Phosphatase Subfamily DSP15
Phosphatase Classification: Fold CC1: Superfamily CC1: Family DSP: Subfamily DSP15
DSP15 subfamily emerged in metazoan and duplicated in vertebrates. It is characterized by a N-termnal myristoylation site which targets it to plasma membrane. Little is known about its molecular function.
Evolution
DSP15 subfamily is found across metazoa, and likely homologs exist in even in several protist lineages. It usually has a single copy in invertebrate genomes and two copies in vertebrate genomes (DUSP15 and DUSP22 in human).
Domain
DSP15 has a N-terminal myristoylation site and a phosphatase domain. The two members in human genome DUSP15 and DUSP22 are myristoylated at Gly-2. The myristoylation site targets the protein to plasma memrane. Mutation of the myristoylation site Gly-2 of DUSP15 abrogated membrane location [1].
Functions
DUSP15 (VHY)
Human DUSP15 is specifically expressed in testis [1] (also see GTEx portal). However, DUSP15 has also been reported to be transcriptionally regulated during oligodendrocyte differentiation and in multiple sclerosis lesions, in which DUSP15 dephosphorylates PDGFR-beta and SNX6 [2].
DUSP22 (VHX/JKAP/JSP1/LMW-DSP2)
Different from DUSP15, human DUSP22 is expressed in various tissues (see GTEx portal).
DUSP22 localizes in the actin filament-enriched region. Expression of DUSP22 reduced cell migration, whereas a DUSP22 mutant lacking catalytic activity promoted cell motility. DUSP22 dephosphorylates tyrosines 397, 576, and 577 of focal adhesion kinase (FAK) [3]. DUSP22 also dephosphorylates Ser-118 of estrogen receptor-alpha (ER-alpha) therefore regulating ER-alpha-mediated signaling [4].
Unexpectedly, DUSP22 is a positive rather than negative regulatory of JNK pathway. It did not interact with or dephosphorylate JNK in vitro, suggesting that DUSP22 exerts its effect on JNK in an indirect manner [5, 6].
DUSP22 may have other functions. It inhibits (may or may not by directly dephospho rylation) PKA activity and thereby determines TAU phosphorylation status and CREB signaling [7]. It also acts as a negative regulator (may or may not by directly dephospho rylation) of the IL-6/LIF/STAT3-mediated signaling pathway [8].
DUSP22 may represent a tumor-suppressor gene, since its loss may contribute to the pathogenesis of cutaneous anaplastic large-cell lymphomas (ALCLs) according to clinic cases [9].
The C. elegans and Drosophila homologs of DSP15 have not been experimentally characterized.
References
- Alonso A, Narisawa S, Bogetz J, Tautz L, Hadzic R, Huynh H, Williams S, Gjörloff-Wingren A, Bremer MC, Holsinger LJ, Millan JL, and Mustelin T. VHY, a novel myristoylated testis-restricted dual specificity protein phosphatase related to VHX. J Biol Chem. 2004 Jul 30;279(31):32586-91. DOI:10.1074/jbc.M403442200 |
- Schmidt F, van den Eijnden M, Pescini Gobert R, Saborio GP, Carboni S, Alliod C, Pouly S, Staugaitis SM, Dutta R, Trapp B, and Hooft van Huijsduijnen R. Identification of VHY/Dusp15 as a regulator of oligodendrocyte differentiation through a systematic genomics approach. PLoS One. 2012;7(7):e40457. DOI:10.1371/journal.pone.0040457 |
- Li JP, Fu YN, Chen YR, and Tan TH. JNK pathway-associated phosphatase dephosphorylates focal adhesion kinase and suppresses cell migration. J Biol Chem. 2010 Feb 19;285(8):5472-8. DOI:10.1074/jbc.M109.060186 |
- Sekine Y, Ikeda O, Hayakawa Y, Tsuji S, Imoto S, Aoki N, Sugiyama K, and Matsuda T. DUSP22/LMW-DSP2 regulates estrogen receptor-alpha-mediated signaling through dephosphorylation of Ser-118. Oncogene. 2007 Sep 6;26(41):6038-49. DOI:10.1038/sj.onc.1210426 |
- Shen Y, Luche R, Wei B, Gordon ML, Diltz CD, and Tonks NK. Activation of the Jnk signaling pathway by a dual-specificity phosphatase, JSP-1. Proc Natl Acad Sci U S A. 2001 Nov 20;98(24):13613-8. DOI:10.1073/pnas.231499098 |
- Chen AJ, Zhou G, Juan T, Colicos SM, Cannon JP, Cabriera-Hansen M, Meyer CF, Jurecic R, Copeland NG, Gilbert DJ, Jenkins NA, Fletcher F, Tan TH, and Belmont JW. The dual specificity JKAP specifically activates the c-Jun N-terminal kinase pathway. J Biol Chem. 2002 Sep 27;277(39):36592-601. DOI:10.1074/jbc.M200453200 |
- Sanchez-Mut JV, Aso E, Heyn H, Matsuda T, Bock C, Ferrer I, and Esteller M. Promoter hypermethylation of the phosphatase DUSP22 mediates PKA-dependent TAU phosphorylation and CREB activation in Alzheimer's disease. Hippocampus. 2014 Apr;24(4):363-8. DOI:10.1002/hipo.22245 |
- Sekine Y, Tsuji S, Ikeda O, Sato N, Aoki N, Aoyama K, Sugiyama K, and Matsuda T. Regulation of STAT3-mediated signaling by LMW-DSP2. Oncogene. 2006 Sep 21;25(42):5801-6. DOI:10.1038/sj.onc.1209578 |
- Csikesz CR, Knudson RA, Greipp PT, Feldman AL, and Kadin M. Primary cutaneous CD30-positive T-cell lymphoproliferative disorders with biallelic rearrangements of DUSP22. J Invest Dermatol. 2013 Jun;133(6):1680-2. DOI:10.1038/jid.2013.22 |
