Pseudophosphatases (obsolete)

Human pseudophosphatases

PTPs

Second phosphatase domains of receptor PTPs

Most receptor PTPs have two tandem phosphatase domains. The 2nd phosphatase domain has no or negligible activity. The 2nd domain can interact with 1st domain in both intra- and intermolecular manners, therefore regulating receptor PTP stability, specificity, and dimerization [1, 2]. Because the first phosphatase domains are active, these receptor PTPs are active at protein level. These phosphatases include:

• Subfamily PTPRA: PTPRA and PTPRE
• Subfamily PTPRC: PTPRC
• Subfamily PTPRD: PTPRD, PTPRF and PTPRS
• Subfamily PTPRG: PTPRG and PTPRZ1
• Subfamily PTPRK: PTPRK, PTPRM, PTPRT and PTPRU

PTPRN subfamily

The PTPRN subfamily has two members in human, PTPRN and PTPRN2. They have single phosphatase domain rather than two phosphatase domains as the members of PTPRA, PTPRC, PTPRD, PTPRK subfamilies. Their phosphatase domains mediate the interactions between them to form homo- and hetero-dimers [3]. PTPRN2 also functions as a phosphatidylinositol phosphatase to regulate insulin secretion in mouse [4].

PTPN14 subfamily

The PTPN14 subfamily has two members in human, PTPN14 and PTPN21. Although PTPN14 and PTPN21 are supposed to lack enzymatic activity, PTPN14 has been shown to dephosphorylate p130Cas on Y128, a Src phosphorylation site [5]. It is worthy pointing out that the substitutions are found around WPD loop but not CX₅R motif.

PTPN23 subfamily

The PTPN23 subfamily has a single member in human, PTPN23 (HD-PTP). Its catalytic activity is plausible. It has been reported to be catalytically inactive, - no phosphatase activity toward tyrosine or lipid. It was proposed that serine at position 1452 within Cx5R catalytic motif caused the inactivity. Replacing serine with alanine, which is found in catalytically active PTPs, can restore the phosphatase activity [6]. However, another study found SRC, E-cadherin, and beta-catenin are direct substrates of PTPN23 [7]. But, yet another study showed that PTPN23 did not modulate the levels of Src phosphorylation both in vitro and in vivo [8].

DSPs

STYX subfamily

The STYX subfamily has a single member in human, STYX. It binds to phosphorylated tyrosine to module signaling [9]. STYX localizes to the nucleus, competes with DUSP4 for binding to ERK, and acts as a nuclear anchor that regulates ERK nuclear export [10].

STYXL1 subfamily

The STYXL1 subfamily has a single member in human, STYXL1 (MK-STYX). STYXL1 binds to phosphatase PTPMT1 and modulates its activity [11, 12]. However, it is unclear whether the interaction between STYXL1 and PTPMT1 is mediated by the inactive phosphatase domain of STYXL1.

DSP3 subfamily: DUSP27 (1 out 5 members)

The function of DUSP27 is unknown, so is its catalytically inactive phosphatase domain.

PTEN-like phosphatases

Tensin subfamily: TNS1 and TNS2 (2 out of 3 members)

The tensin subfamily has 3 members containing phosphatase domains, TNS1-3. TNS1 and TNS2 are predicted to be catalytically inactive, given the arginine residue is replaced by asparagine and lysine at CX₅R motif, respectively. However, TNS2 has been reported to dephosphorylate IRS-1 [13]. The phosphatase domain of TNS1 mediates its interaction with PPP1CA in focal adhesions [14]. TNS3 is predicted to be active as it has CX₅R motif.

Myotubularins

MTMR5 subfamily

The MTMR5 subfamily has two genes in human: MTMR5 (SBF1) and MTMR13 (SBF2). MTMR5 interacts with MTMR2 (see MTMR1 subfamily) via its coiled-coil domain and mutations in the coiled-coil domain of either MTMR2 or MTMR5 abrogate this interaction. Through this interaction, MTMR5 increases the enzymatic activity of MTMR2 and dictates its subcellular localization [15]. This is a good example of inactive phosphatase functions as regulator of active phosphatase. The function of MTMR13 is unclear.

MTMR9 subfamily

The MTMR9 subfamily has a single gene in human. MTMR9 binds to phosphatases of MTMR6 subfamily: MTMR6 [16], MTMR7 [17], MTMR8 [18]. The interactions increase the enzymatic activity of these phosphatases. The interaction between MTMR9 and members of MTMR6 subfamily is also observed in C. elegans [19].

MTMR10 subfamily

The MTMR10 subfamily has three genes in human: MTMR10, MTMR11 and MTMR12. The functions of MTMR10 and MTMR11 are unclear. MTMR12 binds to MTM1 [20].

Other families

TIM50 subfamily of HAD family

The TIM50 subfamily has single member in human, TIMM50. It lacks the residues critical to its activity from yeast to human. However, TIMM50 has been show to possess a phosphatase activity toward both phospho-serine/threonine and phospho-tyrosine in vitro assay [21].

PPIP5K subfamily of HP2 family

The PPIP5K subfamily has two members in human, PPIP5K1 and PPIP5K2. Their phosphatase domains bind to polyphosphoinositide[22]).

TAB1 subfamily of PPM family

The TAB1 subfamily has single member in human, TAB1. The phosphatase domain binds to X-linked inhib- itor of apoptosis (XIAP) [23].

References

1. Blanchetot C, Tertoolen LG, Overvoorde J, and den Hertog J. Intra- and intermolecular interactions between intracellular domains of receptor protein-tyrosine phosphatases. J Biol Chem. 2002 Dec 6;277(49):47263-9. DOI:10.1074/jbc.M205810200 |
2. Barr AJ, Ugochukwu E, Lee WH, King ON, Filippakopoulos P, Alfano I, Savitsky P, Burgess-Brown NA, Müller S, and Knapp S. Large-scale structural analysis of the classical human protein tyrosine phosphatome. Cell. 2009 Jan 23;136(2):352-63. DOI:10.1016/j.cell.2008.11.038 |
3. Gross S, Blanchetot C, Schepens J, Albet S, Lammers R, den Hertog J, and Hendriks W. Multimerization of the protein-tyrosine phosphatase (PTP)-like insulin-dependent diabetes mellitus autoantigens IA-2 and IA-2beta with receptor PTPs (RPTPs). Inhibition of RPTPalpha enzymatic activity. J Biol Chem. 2002 Dec 13;277(50):48139-45. DOI:10.1074/jbc.M208228200 |
4. Caromile LA, Oganesian A, Coats SA, Seifert RA, and Bowen-Pope DF. The neurosecretory vesicle protein phogrin functions as a phosphatidylinositol phosphatase to regulate insulin secretion. J Biol Chem. 2010 Apr 2;285(14):10487-96. DOI:10.1074/jbc.M109.066563 |
5. Zhang P, Guo A, Possemato A, Wang C, Beard L, Carlin C, Markowitz SD, Polakiewicz RD, and Wang Z. Identification and functional characterization of p130Cas as a substrate of protein tyrosine phosphatase nonreceptor 14. Oncogene. 2013 Apr 18;32(16):2087-95. DOI:10.1038/onc.2012.220 |
6. Gingras MC, Zhang YL, Kharitidi D, Barr AJ, Knapp S, Tremblay ML, and Pause A. HD-PTP is a catalytically inactive tyrosine phosphatase due to a conserved divergence in its phosphatase domain. PLoS One. 2009;4(4):e5105. DOI:10.1371/journal.pone.0005105 |
7. Lin G, Aranda V, Muthuswamy SK, and Tonks NK. Identification of PTPN23 as a novel regulator of cell invasion in mammary epithelial cells from a loss-of-function screen of the 'PTP-ome'. Genes Dev. 2011 Jul 1;25(13):1412-25. DOI:10.1101/gad.2018911 |
8. Mariotti M, Castiglioni S, Garcia-Manteiga JM, Beguinot L, and Maier JA. HD-PTP inhibits endothelial migration through its interaction with Src. Int J Biochem Cell Biol. 2009 Mar;41(3):687-93. DOI:10.1016/j.biocel.2008.08.005 |
9. Wishart MJ and Dixon JE. Gathering STYX: phosphatase-like form predicts functions for unique protein-interaction domains. Trends Biochem Sci. 1998 Aug;23(8):301-6. DOI:10.1016/s0968-0004(98)01241-9 |
10. Reiterer V, Fey D, Kolch W, Kholodenko BN, and Farhan H. Pseudophosphatase STYX modulates cell-fate decisions and cell migration by spatiotemporal regulation of ERK1/2. Proc Natl Acad Sci U S A. 2013 Jul 30;110(31):E2934-43. DOI:10.1073/pnas.1301985110 |
11. Niemi NM, Lanning NJ, Klomp JA, Tait SW, Xu Y, Dykema KJ, Murphy LO, Gaither LA, Xu HE, Furge KA, Green DR, and MacKeigan JP. MK-STYX, a catalytically inactive phosphatase regulating mitochondrially dependent apoptosis. Mol Cell Biol. 2011 Apr;31(7):1357-68. DOI:10.1128/MCB.00788-10 |
12. Niemi NM, Sacoman JL, Westrate LM, Gaither LA, Lanning NJ, Martin KR, and MacKeigan JP. The pseudophosphatase MK-STYX physically and genetically interacts with the mitochondrial phosphatase PTPMT1. PLoS One. 2014;9(4):e93896. DOI:10.1371/journal.pone.0093896 |
13. Koh A, Lee MN, Yang YR, Jeong H, Ghim J, Noh J, Kim J, Ryu D, Park S, Song P, Koo SH, Leslie NR, Berggren PO, Choi JH, Suh PG, and Ryu SH. C1-Ten is a protein tyrosine phosphatase of insulin receptor substrate 1 (IRS-1), regulating IRS-1 stability and muscle atrophy. Mol Cell Biol. 2013 Apr;33(8):1608-20. DOI:10.1128/MCB.01447-12 |
14. Eto M, Kirkbride J, Elliott E, Lo SH, and Brautigan DL. Association of the tensin N-terminal protein-tyrosine phosphatase domain with the alpha isoform of protein phosphatase-1 in focal adhesions. J Biol Chem. 2007 Jun 15;282(24):17806-15. DOI:10.1074/jbc.M700944200 |
15. Kim SA, Vacratsis PO, Firestein R, Cleary ML, and Dixon JE. Regulation of myotubularin-related (MTMR)2 phosphatidylinositol phosphatase by MTMR5, a catalytically inactive phosphatase. Proc Natl Acad Sci U S A. 2003 Apr 15;100(8):4492-7. DOI:10.1073/pnas.0431052100 |
16. Zou J, Chang SC, Marjanovic J, and Majerus PW. MTMR9 increases MTMR6 enzyme activity, stability, and role in apoptosis. J Biol Chem. 2009 Jan 23;284(4):2064-71. DOI:10.1074/jbc.M804292200 |
17. Mochizuki Y and Majerus PW. Characterization of myotubularin-related protein 7 and its binding partner, myotubularin-related protein 9. Proc Natl Acad Sci U S A. 2003 Aug 19;100(17):9768-73. DOI:10.1073/pnas.1333958100 |
18. Zou J, Zhang C, Marjanovic J, Kisseleva MV, Majerus PW, and Wilson MP. Myotubularin-related protein (MTMR) 9 determines the enzymatic activity, substrate specificity, and role in autophagy of MTMR8. Proc Natl Acad Sci U S A. 2012 Jun 12;109(24):9539-44. DOI:10.1073/pnas.1207021109 |
19. Silhankova M, Port F, Harterink M, Basler K, and Korswagen HC. Wnt signalling requires MTM-6 and MTM-9 myotubularin lipid-phosphatase function in Wnt-producing cells. EMBO J. 2010 Dec 15;29(24):4094-105. DOI:10.1038/emboj.2010.278 |
20. Nandurkar HH, Layton M, Laporte J, Selan C, Corcoran L, Caldwell KK, Mochizuki Y, Majerus PW, and Mitchell CA. Identification of myotubularin as the lipid phosphatase catalytic subunit associated with the 3-phosphatase adapter protein, 3-PAP. Proc Natl Acad Sci U S A. 2003 Jul 22;100(15):8660-5. DOI:10.1073/pnas.1033097100 |
21. Guo Y, Cheong N, Zhang Z, De Rose R, Deng Y, Farber SA, Fernandes-Alnemri T, and Alnemri ES. Tim50, a component of the mitochondrial translocator, regulates mitochondrial integrity and cell death. J Biol Chem. 2004 Jun 4;279(23):24813-25. DOI:10.1074/jbc.M402049200 |
22. Gokhale NA, Zaremba A, and Shears SB. Receptor-dependent compartmentalization of PPIP5K1, a kinase with a cryptic polyphosphoinositide binding domain. Biochem J. 2011 Mar 15;434(3):415-26. DOI:10.1042/BJ20101437 |
23. Lu M, Lin SC, Huang Y, Kang YJ, Rich R, Lo YC, Myszka D, Han J, and Wu H. XIAP induces NF-kappaB activation via the BIR1/TAB1 interaction and BIR1 dimerization. Mol Cell. 2007 Jun 8;26(5):689-702. DOI:10.1016/j.molcel.2007.05.006 |
24. Kharitidi D, Manteghi S, and Pause A. Pseudophosphatases: methods of analysis and physiological functions. Methods. 2014 Jan 15;65(2):207-18. DOI:10.1016/j.ymeth.2013.09.009 |