Phosphatase Subfamily DSP10

Phosphatase Classification: Fold CC1: Superfamily CC1: Family DSP: Subfamily DSP10 (MKP5)

DSP10 selectively dephosphorylates p38 and JNK. It is conserved across holozoan but lost in nematodes.

Evolution

DSP10 (MKP5) subfamily is found in most [holozoa] except nematodes. DSP10 is usually one copy per genome, e.g. DUSP10 (MKP5) in human.

Domain

DSP10 has two domains: rhodanese domain and phosphatase domain. Rhodanese domain can bind to kinases [1].

Function

DUSP10 is phosphatase specific for p38 and SAPK/JNK. It binds to p38 and SAPK/JNK, but not to MAPK/ERK, and inactivates p38 and SAPK/JNK, but not MAPK/ERK. p38 is a preferred substrate. It is present evenly in both the cytoplasm and the nucleus. DUSP10 is widely expressed in various tissues and organs, and its expression in cultured cells is elevated by stress stimuli [2, 3, 4].

On the other hand, it has been reported that DUSP10 interacts with ERK, retains it in the cytoplasm, suppresses its activation and downregulates ERK-dependent transcription [5].

Human DUSP10 is frequently upregulated in colorectal cancer (CRC). Certain mutations in DUSP10 correlate with the incidence of CRC. DUSP10/MKP5 also negatively regulates intestinal epithelial cell growth [6].

DUSP10/MKP5 is involved in immune system. It interacts with and dephosphorylates IRF3. Our study reveals a critical function of a DUSP in negative regulation of IRF3 activity and demonstrates a mechanism by which influenza and other RNA viruses inhibit type I interferon response in the host through MKP5.

DUSP10/MKP5 is implicated in immune system. It functions in the type I interferon system responding to viral infection. It interacts with, dephosphorylates and inactivates Interferon regulatory factor 3 (IRF3), an interferon regulatory factor which plays an important role in the type I interferon system. Increased type I interferon responses were observed in DUSP10/MKP5-deficient cells and animals upon various RNA virus infection, including H1N1 influenza virus, vesicular stomatitis virus and sendai virus [7]. DUSP10/MKP5 also regulates adipose tissue inflammation and insulin resistance [8].

References

1. Tao X and Tong L. Crystal structure of the MAP kinase binding domain and the catalytic domain of human MKP5. Protein Sci. 2007 May;16(5):880-6. DOI:10.1110/ps.062712807 |
2. Tanoue T, Moriguchi T, and Nishida E. Molecular cloning and characterization of a novel dual specificity phosphatase, MKP-5. J Biol Chem. 1999 Jul 9;274(28):19949-56. DOI:10.1074/jbc.274.28.19949 |
3. Theodosiou A, Smith A, Gillieron C, Arkinstall S, and Ashworth A. MKP5, a new member of the MAP kinase phosphatase family, which selectively dephosphorylates stress-activated kinases. Oncogene. 1999 Nov 25;18(50):6981-8. DOI:10.1038/sj.onc.1203185 |
4. Jeong DG, Yoon TS, Kim JH, Shim MY, Jung SK, Son JH, Ryu SE, and Kim SJ. Crystal structure of the catalytic domain of human MAP kinase phosphatase 5: structural insight into constitutively active phosphatase. J Mol Biol. 2006 Jul 28;360(5):946-55. DOI:10.1016/j.jmb.2006.05.059 |
5. Nomura M, Shiiba K, Katagiri C, Kasugai I, Masuda K, Sato I, Sato M, Kakugawa Y, Nomura E, Hayashi K, Nakamura Y, Nagata T, Otsuka T, Katakura R, Yamashita Y, Sato M, Tanuma N, and Shima H. Novel function of MKP-5/DUSP10, a phosphatase of stress-activated kinases, on ERK-dependent gene expression, and upregulation of its gene expression in colon carcinomas. Oncol Rep. 2012 Sep;28(3):931-6. DOI:10.3892/or.2012.1862 |
6. Png CW, Weerasooriya M, Guo J, James SJ, Poh HM, Osato M, Flavell RA, Dong C, Yang H, and Zhang Y. DUSP10 regulates intestinal epithelial cell growth and colorectal tumorigenesis. Oncogene. 2016 Jan 14;35(2):206-17. DOI:10.1038/onc.2015.74 |
7. James SJ, Jiao H, Teh HY, Takahashi H, Png CW, Phoon MC, Suzuki Y, Sawasaki T, Xiao H, Chow VTK, Yamamoto N, Reynolds JM, Flavell RA, Dong C, and Zhang Y. MAPK Phosphatase 5 Expression Induced by Influenza and Other RNA Virus Infection Negatively Regulates IRF3 Activation and Type I Interferon Response. Cell Rep. 2015 Mar 17;10(10):1722-1734. DOI:10.1016/j.celrep.2015.02.030 |
8. Zhang Y, Nguyen T, Tang P, Kennedy NJ, Jiao H, Zhang M, Reynolds JM, Jaeschke A, Martin-Orozco N, Chung Y, He WM, Wang C, Jia W, Ge B, Davis RJ, Flavell RA, and Dong C. Regulation of Adipose Tissue Inflammation and Insulin Resistance by MAPK Phosphatase 5. J Biol Chem. 2015 Jun 12;290(24):14875-83. DOI:10.1074/jbc.M115.660969 |