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 Drosophila DMKP-4 has activity on the synthetic substrate pNPP [2].

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 [3]. The Zinc binding domain may act as a redox sensor to impede the active site cysteine from inactivating oxidation [4].

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 [5]. Human DUSP12 modulates cell cycle progression, which is mediated by its C-terminal zinc-binding domain. Similarly, yeast YVH1, regulates cell growth and morphogenesis [6], and these functions map to the C-terminal Zinc binding domain [6, 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 [2].

References

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