Phosphatase Subfamily DSP12

Phosphatase Classification: Fold CC1: Superfamily CC1: Family DSP: Subfamily DSP12

DSP12 is a unikont phosphatase with roles in heat shock response and cell cycle.

Evolution

DSP12 is conserved throughout unikonts and usually a single copy in each genome, including human DUSP12 and yeast YVH1.

Domain

DSP12 has an N-terminal phosphatase domain and a C-terminal zinc binding domain. Rat DUSP12 has dual-specificity catalytic activity [1] and both human DUSP12 and Drosophila DMKP-4 have in vitro activity on the synthetic substrate pNPP [2, 3].

The zinc binding domain is dispensable for in vitro phosphatase activity but is essential for function in vivo. There is a phosphorylation site in Zinc binding domain, serine 335. The phosphorylation regulates subcellular targeting of DUSP12 and augments the DUSP12 G2/M phenotype [4]. The Zinc binding domain may act as a redox sensor to impede the active site cysteine from inactivating oxidation [5].

Functions

DSP12 has several cellular functions. It interacts with Hsp70 and prevents heat-shock-induced cell death. This function is dependent on its phosphatase catalytic activity, since catalytically inactive DUSP12 is unable to interact with Hsp70 [6]. Human DUSP12 modulates cell cycle progression, which is mediated by its C-terminal zinc-binding domain. Similarly, yeast YVH1, regulates cell growth and morphogenesis [7], and these functions map to the C-terminal Zinc binding domain [2, 7, 8]. Yeast YVH1 participates in 60S ribosome maturation in a phosphatase-independent manner [9, 10].

Human DUSP12 is downregulated during brown fat development, and overexpression blocks adipogenesis [11], while C. elegans C24F3.2 was found in an RNAi screen for genes whose knockdown increased fat content [12]. Rat DUSP12 (GKAP) dephosphyorylates glucokinase [1], and human DUSP12 is weakly genetically associated with type 2 diabetes [13].

In addition, human DUSP12 has been shown to be a putative oncogene [8]

Yeast YVH1 is a ribosome maturation factor, and interacts with another maturation factor, pescadillo, in both yeast [14] and the malaria parasite, Plasmodium [15]. YVH1 is also required for pre-autophagosomal structure formation after TORC1 inactivation [16].

Drosophila DMKP-4 physically interacts with Jnk via its phosphatase domain, and negatively regulates Jnk activation by peptidoglycan. When transfected to human cells, it also negatively regulates MAPK induction by heat or oxidative stress [3].

References

1. Muñoz-Alonso MJ, Guillemain G, Kassis N, Girard J, Burnol AF, and Leturque A. A novel cytosolic dual specificity phosphatase, interacting with glucokinase, increases glucose phosphorylation rate. J Biol Chem. 2000 Oct 20;275(42):32406-12. DOI:10.1074/jbc.M000841200 |
2. Muda M, Manning ER, Orth K, and Dixon JE. Identification of the human YVH1 protein-tyrosine phosphatase orthologue reveals a novel zinc binding domain essential for in vivo function. J Biol Chem. 1999 Aug 20;274(34):23991-5. DOI:10.1074/jbc.274.34.23991 |
3. Sun L, Yu MC, Kong L, Zhuang ZH, Hu JH, and Ge BX. Molecular identification and functional characterization of a Drosophila dual-specificity phosphatase DMKP-4 which is involved in PGN-induced activation of the JNK pathway. Cell Signal. 2008 Jul;20(7):1329-37. DOI:10.1016/j.cellsig.2008.03.003 |
4. Kozarova A, Hudson JW, and Vacratsis PO. The dual-specificity phosphatase hYVH1 (DUSP12) is a novel modulator of cellular DNA content. Cell Cycle. 2011 May 15;10(10):1669-78. DOI:10.4161/cc.10.10.15641 |
5. Bonham CA and Vacratsis PO. Redox regulation of the human dual specificity phosphatase YVH1 through disulfide bond formation. J Biol Chem. 2009 Aug 21;284(34):22853-64. DOI:10.1074/jbc.M109.038612 |
6. Sharda PR, Bonham CA, Mucaki EJ, Butt Z, and Vacratsis PO. The dual-specificity phosphatase hYVH1 interacts with Hsp70 and prevents heat-shock-induced cell death. Biochem J. 2009 Mar 1;418(2):391-401. DOI:10.1042/BJ20081484 |
7. Beeser AE and Cooper TG. The dual-specificity protein phosphatase Yvh1p regulates sporulation, growth, and glycogen accumulation independently of catalytic activity in Saccharomyces cerevisiae via the cyclic AMP-dependent protein kinase cascade. J Bacteriol. 2000 Jun;182(12):3517-28. DOI:10.1128/JB.182.12.3517-3528.2000 |
8. Cain EL, Braun SE, and Beeser A. Characterization of a human cell line stably over-expressing the candidate oncogene, dual specificity phosphatase 12. PLoS One. 2011 Apr 20;6(4):e18677. DOI:10.1371/journal.pone.0018677 |
9. Kemmler S, Occhipinti L, Veisu M, and Panse VG. Yvh1 is required for a late maturation step in the 60S biogenesis pathway. J Cell Biol. 2009 Sep 21;186(6):863-80. DOI:10.1083/jcb.200904111 |
10. Lo KY, Li Z, Wang F, Marcotte EM, and Johnson AW. Ribosome stalk assembly requires the dual-specificity phosphatase Yvh1 for the exchange of Mrt4 with P0. J Cell Biol. 2009 Sep 21;186(6):849-62. DOI:10.1083/jcb.200904110 |
11. Choi HR, Kim WK, Park A, Jung H, Han BS, Lee SC, and Bae KH. Protein tyrosine phosphatase profiling studies during brown adipogenic differentiation of mouse primary brown preadipocytes. BMB Rep. 2013 Nov;46(11):539-43. DOI:10.5483/bmbrep.2013.46.11.058 |
12. Ashrafi K, Chang FY, Watts JL, Fraser AG, Kamath RS, Ahringer J, and Ruvkun G. Genome-wide RNAi analysis of Caenorhabditis elegans fat regulatory genes. Nature. 2003 Jan 16;421(6920):268-72. DOI:10.1038/nature01279 |
13. Das SK, Chu WS, Hale TC, Wang X, Craig RL, Wang H, Shuldiner AR, Froguel P, Deloukas P, McCarthy MI, Zeggini E, Hasstedt SJ, and Elbein SC. Polymorphisms in the glucokinase-associated, dual-specificity phosphatase 12 (DUSP12) gene under chromosome 1q21 linkage peak are associated with type 2 diabetes. Diabetes. 2006 Sep;55(9):2631-9. DOI:10.2337/db05-1369 |
14. Sakumoto N, Yamashita H, Mukai Y, Kaneko Y, and Harashima S. Dual-specificity protein phosphatase Yvh1p, which is required for vegetative growth and sporulation, interacts with yeast pescadillo homolog in Saccharomyces cerevisiae. Biochem Biophys Res Commun. 2001 Nov 30;289(2):608-15. DOI:10.1006/bbrc.2001.6021 |
15. Kumar R, Musiyenko A, Cioffi E, Oldenburg A, Adams B, Bitko V, Krishna SS, and Barik S. A zinc-binding dual-specificity YVH1 phosphatase in the malaria parasite, Plasmodium falciparum, and its interaction with the nuclear protein, pescadillo. Mol Biochem Parasitol. 2004 Feb;133(2):297-310. DOI:10.1016/j.molbiopara.2003.11.005 |
16. Yeasmin AM, Waliullah TM, Kondo A, and Ushimaru T. Yvh1 protein phosphatase is required for pre-autophagosomal structure formation after TORC1 inactivation. Biosci Biotechnol Biochem. 2015;79(12):2022-5. DOI:10.1080/09168451.2015.1060846 |