Skip to main content
SpringerLink
Log in

Serine/Threonine-Protein Phosphatase 2A

  • Reference work entry
  • First Online:
Encyclopedia of Signaling Molecules

  • 215 Accesses

Synonyms

PCS phosphatase; Polycation-stimulated phosphatase; PP2A; Protein phosphatase 2A

Historical Background

Since Krebs and Fischer (1956) discovered that the activity of an enzyme (glycogen phosphorylase) can be regulated by a reversible phosphorylation, much attention has been paid to the enzymes catalyzing these covalent modifications: the protein kinases and protein phosphatases. As opposed to protein kinases, it has taken much more time to understand the action of protein phosphatases, mainly because of their complex molecular structure and broad substrate specificities. Nevertheless, protein phosphatases are equally important in controlling biochemical pathways, adding reversibility and sensitivity to these processes.

While the first kinase (phosphorylase kinase) was isolated soon after the discovery of the concept of reversible protein phosphorylation, the biochemical isolation of the first phosphataseneeded about 20 more years: ethanol denaturation (accidently applied!)...

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 4,499.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 4,499.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Ahn JH, McAvoy T, Rakhilin SV, Nishi A, Greengard P, Nairn AC. Protein kinase A activates protein phosphatase 2A by phosphorylation of the B56δ subunit. Proc Natl Acad Sci U S A. 2007a;104:2979–84.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ahn JH, Sung JY, McAvoy T, Nishi A, Janssens V, Goris J, et al. The B″/PR72 subunit mediates Ca2+-dependent dephosphorylation of DARPP-32 by protein phosphatase 2A. Proc Natl Acad Sci U S A. 2007b;104:9876–81.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Basu S. PP2A in the regulation of cell motility and invasion. Curr Protein Pept Sci. 2011;12:3–11.

    Article  PubMed  CAS  Google Scholar 

  • Brandt H, Capulong ZL, Lee EY. Purification and properties of rabbit liver phosphorylase phosphatase. J Biol Chem. 1975;250:8038–44.

    PubMed  CAS  Google Scholar 

  • Chen J, Martin BL, Brautigan DL. Regulation of protein serine-threonine phosphatase type-2A by tyrosine phosphorylation. Science. 1992;257:1261–4.

    Article  PubMed  CAS  Google Scholar 

  • Cheng YS, Seibert O, Klöting N, Dietrich A, Straßburger K, Fernández-Veledo S, et al. PPP2R5C couples hepatic glucose and lipid homeostasis. PLoS Genet. 2015;11:e1005561. doi:10.1371/journal.pgen.1005561.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Cundell MJ, Hutter LH, Nunes Bastos R, Poser E, Holder J, Mohammed S, et al. A PP2A-B55 recognition signal controls substrate dephosphorylation kinetics during mitotic exit. J Cell Biol. 2016;214:539–54. doi:10.1083/jcb.201606033.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Dodge-Kafka KL, Bauman A, Mayer N, Henson E, Heredia L, Ahn J, et al. cAMP-stimulated protein phosphatase 2A activity associated with muscle A kinase-anchoring protein (mAKAP) signaling complexes inhibits the phosphorylation and activity of the cAMP-specific phosphodiesterase PDE4D3. J Biol Chem. 2010;285:11078–86. doi:10.1074/jbc.M109.034868.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Eichhorn PJ, Creyghton MP, Bernards R. Protein phosphatase 2A regulatory subunits and cancer. Biochim Biophys Acta. 2009;1795:1–15. doi:10.1016/j.bbcan.2008.05.005.

    Article  PubMed  CAS  Google Scholar 

  • Guergnon J, Godet AN, Galioot A, Falanga PB, Colle JH, Cayla X, et al. PP2A targeting by viral proteins: a widespread biological strategy from DNA/RNA tumor viruses to HIV-1. Biochim Biophys Acta. 2011;1812:1498–507. doi:10.1016/j.bbadis.2011.07.001.

    Article  PubMed  CAS  Google Scholar 

  • Haesen D, Sents W, Ivanova E, Lambrecht C, Janssens V. Cellular inhibitors of protein phosphatase PP2A in cancer. Biomed Res India. 2012;23:197–211.

    CAS  Google Scholar 

  • Hahn WC, Weinberg RA. Rules for making human tumor cells. N Engl J Med. 2002;347:1593–603.

    Article  PubMed  CAS  Google Scholar 

  • Hertz EP, Kruse T, Davey NE, López-Méndez B, Sigurðsson JO, Montoya G, et al. A conserved motif provides binding specificity to the PP2A-B56 phosphatase. Mol Cell. 2016;63:686–95. doi:10.1016/j.molcel.2016.06.024.

    Article  PubMed  CAS  Google Scholar 

  • Hombauer H, Weismann D, Mudrak I, Stanzel C, Fellner T, Lackner DH, et al. Generation of active protein phosphatase 2A is coupled to holoenzyme assembly. PLoS Biol. 2007;5:e155.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Houge G, Haesen D, Vissers LE, Mehta S, Parker MJ, Wright M, et al. B56δ-related protein phosphatase 2A dysfunction identified in patients with intellectual disability. J Clin Invest. 2015;125:3051–62. doi:10.1172/JCI79860.

    Article  PubMed  PubMed Central  Google Scholar 

  • Hunt T. On the regulation of protein phosphatase 2A and its role in controlling entry into and exit from mitosis. Adv Biol Regul. 2013;53:173–8. doi:10.1016/j.jbior.2013.04.001.

    Article  PubMed  CAS  Google Scholar 

  • Ingebritsen TS, Cohen P. The protein phosphatases involved in cellular regulation. 1. Classification and substrate specificities. Eur J Biochem. 1983;132:255–61.

    Article  PubMed  CAS  Google Scholar 

  • Janssens V, Goris J. Protein phosphatase 2A: a highly regulated family of serine/threonine phosphatases implicated in cell growth and signalling. Biochem J. 2001;353:417–39.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Janssens V, Rebollo A. The role and therapeutic potential of Ser/Thr phosphatase PP2A in apoptotic signalling networks in human cancer cells. Curr Mol Med. 2012;12:268–87.

    Article  PubMed  CAS  Google Scholar 

  • Janssens V, Jordens J, Stevens I, Van Hoof C, Martens E, De Smedt H, et al. Identification and functional analysis of two Ca2+-binding EF-hand motifs in the B″/PR72 subunit of protein phosphatase 2A. J Biol Chem. 2003;278:10697–706.

    Article  PubMed  CAS  Google Scholar 

  • Janssens V, Longin S, Goris J. PP2A holoenzyme assembly: in cauda venenum (the sting is in the tail). Trends Biochem Sci. 2008;33:113–21. doi:10.1016/j.tibs.2007.12.004.

    Article  PubMed  CAS  Google Scholar 

  • Kirchhefer U, Brekle C, Eskandar J, Isensee G, Kučerová D, Müller FU, et al. Cardiac function is regulated by B56α-mediated targeting of protein phosphatase 2A (PP2A) to contractile relevant substrates. J Biol Chem. 2014;289:33862–73.

    Article  PubMed  PubMed Central  Google Scholar 

  • Kolupaeva V, Janssens V. PP1 and PP2A phosphatases – cooperating partners in modulating retinoblastoma protein activation. FEBS J. 2013;280:627–43. doi:10.1111/j.1742-4658.2012.08511.x.

    Article  PubMed  CAS  Google Scholar 

  • Kolupaeva V, Daempfling L, Basilico C. The B55α regulatory subunit of protein phosphatase 2A mediates fibroblast growth factor-induced p107 dephosphorylation and growth arrest in chondrocytes. Mol Cell Biol. 2013;33:2865–78. doi:10.1128/MCB.01730-12.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kowluru A, Matti A. Hyperactivation of protein phosphatase 2A in models of glucolipotoxicity and diabetes: potential mechanisms and functional consequences. Biochem Pharmacol. 2012;84:591–7. doi:10.1016/j.bcp.2012.05.003.

    Article  PubMed  CAS  Google Scholar 

  • Krebs EG, Fischer EH. The phosphorylase b to a converting enzyme of rabbit skeletal muscle. Biochim Biophys Acta. 1956;20:150–7.

    Article  PubMed  CAS  Google Scholar 

  • Lambrecht C, Haesen D, Sents W, Ivanova E, Janssens V. Structure, regulation, and pharmacological modulation of PP2A phosphatases. Methods Mol Biol. 2013;1053:283–305. doi:10.1007/978-1-62703-562-0_17.

    Article  PubMed  CAS  Google Scholar 

  • Letourneux C, Rocher G, Porteu F. B56-containing PP2A dephosphorylate ERK and their activity is controlled by the early gene IEX-1 and ERK. EMBO J. 2006;25:727–38.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Loveday C, Tatton-Brown K, Clarke M, Westwood I, Renwick A, Ramsay E, et al. Mutations in the PP2A regulatory subunit B family genes PPP2R5B, PPP2R5C and PPP2R5D cause human overgrowth. Hum Mol Genet. 2015;24:4775–9. doi:10.1093/hmg/ddv182.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Low IC, Loh T, Huang Y, Virshup DM, Pervaiz S. Ser70 phosphorylation of Bcl-2 by selective tyrosine nitration of PP2A-B56δ stabilizes its antiapoptotic activity. Blood. 2014;124:2223–34. doi:10.1182/blood-2014-03-563296.

    Article  PubMed  CAS  Google Scholar 

  • Lubbers ER, Mohler PJ. Roles and regulation of protein phosphatase 2A (PP2A) in the heart. J Mol Cell Cardiol. 2016;101:127–33. doi:10.1016/j.yjmcc.2016.11.003.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Millward TA, Zolnierowicz S, Hemmings BA. Regulation of protein kinase cascades by protein phosphatase 2A. Trends Biochem Sci. 1999;24:186–91.

    Article  PubMed  CAS  Google Scholar 

  • Oaks J, Ogretmen B. Regulation of PP2A by sphingolipid metabolism and signaling. Front Oncol. 2015;4:388. doi:10.3389/fonc.2014.00388.

    Article  PubMed  PubMed Central  Google Scholar 

  • Ohama T, Brautigan DL. Endotoxin conditioning induces VCP/p97-mediated and inducible nitric-oxide synthase-dependent Tyr284 nitration in protein phosphatase 2A. J Biol Chem. 2010;285:8711–8. doi:10.1074/jbc.M109.099788.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Perrotti D, Neviani P. Protein phosphatase 2A: a target for anticancer therapy. Lancet Oncol. 2013;14:e229–38. doi:10.1016/S1470-2045(12)70558-2.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ruvolo PP. The broken “off” switch in cancer signaling: PP2A as a regulator of tumorigenesis, drug resistance, and immune surveillance. BBA Clin. 2016;6:87–99. doi:10.1016/j.bbacli.2016.08.002.

    Article  PubMed  PubMed Central  Google Scholar 

  • Sangodkar J, Farrington CC, McClinch K, Galsky MD, Kastrinsky DB, Narla G. All roads lead to PP2A: exploiting the therapeutic potential of this phosphatase. FEBS J. 2016;283:1004–24. doi:10.1111/febs.13573.

    Article  PubMed  CAS  Google Scholar 

  • Schmitz MH, Held M, Janssens V, Hutchins JR, Hudecz O, Ivanova E, et al. Live-cell imaging RNAi screen identifies PP2A-B55alpha and importin-beta1 as key mitotic exit regulators in human cells. Nat Cell Biol. 2010;12:886–93. doi:10.1038/ncb2092.

    Article  PubMed  CAS  Google Scholar 

  • Sents W, Ivanova E, Lambrecht C, Haesen D, Janssens V. The biogenesis of active protein phosphatase 2A holoenzymes: a tightly regulated process creating phosphatase specificity. FEBS J. 2013;280:644–61. doi:10.1111/j.1742-4658.2012.08579.x.

    Article  PubMed  CAS  Google Scholar 

  • Shi Y. Serine/threonine phosphatases: mechanism through structure. Cell. 2009;139:468–84. doi:10.1016/j.cell.2009.10.006.

    Article  PubMed  CAS  Google Scholar 

  • Shouse GP, Nobumori Y, Panowicz MJ, Liu X. ATM-mediated phosphorylation activates the tumor-suppressive function of B56γ-PP2A. Oncogene. 2011;30:3755–65. doi:10.1038/onc.2011.95.

    Article  PubMed  CAS  Google Scholar 

  • Sontag JM, Sontag E. Protein phosphatase 2A dysfunction in Alzheimer’s disease. Front Mol Neurosci. 2014;7:16. doi:10.3389/fnmol.2014.00016.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Taymans JM, Baekelandt V. Phosphatases of α-synuclein, LRRK2, and tau: important players in the phosphorylation-dependent pathology of Parkinsonism. Front Genet. 2014;5:382. doi:10.3389/fgene.2014.00382.13.

    Article  PubMed  PubMed Central  Google Scholar 

  • Voronkov M, Braithwaite SP, Stock JB. Phosphoprotein phosphatase 2A: a novel druggable target for Alzheimer’s disease. Future Med Chem. 2011;3:821–33. doi:10.4155/fmc.11.47.

    Article  PubMed  CAS  Google Scholar 

  • Waelkens E, Goris J, Merlevede W. Purification and properties of polycation-stimulated phosphorylase phosphatases from rabbit skeletal muscle. J Biol Chem. 1987;262:1049–59.

    PubMed  CAS  Google Scholar 

  • Wlodarchak N, Xing Y. PP2A as a master regulator of the cell cycle. Crit Rev Biochem Mol Biol. 2016;51:162–84. doi:10.3109/10409238.2016.1143913.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Cellular and Molecular Medicine, Laboratory of Protein Phosphorylation and Proteomics, University of Leuven (KU LEUVEN), Herestraat 49, PO-Box 901, B-3000, Leuven, Belgium

    Veerle Janssens

Authors
  1. Veerle Janssens
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Veerle Janssens .

Editor information

Editors and Affiliations

  1. Department of Molecular Science and Technology, Ajou University, Suwon, Korea

    Sangdun Choi

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer International Publishing AG

About this entry

Check for updates. Verify currency and authenticity via CrossMark

Cite this entry

Janssens, V. (2018). Serine/Threonine-Protein Phosphatase 2A. In: Choi, S. (eds) Encyclopedia of Signaling Molecules. Springer, Cham. https://doi.org/10.1007/978-3-319-67199-4_101865

Download citation

Publish with us

Policies and ethics

Search

Navigation