Phosphatase Subfamily PPM1E

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Phosphatase Classification: Superfamily PPM (PP2C): Family PPM (PP2C): Subfamily PPM1E (POXP, FEM-2)

Evolution

The PPM1E subfamily emerged in holozoa. Its substrates emerged earlier or at the same time: human CAMK1 and CAMK4 belong to CAMK1 kinase subfamily which is found throughout eukaryotes; human CAMK2 belong to CAMK2 subfamily which emerged in holozoa ; human PAK belongs to PAKA subfamily which is common in eukaryotes.

Human has two members: PPM1E and PPM1F. They arose by gene duplication in jawed vertebrates, since both of them presented in jawed vertebrates, but only one is present in lamprey and other metazoa.

Domain

The PPM1E subfamily has a phosphatase domain. C. elegans fem-2 has an additional N-terminal structural domain, which is only found in nematodes. It is unclear whether the N-terminal regions of human PPM1E and PPM1F, or vertebrate PPM1Es and PPM1Fs in general, encode a structural domain.

Human PPM1F has two nuclear localization signals (NLSs) at C-terminal, whichc cannot be predicted by NLS prediction tools such as NLS mapper and NLStradamus.

Functions

Human PPM1E and PPM1F

Human has two members: PPM1E (POPX1, PP2CH, caMKN, CaMKP-N) and PPM1F (POPX2, CAMKP, CaMKPase, FEM-2, hFEM-2).

Human PPM1EHuman PPM1F is widely expressed in different tissues, as shown by Western blotting analysis [1, 2].

PPM1E and PPM1F have different sub-cellular localizations. Human PPM1E is localized to nculear [3]; PPM1F is localized to cytosol [1, 2]. Human PPM1E has two C-terminal nuclear localization signals (NLSs), at 668-702 and 706-742, respectively [4]. The two NLSs can not be computational identified by NLS prediction tools NLS mapper and NLStradamus.

Both PPM1E and PPM1F dephosphorylate and deactivates kinases of CAMK (Ca2+/calmodulin-dependent protein kinase) group as evidenced by extensive studies. CAMK2 is regulated by autophosphorylation at multiple sites, including Thr-286 activates CAMK2. PPM1F dephosphorylate Thr-286 on CAMK2 in fibroblasts [5]. Human PPM1E dephosphorylates CAMK4 and nuclear CAMK2, while PPM1F dephosphorylates CAMK1 and cytosolic CAMK2 [2, 3]. Rat PPM1F extracted from brain also dephosphorylates CAMK2, but not phosphorylase kinase, histones, MBP, α-casein, andd phosphorylase α [6]. In addition, human PPM1F regulates the phosphorylation level of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in by dephosphorylating and deactivating CAMKs that are responsible for the phosphorylation of GAPDH.

Both PPM1E and PPM1F can dephosphorylate and inactivate p21 (Cdc42/Rac)-activated kinase (PAK), which is potently activated by autophosphorylation at multiple sites [7]. PPM1E can bind to PAK interacting guanine nucleotide exchange factor PIX [7]. The association between PPM1E/PPM1F with PAX complex may allow PAK to cycle rapidly between active and inactive states [7].

Other substrates and interacting partners:

  • Human PPM1F dephoshorylates serine-690 of KIF3A, which is phosphorylated by CAMK2. KIF3A is a motor subunit which forms a heterotrimeric complex with KIF3B, another motor subunit, and KAP3, the non-motor subunit [8].
  • Human PPM1E dephosphorylates 5'-AMP-activated protein kinase (AMPK) [9].
  • Human PPM1F can dephosphorylate C. elegans fem-3 [2], but fem-3 is only found in Caenorhabditis according to OrthoDB.
  • By proteomic approach, it was found that human PPM1F regulates the activity of glycogen synthase kinase-3 (GSK3) [10] and MAPK1/3 [11], therefore regulating cancer cell motility [12]. GSK3 is not the subtratre of PPM1F, and it is unclear whether PPM1F directly dephosphorylate MAPK1/3.
  • Human PPM1F interacts with the formin protein mDia1 (DIAPH1) and decreases the ability of mDia1 to activate the transcription of serum response element (SRE) [13].

PPM1E is proposed to be regulated by oxidation/reduction at Cys-359 [14].

C. elegans fem-2

Fem-2 is C. elegans PPM1E, which, together with fem-1 and fem-3, is required by male sexual development in C. elegans [15]. Crystal structure of C. elegans Fem-2 shows two structural domains: N-terminal domain from 13-160 and C-terminal phosphatase domain from 161-436 [16]. Fem-2 associates with fem-1 and fem-3 via its N-terminal domain [16]. However, the N-terminal domain is only found in several nematodes, by BLASTing the region against NR database. Meanwhile, fem-3 is only present in Caenorhabditis by BLASTing the protein sequence of longest isoform against NR database; Fem-1 is found throughout metazoa (see internal data).

Fem-2 exhibits magnesium-dependent casein phosphatase activity in vitro [15].

References

  1. Kitani T, Ishida A, Okuno S, Takeuchi M, Kameshita I, and Fujisawa H. Molecular cloning of Ca2+/calmodulin-dependent protein kinase phosphatase. J Biochem. 1999 Jun;125(6):1022-8. DOI:10.1093/oxfordjournals.jbchem.a022381 | PubMed ID:10348902 | HubMed [Kitani99]
  2. Tan KM, Chan SL, Tan KO, and Yu VC. The Caenorhabditis elegans sex-determining protein FEM-2 and its human homologue, hFEM-2, are Ca2+/calmodulin-dependent protein kinase phosphatases that promote apoptosis. J Biol Chem. 2001 Nov 23;276(47):44193-202. DOI:10.1074/jbc.M105880200 | PubMed ID:11559703 | HubMed [Tan01]
  3. Takeuchi M, Ishida A, Kameshita I, Kitani T, Okuno S, and Fujisawa H. Identification and characterization of CaMKP-N, nuclear calmodulin-dependent protein kinase phosphatase. J Biochem. 2001 Dec;130(6):833-40. DOI:10.1093/oxfordjournals.jbchem.a003055 | PubMed ID:11726284 | HubMed [Takeuchi01]
  4. Takeuchi M, Taniguchi T, and Fujisawa H. Identification and characterization of nuclear localization signals of CaMKP-N. J Biochem. 2004 Aug;136(2):183-8. DOI:10.1093/jb/mvh109 | PubMed ID:15496589 | HubMed [Takeuchi04]
  5. Harvey BP, Banga SS, and Ozer HL. Regulation of the multifunctional Ca2+/calmodulin-dependent protein kinase II by the PP2C phosphatase PPM1F in fibroblasts. J Biol Chem. 2004 Jun 4;279(23):24889-98. DOI:10.1074/jbc.M400656200 | PubMed ID:15140879 | HubMed [Harvey04]
  6. Ishida A, Kameshita I, and Fujisawa H. A novel protein phosphatase that dephosphorylates and regulates Ca2+/calmodulin-dependent protein kinase II. J Biol Chem. 1998 Jan 23;273(4):1904-10. DOI:10.1074/jbc.273.4.1904 | PubMed ID:9442023 | HubMed [Ishida98]
  7. Koh CG, Tan EJ, Manser E, and Lim L. The p21-activated kinase PAK is negatively regulated by POPX1 and POPX2, a pair of serine/threonine phosphatases of the PP2C family. Curr Biol. 2002 Feb 19;12(4):317-21. PubMed ID:11864573 | HubMed [Koh02]
  8. Phang HQ, Hoon JL, Lai SK, Zeng Y, Chiam KH, Li HY, and Koh CG. POPX2 phosphatase regulates the KIF3 kinesin motor complex. J Cell Sci. 2014 Feb 15;127(Pt 4):727-39. DOI:10.1242/jcs.126482 | PubMed ID:24338362 | HubMed [Phang14]
  9. Voss M, Paterson J, Kelsall IR, Martín-Granados C, Hastie CJ, Peggie MW, and Cohen PT. Ppm1E is an in cellulo AMP-activated protein kinase phosphatase. Cell Signal. 2011 Jan;23(1):114-24. DOI:10.1016/j.cellsig.2010.08.010 | PubMed ID:20801214 | HubMed [Voss12]
  10. Singh P, Gan CS, Guo T, Phang HQ, Sze SK, and Koh CG. Investigation of POPX2 phosphatase functions by comparative phosphoproteomic analysis. Proteomics. 2011 Jul;11(14):2891-900. DOI:10.1002/pmic.201100044 | PubMed ID:21656682 | HubMed [Singh11]
  11. Zhang S, Guo T, Chan H, Sze SK, and Koh CG. Integrative transcriptome and proteome study to identify the signaling network regulated by POPX2 phosphatase. J Proteome Res. 2013 Jun 7;12(6):2525-36. DOI:10.1021/pr301113c | PubMed ID:23621870 | HubMed [Zhang13]
  12. Susila A, Chan H, Loh AX, Phang HQ, Wong ET, Tergaonkar V, and Koh CG. The POPX2 phosphatase regulates cancer cell motility and invasiveness. Cell Cycle. 2010 Jan 1;9(1):179-87. DOI:10.4161/cc.9.1.10406 | PubMed ID:20016286 | HubMed [Susila10]
  13. Xie Y, Tan EJ, Wee S, Manser E, Lim L, and Koh CG. Functional interactions between phosphatase POPX2 and mDia modulate RhoA pathways. J Cell Sci. 2008 Feb 15;121(Pt 4):514-21. DOI:10.1242/jcs.013557 | PubMed ID:18230650 | HubMed [Xie08]
  14. Baba H, Sueyoshi N, Shigeri Y, Ishida A, and Kameshita I. Regulation of Ca(2+)/calmodulin-dependent protein kinase phosphatase (CaMKP) by oxidation/reduction at Cys-359. Arch Biochem Biophys. 2012 Oct 1;526(1):9-15. DOI:10.1016/j.abb.2012.06.005 | PubMed ID:22743349 | HubMed [Baba12]
  15. Chin-Sang ID and Spence AM. Caenorhabditis elegans sex-determining protein FEM-2 is a protein phosphatase that promotes male development and interacts directly with FEM-3. Genes Dev. 1996 Sep 15;10(18):2314-25. DOI:10.1101/gad.10.18.2314 | PubMed ID:8824590 | HubMed [Chin-Sang96]
  16. Zhang Y, Zhao H, Wang J, Ge J, Li Y, Gu J, Li P, Feng Y, and Yang M. Structural insight into Caenorhabditis elegans sex-determining protein FEM-2. J Biol Chem. 2013 Jul 26;288(30):22058-66. DOI:10.1074/jbc.M113.464339 | PubMed ID:23760267 | HubMed [Zhang13b]
  17. Ishida A, Tada Y, Nimura T, Sueyoshi N, Katoh T, Takeuchi M, Fujisawa H, Taniguchi T, and Kameshita I. Identification of major Ca(2+)/calmodulin-dependent protein kinase phosphatase-binding proteins in brain: biochemical analysis of the interaction. Arch Biochem Biophys. 2005 Mar 1;435(1):134-46. DOI:10.1016/j.abb.2004.11.022 | PubMed ID:15680915 | HubMed [Ishida05]
  18. Sueyoshi N, Takao T, Nimura T, Sugiyama Y, Numano T, Shigeri Y, Taniguchi T, Kameshita I, and Ishida A. Inhibitors of the Ca(2+)/calmodulin-dependent protein kinase phosphatase family (CaMKP and CaMKP-N). Biochem Biophys Res Commun. 2007 Nov 23;363(3):715-21. DOI:10.1016/j.bbrc.2007.09.022 | PubMed ID:17897624 | HubMed [Ishida07]
All Medline abstracts: PubMed | HubMed