ..These results show that a common, bicyclic protein kinase cascade can potently inactivate the regulatory enzymes of both fatty acid and cholesterol biosynthesis. ..
  3. Donella Deana A, Krinks M, Ruzzene M, Klee C, Pinna L. Dephosphorylation of phosphopeptides by calcineurin (protein phosphatase 2B). Eur J Biochem. 1994;219:109-17 pubmed
  4. Huang S, Liu Z, Ma Z, Zhang J, Huang L. Isolation and characterization of the 5'-flanking region of the human PDXK gene. Gene. 2017;628:218-223 pubmed publisher
    ..Knockdown of Sp1 by RNA interference and chromatin immunoprecipitation analysis further proved that the Sp1 is involved in the regulation of the PDXK gene expression. ..
  5. Begum N, Ragolia L. Effect of tumor necrosis factor-alpha on insulin action in cultured rat skeletal muscle cells. Endocrinology. 1996;137:2441-6 pubmed
    ..We conclude that TNF-alpha blocks insulin-stimulated glycogen synthesis by inhibiting PP-1 activation via ceramide release. ..
  6. Márkus B, Szabo K, Pfliegler W, Petrényi K, Boros E, Pocsi I, et al. Proteomic analysis of protein phosphatase Z1 from Candida albicans. PLoS ONE. 2017;12:e0183176 pubmed publisher
    ..Thus our unbiased proteomic approach lead to the discovery of a novel function for this phosphatase in C. albicans. ..
  7. Saito S, Zhuang Y, Shan B, Danchuk S, Luo F, Korfei M, et al. Tubastatin ameliorates pulmonary fibrosis by targeting the TGFβ-PI3K-Akt pathway. PLoS ONE. 2017;12:e0186615 pubmed publisher
    ..Our data suggest that Tubastatin ameliorates pulmonary fibrosis, by targeting the TGFβ-PI3K-Akt pathway, likely via an HDAC6-independent mechanism. ..
  8. Bito H, Deisseroth K, Tsien R. CREB phosphorylation and dephosphorylation: a Ca(2+)- and stimulus duration-dependent switch for hippocampal gene expression. Cell. 1996;87:1203-14 pubmed
  9. Takai A, Murata M, Torigoe K, Isobe M, Mieskes G, Yasumoto T. Inhibitory effect of okadaic acid derivatives on protein phosphatases. A study on structure-affinity relationship. Biochem J. 1992;284 ( Pt 2):539-44 pubmed
  10. Pei J, Gong C, Iqbal K, Grundke Iqbal I, Wu Q, Winblad B, et al. Subcellular distribution of protein phosphatases and abnormally phosphorylated tau in the temporal cortex from Alzheimer's disease and control brains. J Neural Transm (Vienna). 1998;105:69-83 pubmed
  11. Otto H, Dreger M, Bengtsson L, Hucho F. Identification of tyrosine-phosphorylated proteins associated with the nuclear envelope. Eur J Biochem. 2001;268:420-8 pubmed
  12. Peter M, Heitlinger E, Haner M, Aebi U, Nigg E. Disassembly of in vitro formed lamin head-to-tail polymers by CDC2 kinase. EMBO J. 1991;10:1535-44 pubmed
  13. Wang B, Zhao A, Sun L, Zhong X, Zhong J, Wang H, et al. Protein phosphatase PP4 is overexpressed in human breast and lung tumors. Cell Res. 2008;18:974-7 pubmed publisher
  14. Li M, Hirsch E. Akt activation by PHLPP1 ablation prevents pathological hypertrophy by promoting angiogenesis. Cardiovasc Res. 2015;105:129-30 pubmed publisher
  15. Aviv Y, Kirshenbaum L. Novel phosphatase PHLPP-1 regulates mitochondrial Akt activity and cardiac cell survival. Circ Res. 2010;107:448-50 pubmed publisher
  16. Chen Y, Hung M, Chu P, Chao T, Tsai M, Chen L, et al. Protein phosphatase 5 promotes hepatocarcinogenesis through interaction with AMP-activated protein kinase. Biochem Pharmacol. 2017;138:49-60 pubmed publisher
    ..Overall, our results establish a pathological function of PP5 in hepatocarcinogenesis via affecting AMPK signaling and suggest that PP5 inhibition is an attractive therapeutic approach for HCC. ..
  17. Guo X, Niemi N, Coon J, Pagliarini D. Integrative proteomics and biochemical analyses define Ptc6p as the Saccharomyces cerevisiae pyruvate dehydrogenase phosphatase. J Biol Chem. 2017;292:11751-11759 pubmed publisher
    ..Our findings highlight the power of integrative omics and biochemical analyses for annotating the functions of poorly characterized signaling proteins. ..
  18. Hos N, Ganesan R, Gutierrez S, Hos D, Klimek J, Abdullah Z, et al. Type I interferon enhances necroptosis of Salmonella Typhimurium-infected macrophages by impairing antioxidative stress responses. J Cell Biol. 2017;216:4107-4121 pubmed publisher
    ..Collectively, we identify impaired Nrf2-dependent redox homeostasis as an important mechanism that promotes cell death downstream of IFN-I and RIP3 signaling in S Typhimurium-infected macrophages. ..
  19. Bhalla U, Iyengar R. Emergent properties of networks of biological signaling pathways. Science. 1999;283:381-7 pubmed
    ..These properties of signaling networks raise the possibility that information for "learned behavior" of biological systems may be stored within intracellular biochemical reactions that comprise signaling pathways. ..
  20. O Hayre M, Niederst M, Fecteau J, Nguyen V, Kipps T, Messmer D, et al. Mechanisms and consequences of the loss of PHLPP1 phosphatase in chronic lymphocytic leukemia (CLL). Leukemia. 2012;26:1689-92 pubmed publisher
  21. Kim K, Ryu D, Dongiovanni P, Ozcan L, Nayak S, Ueberheide B, et al. Degradation of PHLPP2 by KCTD17, via a Glucagon-Dependent Pathway, Promotes Hepatic Steatosis. Gastroenterology. 2017;153:1568-1580.e10 pubmed publisher
    ..Inhibitors of this pathway might be developed for treatment of patients with NAFLD. ..
  22. Trentini D, Fuhrmann J, Mechtler K, Clausen T. Chasing Phosphoarginine Proteins: Development of a Selective Enrichment Method Using a Phosphatase Trap. Mol Cell Proteomics. 2014;13:1953-64 pubmed publisher
    ..In conclusion, we present a novel tool for the selective enrichment and subsequent MS analysis of arginine phosphorylation, which is a largely overlooked protein modification that might be important for eukaryotic cell signaling. ..
  23. Ziembik M, Bender T, Larner J, Brautigan D. Functions of protein phosphatase-6 in NF-?B signaling and in lymphocytes. Biochem Soc Trans. 2017;45:693-701 pubmed publisher
    ..Recent efforts at conditionally knocking out genes for PP6c or PP6R1 (SAPS1) have revealed distinctive effects on development of and signaling in lymphocytes. ..
  24. Pantopoulos K, Hentze M. Rapid responses to oxidative stress mediated by iron regulatory protein. EMBO J. 1995;14:2917-24 pubmed
    ..Thus okadaic acid separates the activation pathways by iron depletion and oxidative stress, suggesting the involvement of stress-induced kinase/phosphatase pathways in the latter. ..
  25. Dulic V, Drullinger L, Lees E, Reed S, Stein G. Altered regulation of G1 cyclins in senescent human diploid fibroblasts: accumulation of inactive cyclin E-Cdk2 and cyclin D1-Cdk2 complexes. Proc Natl Acad Sci U S A. 1993;90:11034-8 pubmed
  26. Yamada T, Tahara E, Kanke M, Kuwata K, Nishiyama T. Drosophila Dalmatian combines sororin and shugoshin roles in establishment and protection of cohesion. EMBO J. 2017;36:1513-1527 pubmed publisher
  27. Guan K, Dixon J. Eukaryotic proteins expressed in Escherichia coli: an improved thrombin cleavage and purification procedure of fusion proteins with glutathione S-transferase. Anal Biochem. 1991;192:262-7 pubmed
    ..The vector, pGEX-KG, has also been modified to facilitate cloning of a variety of cDNAs in all reading frames and has been successfully used to express several eukaryotic proteins. ..
  28. Burke B. Lamins and apoptosis: a two-way street?. J Cell Biol. 2001;153:F5-7 pubmed
  29. Tan P, He L, Cui J, Qian C, Cao X, Lin M, et al. Assembly of the WHIP-TRIM14-PPP6C Mitochondrial Complex Promotes RIG-I-Mediated Antiviral Signaling. Mol Cell. 2017;68:293-307.e5 pubmed publisher
    ..Moreover, phosphatase PPP6C is responsible for RIG-I dephosphorylation. Together, our findings define the WHIP-TRIM14-PPP6C mitochondrial signalosome required for RIG-I-mediated innate antiviral immunity...
  30. Dedobbeleer M, Willems E, Freeman S, Lombard A, Goffart N, Rogister B. Phosphatases and solid tumors: focus on glioblastoma initiation, progression and recurrences. Biochem J. 2017;474:2903-2924 pubmed publisher
  31. Wang L, Yan F. Deprotonation states of the two active site water molecules regulate the binding of protein phosphatase 5 with its substrate: A molecular dynamics study. Protein Sci. 2017;26:2010-2020 pubmed publisher
    ..Furthermore, the deprotonation state that is preferable for PP5 binding of its substrate has been identified. These findings could provide new design strategy for PP5 inhibitor. ..
  32. King M, Huang C, Chock P, Nairn A, Hemmings H, Chan K, et al. Mammalian brain phosphoproteins as substrates for calcineurin. J Biol Chem. 1984;259:8080-3 pubmed
    ..053 s-1; synapsin I (site II), 0.040 s-1. Comparisons of the catalytic efficiency (kcat/Km) for each substrate indicated that DARPP-32, G-substrate, and Protein K.-F. are all potential substrates for calcineurin in vivo. ..
  33. Wadzinski B, Wheat W, Jaspers S, Peruski L, Lickteig R, Johnson G, et al. Nuclear protein phosphatase 2A dephosphorylates protein kinase A-phosphorylated CREB and regulates CREB transcriptional stimulation. Mol Cell Biol. 1993;13:2822-34 pubmed
    ..Nuclear PP2A appears to be the primary phosphatase that dephosphorylates PKA-phosphorylated CREB. ..
  34. Rauschenberger V, Bernkopf D, Krenn S, Jalal K, Heller J, Behrens J, et al. The phosphatase Pgam5 antagonizes Wnt/?-Catenin signaling in embryonic anterior-posterior axis patterning. Development. 2017;144:2234-2247 pubmed publisher
  35. Pradhan S, Vijayan K. Lipid rafts contribute to agonist-induced serine/threonine phosphatase activation and platelet aggregation. J Thromb Haemost. 2013;11:1612-5 pubmed publisher
  36. Moon B, Yun H, Chang W, Steele B, Cai M, Choi S, et al. Smek promotes corticogenesis through regulating Mbd3's stability and Mbd3/NuRD complex recruitment to genes associated with neurogenesis. PLoS Biol. 2017;15:e2001220 pubmed publisher
    ..These results reveal a novel molecular mechanism underlying Smek/Mbd3/NuRD axis-mediated control of NPCs' self-renewal and neuronal differentiation during mammalian corticogenesis. ..
  37. Im Y, Lee J, Lee S, Oh S, Park K. Developmental changes in contractile responses to cholinergic stimuli: role of calcium sensitization and related pathways. Am J Physiol Renal Physiol. 2017;313:F370-F377 pubmed publisher
    ..This included dominance of phasic contractions over tonic contractions due to increased calcium dependence and the maturational shift of the calcium sensitivity mechanism from PKC to ROCK. ..
  38. Birot A, Eguienta K, Vazquez S, Claverol S, Bonneu M, Ekwall K, et al. A second Wpl1 anti-cohesion pathway requires dephosphorylation of fission yeast kleisin Rad21 by PP4. EMBO J. 2017;36:1364-1378 pubmed publisher
    ..These results reveal that Wpl1 antagonizes sister chromatid cohesion by a novel pathway regulated by the phosphorylation status of the cohesin kleisin subunit. ..
  39. Tonks N. Special issue: Protein phosphatases: from molecules to networks: introduction. FEBS J. 2013;280:323 pubmed publisher
    ..This Special Issue of FEBS Journal presents articles that reflect the theme of specificity in protein phosphatase function and emphasize the critical role played by these enzymes in the regulation of signal transduction. ..
  40. Mathur A, Pandey V, Kakkar P. PHLPP: a putative cellular target during insulin resistance and type 2 diabetes. J Endocrinol. 2017;233:R185-R198 pubmed publisher
  41. Sontag E, Nunbhakdi Craig V, Lee G, Bloom G, Mumby M. Regulation of the phosphorylation state and microtubule-binding activity of Tau by protein phosphatase 2A. Neuron. 1996;17:1201-7 pubmed
    ..Taken together, these results support the hypothesis that PP2A controls the phosphorylation state of tau in vivo. ..
  42. Lawson M, Maxfield F. Ca(2+)- and calcineurin-dependent recycling of an integrin to the front of migrating neutrophils. Nature. 1995;377:75-9 pubmed
    ..We show that the polarized distribution of alpha v beta 3 integrins in migrating neutrophils is maintained by [Ca2+]i-dependent release of adhesion followed by endocytosis of these integrins and recycling to the leading edge. ..
  43. Hemmings H, Nairn A, Elliott J, Greengard P. Synthetic peptide analogs of DARPP-32 (Mr 32,000 dopamine- and cAMP-regulated phosphoprotein), an inhibitor of protein phosphatase-1. Phosphorylation, dephosphorylation, and inhibitory activity. J Biol Chem. 1990;265:20369-76 pubmed
    ..These findings support the hypothesis that a 30-amino acid domain in the NH2-terminal region of phospho-DARPP-32 is sufficient for the inhibition of protein phosphatase-1. ..
  44. Cohen P, Alemany S, Hemmings B, Resink T, Stralfors P, Tung H. Protein phosphatase-1 and protein phosphatase-2A from rabbit skeletal muscle. Methods Enzymol. 1988;159:390-408 pubmed
  45. Huang H, Horiuchi A, Watanabe T, Shih S, Tsay H, Li H, et al. Characterization of the inhibition of protein phosphatase-1 by DARPP-32 and inhibitor-2. J Biol Chem. 1999;274:7870-8 pubmed
    ..Moreover, residues 14-84 of inhibitor-2 and residues 6-38 of phospho-DARPP-32 share elements that are important for interaction with PP1. ..
  46. Dou L, Wang S, Sun L, Huang X, Zhang Y, Shen T, et al. Mir-338-3p Mediates Tnf-A-Induced Hepatic Insulin Resistance by Targeting PP4r1 to Regulate PP4 Expression. Cell Physiol Biochem. 2017;41:2419-2431 pubmed publisher
    ..miR-338-3p might mediate TNF-?-induced hepatic insulin resistance by targeting PP4R1 to regulate PP4 expression. ..
  47. Tarulli G, De Silva D, Ho V, Kunasegaran K, Ghosh K, Tan B, et al. Hormone-sensing cells require Wip1 for paracrine stimulation in normal and premalignant mammary epithelium. Breast Cancer Res. 2013;15:R10 pubmed publisher
    ..The instructive role of hormone-sensing cells in premalignant development suggests targeting Wip1 or prolactin signaling as an orthogonal strategy for inhibiting breast cancer development or relapse. ..
  48. Arias C, Becerra Garcia F, Arrieta I, Tapia R. The protein phosphatase inhibitor okadaic acid induces heat shock protein expression and neurodegeneration in rat hippocampus in vivo. Exp Neurol. 1998;153:242-54 pubmed
    ..These results suggest that protein hyperphosphorylation due to inhibition of phosphatases in vivo induces neuronal stress and subsequent neurodegeneration. ..
  49. Billingsley M, Kincaid R. Regulated phosphorylation and dephosphorylation of tau protein: effects on microtubule interaction, intracellular trafficking and neurodegeneration. Biochem J. 1997;323 ( Pt 3):577-91 pubmed
    ..Continued work will help to determine what is causal and what is coincidental in Alzheimer's disease, and may lead to identification of therapeutic targets for halting the progression of paired helical filament formation. ..
  50. Wiederrecht G, Lam E, Hung S, Martin M, Sigal N. The mechanism of action of FK-506 and cyclosporin A. Ann N Y Acad Sci. 1993;696:9-19 pubmed
    ..Calcineurin, a component of the signal transduction pathway resulting in IL-2 expression, catalyzes critical dephosphorylation events required for early lymphokine gene transcription. ..
  51. Engin A. Human Protein Kinases and Obesity. Adv Exp Med Biol. 2017;960:111-134 pubmed publisher
    ..Defective responses of AMPK to leptin may contribute to resistance to leptin action on food intake and energy expenditure in obese states. ..
  52. Ashton N, Paquet N, Shirran S, Bolderson E, Kariawasam R, Touma C, et al. hSSB1 phosphorylation is dynamically regulated by DNA-PK and PPP-family protein phosphatases. DNA Repair (Amst). 2017;54:30-39 pubmed publisher
    ..Together, these data thereby represent a novel mechanism for hSSB1 regulation following the inhibition of replication. ..