Phosphatase Subfamily DSP12
Phosphatase Classification: Fold CC1: Superfamily CC1: Family DSP: Subfamily DSP12
DSP12 is a subfamily conserved throughout unikonts, but its function is poorly understood.
Evolution
DSP12 is conserved throughout unikonts and usually a single copy in each genome.
Domain
DSP12 has two domains: phosphatase domain and C-terminal Zinc binding domain. 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 hYVH1 and augments the DUSP12 G2/M phenotype [1]. The Zinc binding domain may act as a redox sensor to impede the active site cysteine from inactivating oxidation [2].
Function
The function of human DUSP12 is poorly understood, particularly in the aspect of its substrate. 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 [3]. Human DUSP12 modulates cell cycle progression, which is mediated by its C-terminal zinc-binding domain. Similarly, in yeast, YVH1 which is human DUSP12 orthologs, regulates cell growth and morphogenesis [4], and these functions do not map to the phosphatase domain, but to the C-terminal Zinc binding domain [4, 5, 6]. Yeast YVH1 participates in 60S ribosome maturation in a phosphatase-independent manner [7, 8].
In addition, human DUSP12 has been shown to be a putative oncogene [6] and contribute to type 2 diabetes susceptibility in Caucasians [9].
References
- 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 |
- 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 |
- 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 |
- 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 |
- 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 |
- 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 |
- 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 |
- 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 |
- 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 |
