Phosphatase Subfamily PPP2C

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Phosphatase Classification: Fold PPPL: Superfamily PPPL: Family PPP: Subfamily PPP2C (PP2A, catalytic subunit)

PPP2C is the catalytic subunit of the holoenzyme PP2A. PP2A is heterotrimer consisting of a core dimer of two catalytic (C) subunits and an A regulatory subunit, along with one (C) and regulatory subunit A (PR65), and a third regulatory subunit B-type [1]. Multiple genes encode each subunits, which resulting in a total of about 75 different holoenzyme compositions [2].

Evolution

PPP2C is found throughout eukaryotes. Human has two PPP2C: PPP2CA and PPP2CB, along with two A subunits (PPP2R1A, PPP2R1B) and at least 12 B regulatory subunits. Most invertebrates have a single copy of the catalytic subunit, and yeast has two PPH21 and PPH22.

Domain

PPP1C has a single domain - phosphatase domain. The activity of phosphatase is inhibited by binding to Zinc2+ in vitro [3].

Functions

PP2A accounts for the majority of phospho-serine/threonine phosphatase activity in most cells and is involved in the regulation of nearly every cellular process, including multiple inflammatory signaling pathways [4], cell cycle progression, autophagy [5], DNA replication, gene transcription and protein translation [6, 7]. It is considered to be a principal guardian against tumorigenic transformation [8]. Some viruses target this protein to hijack the host cell [1].

PP2A controls the activity of at least 50 different kinases by directly interaction or linked via a anchoring protein. PP2A not only integrate signals within phoshorylation cascades but also to be the focal point of a distinct post-translational modification, reversible protein methylation [2]. Here are some examples of PP2A functions:

  • Hedgehog signaling. PP2A functions with PPFIA1 to promote the dephosphorylation of Kif7, triggering Kif7 localization to the tips of primary cilia and promoting Gli transcriptional activity. Both Kif7 and Gli are components in Hedgehog signaling [9]. (PS: Interestingly, PPFIA1 is known as interacting partner with tyrosine phosphatase PTPRF.)
  • PP2A/B55 complex dephosphorylates heat shock factor 1. The regulatory subunit B55 directly binds to HSF1 [10].
  • PP2A-B56ϵ complex is involved in dephosphorylation of γ-H2AX in the repair process of topoisomerase I inhibitor camptothecin-induced DNA double-strand breaks [11].

PP2A is regulated by Lyn, a Src kinase, through phosphorylation at Tyr-307 [12].

References

  1. Janssens V, Longin S, and Goris J. PP2A holoenzyme assembly: in cauda venenum (the sting is in the tail). Trends Biochem Sci. 2008 Mar;33(3):113-21. DOI:10.1016/j.tibs.2007.12.004 | PubMed ID:18291659 | HubMed [janssens08]
  2. Janssens V, Goris J, and Van Hoof C. PP2A: the expected tumor suppressor. Curr Opin Genet Dev. 2005 Feb;15(1):34-41. DOI:10.1016/j.gde.2004.12.004 | PubMed ID:15661531 | HubMed [janssens05]
  3. Xiong Y, Luo DJ, Wang XL, Qiu M, Yang Y, Yan X, Wang JZ, Ye QF, and Liu R. Zinc binds to and directly inhibits protein phosphatase 2A in vitro. Neurosci Bull. 2015 Jun;31(3):331-7. DOI:10.1007/s12264-014-1519-z | PubMed ID:25854679 | HubMed [Xiong15]
  4. Rahman MM, Rumzhum NN, Morris JC, Clark AR, Verrills NM, and Ammit AJ. Basal protein phosphatase 2A activity restrains cytokine expression: role for MAPKs and tristetraprolin. Sci Rep. 2015 May 18;5:10063. DOI:10.1038/srep10063 | PubMed ID:25985190 | HubMed [Rahman15]
  5. Wong PM, Feng Y, Wang J, Shi R, and Jiang X. Regulation of autophagy by coordinated action of mTORC1 and protein phosphatase 2A. Nat Commun. 2015 Aug 27;6:8048. DOI:10.1038/ncomms9048 | PubMed ID:26310906 | HubMed [Wong15]
  6. Janssens V and Goris J. Protein phosphatase 2A: a highly regulated family of serine/threonine phosphatases implicated in cell growth and signalling. Biochem J. 2001 Feb 1;353(Pt 3):417-39. PubMed ID:11171037 | HubMed [janssens01]
  7. Sontag E. Protein phosphatase 2A: the Trojan Horse of cellular signaling. Cell Signal. 2001 Jan;13(1):7-16. PubMed ID:11257442 | HubMed [sontag01]
  8. Westermarck J and Hahn WC. Multiple pathways regulated by the tumor suppressor PP2A in transformation. Trends Mol Med. 2008 Apr;14(4):152-60. DOI:10.1016/j.molmed.2008.02.001 | PubMed ID:18329957 | HubMed [westermarck08]
  9. Liu YC, Couzens AL, Deshwar AR, B McBroom-Cerajewski LD, Zhang X, Puviindran V, Scott IC, Gingras AC, Hui CC, and Angers S. The PPFIA1-PP2A protein complex promotes trafficking of Kif7 to the ciliary tip and Hedgehog signaling. Sci Signal. 2014 Dec 9;7(355):ra117. DOI:10.1126/scisignal.2005608 | PubMed ID:25492966 | HubMed [liu14]
  10. Ishikawa Y, Kawabata S, and Sakurai H. HSF1 transcriptional activity is modulated by IER5 and PP2A/B55. FEBS Lett. 2015 Apr 28;589(10):1150-5. DOI:10.1016/j.febslet.2015.03.019 | PubMed ID:25816751 | HubMed [Ishikawa15]
  11. Li X, Nan A, Xiao Y, Chen Y, and Lai Y. PP2A-B56ϵ complex is involved in dephosphorylation of γ-H2AX in the repair process of CPT-induced DNA double-strand breaks. Toxicology. 2015 May 4;331:57-65. DOI:10.1016/j.tox.2015.03.007 | PubMed ID:25772433 | HubMed [Li15]
  12. Zonta F, Pagano MA, Trentin L, Tibaldi E, Frezzato F, Trimarco V, Facco M, Zagotto G, Pavan V, Ribaudo G, Bordin L, Semenzato G, and Brunati AM. Lyn sustains oncogenic signaling in chronic lymphocytic leukemia by strengthening SET-mediated inhibition of PP2A. Blood. 2015 Jun 11;125(24):3747-55. DOI:10.1182/blood-2014-12-619155 | PubMed ID:25931585 | HubMed [Zonta15]
All Medline abstracts: PubMed | HubMed