Pseudophosphatases (obsolete)

Human pseudophosphatases

PTPs

Second phosphatase domain (D2) in 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 [[Phosphatase_Subfamily_Auxilin|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.

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 |
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 |
12. 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 |
13. 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 |