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

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 [3]. However, another study found SRC, E-cadherin, and beta-catenin are direct substrates of PTPN23 [4]. But, yet another study showed that PTPN23 did not modulate the levels of Src phosphorylation both in vitro and in vivo [5].

DSPs

STYX subfamily

The STYX subfamily has a single member in human, STYX. It binds to phosphorylated tyrosine to module signaling [6]. STYX localizes to the nucleus, competes with DUSP4 for binding to ERK, and acts as a nuclear anchor that regulates ERK nuclear export [7].

STYXL1 subfamily

The STYXL1 subfamily has a single member in human, STYXL1 (MK-STYX). STYXL1 binds to phosphatase PTPMT1 and modulates its activity [8, 9]. However, it is unclear whether the interaction between STYXL1 and PTPMT1 is mediated by the inactive phosphatase domain of STYXL1.

One of the five of DSP3 subfamily: DUSP27

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

PTEN-like phosphatases

Auxilin subfamily

There are two members of auxilin subfamily in human, GAK and DNAJC6. Both GAK and DNAJC6 phosphatase domains have been shown to bind to phospholipids [10, 11]. The phosphatase domains of both are predicted to be inactive due to arginine in catalytic motif Cx5R is replaced by alanine.

Tensin subfamily

The tensin subfamily has four members, TNS1-4. 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 [12].

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 [13]. 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 [14], MTMR7 [15], MTMR8 [16]. The interactions increase the enzymatic activity of these phosphatases. The interaction between MTMR9 and members of MTMR6 subfamily is also observed in C. elegans [17].

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 [18].

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. 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 |
4. 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 |
5. 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 |
6. 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 |
7. 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 |
8. 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 |
9. 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 |
10. Lee DW, Wu X, Eisenberg E, and Greene LE. Recruitment dynamics of GAK and auxilin to clathrin-coated pits during endocytosis. J Cell Sci. 2006 Sep 1;119(Pt 17):3502-12. DOI:10.1242/jcs.03092 |
11. Kalli AC, Morgan G, and Sansom MS. Interactions of the auxilin-1 PTEN-like domain with model membranes result in nanoclustering of phosphatidyl inositol phosphates. Biophys J. 2013 Jul 2;105(1):137-45. DOI:10.1016/j.bpj.2013.05.012 |
13. 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 |
14. 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 |
15. 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 |
16. 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 |
17. 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 |
18. 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 |
19. 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 |
20. 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 |
21. 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 |