Difference between revisions of "Phosphatase Subfamily PPM1E"

Revision as of 16:46, 10 June 2015

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

The subfamily is named named after two human PPMs, PPM1E (also known as POXP1, PP2CH, caMKN, CaMKP-N) and PPM1F (also known as POXP2, CAMKP, FEM-2, hFEM-2, CaMKPase). The subfamily has a single copy in most non-vertebrates from Monosiga to ciona, and duplicated when vertebrates emerged. Both PPM1E and PPM1F dephosphorylate kinases CaMK2g [1, 2, 3] and PAK [4], and PPM1E can also dephosphorylate CaMK4 (of different families from CaMK2g).

The subfamily has some potent inhibitors [5].

The subfamily also dephosphorylate 5'-AMP-activated protein kinase (AMPK) [6]. The activation of AMPK is related to the treatment of type 2 diabetes.

Evolution

CAMK2

Domain

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 [7, 8].

PPM1E and PPM1F have different sub-cellular localizations. Human PPM1E is localized to nculear [1]; PPM1F is localized to cytosol [7, 8]. Human PPM1E has two C-terminal nuclear localization signals (NLSs), at 668-702 and 706-742, respectively [2]. 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 [9]. Human PPM1E dephosphorylates CAMK4 and nuclear CAMK2, while PPM1F dephosphorylates CAMK1 and cytosolic CAMK2 [1, 8]. Rat PPM1F extracted from brain also dephosphorylates CAMK2, but not phosphorylase kinase, histones, MBP, α-casein, andd phosphorylase α [10]. 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 [4]. PPM1E can bind to PAK interacting guanine nucleotide exchange factor PIX [4]. The association between PPM1E/PPM1F with PAX complex may allow PAK to cycle rapidly between active and inactive states [4].

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 [11].

• Human PPM1E dephosphorylates 5'-AMP-activated protein kinase (AMPK) [6].

• Human PPM1F can dephosphorylate C. elegans fem-3 [8], 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) [12] and MAPK1/3 [13], therefore regulating cancer cell motility [14]. 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) [15].

PPM1E is proposed to be regulated by oxidation/reduction at Cys-359 [16].

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 [17]. 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 [18]. Fem-2 associates with fem-1 and fem-3 via its N-terminal domain [18]. 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 [17].

References

1. 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]
2. 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]
3. 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]
4. 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. DOI:10.1016/s0960-9822(02)00652-8 | PubMed ID:11864573 | HubMed [Koh02]
5. 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]
6. 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]
7. 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]
8. 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]
9. 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]
10. 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]
11. 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]
12. 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]
13. 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]
14. 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]
15. 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]
16. 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]
17. 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]
18. 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]