Difference between revisions of "Phosphatase Subfamily DSP1"

Revision as of 02:09, 6 March 2015

Phosphatase Classification: Superfamily CC1: Family DSP: Subfamily DSP1

summary....

Evolution

DSP1 subfamily is widely found across eukaryotes. It is present in animals, plants, amoeba, and some basal eukaryotes, but is absent from ecdysozoa (nematodes and arthropods), most fungi and monosiga (unpublished data, DUSP1, DUSP2, DUSP4, DUSP5).

Domain Structure

DSP1 has an inactive Rhodanese domain, followed by a CC1-fold phosphatase domain.

Functions

In general, DSP1 are inducible nuclear MAP Kinase phosphatases (MKPs), also known as the Group A DSPs. Human members are DUSP1, DUSP2, DUSP4 and DUSP5. Their substrate specificity, subcellular localization and etc have been summarized in Table 1 in review paper [1].

DUSP1 (MKP1/hVH1)

DUSP1 is the best characterized phosphatase within this subfamily. It prefers to dephosphorylates p38 and JNK over ERK. DUSP1 is involved in immune regulation and cancer. DUSP1 is an important negative-feedback regulator of macrophage function and the inflammatory response to TLR signalling, and plays key regulatory roles in both innate and adaptive immune responses via inactivation of p38 and JNK (reviewed in [1]). It is worthy pointing out that DUSP1 expression is strictly regulated in brain (see GTEx).

(PS: more reading is needed).

DUSP2 (PAC1)

DUSP2 is inactive when alone in vitro, and dephosphorylates extracellular signal-regulated kinase 2 (ERK2) but not p38alpha or c-Jun NH(2)-terminal kinase 2 (JNK2). ERK2 dephosphorylation by DUSP2 requires association of its rhodanese domain and ERK2 that results in catalytic activation of the phosphatase. p38alpha interacts with but does not activate DUSP2, whereas JNK2 does not bind to or cause catalytic activation by DUSP2 [2, 3].

It has been shown that individual mutation of the conserved Arg294 and Arg295 that likely comprise the phosphothreonine-binding pocket in DUSP2 to either alanine or lysine results in a nearly complete loss of its phosphatase activity even in the presence of ERK2 [3]. (PS: However, the conservation is not found within DSP1 subfamily. On the other hand, they are found in other subfamilies no matters they dephosphorylate ERK or not, which suggested the two arginine residues do not determine phosphatase activity or the specific phosphatase activity towards ERK.)

DUSP2 is expressed in various tissues (see GTEx). Its expression is regulated by p53 which binds to palindromic site in DUSP2 promoter [4]. Its expression is regulated, or more precisely speaking, inhibited by hypoxia inducible factor-1 (HIF-1) [5, 6].

References

1. Patterson KI, Brummer T, O'Brien PM, and Daly RJ. Dual-specificity phosphatases: critical regulators with diverse cellular targets. Biochem J. 2009 Mar 15;418(3):475-89. DOI:10.1042/bj20082234 | PubMed ID:19228121 | HubMed [Patterson09]
2. Farooq A, Plotnikova O, Chaturvedi G, Yan S, Zeng L, Zhang Q, and Zhou MM. Solution structure of the MAPK phosphatase PAC-1 catalytic domain. Insights into substrate-induced enzymatic activation of MKP. Structure. 2003 Feb;11(2):155-64. DOI:10.1016/s0969-2126(02)00943-7 | PubMed ID:12575935 | HubMed [Farooq03]
3. Zhang Q, Muller M, Chen CH, Zeng L, Farooq A, and Zhou MM. New insights into the catalytic activation of the MAPK phosphatase PAC-1 induced by its substrate MAPK ERK2 binding. J Mol Biol. 2005 Dec 9;354(4):777-88. DOI:10.1016/j.jmb.2005.10.006 | PubMed ID:16288922 | HubMed [Zhang05]
4. Yin Y, Liu YX, Jin YJ, Hall EJ, and Barrett JC. PAC1 phosphatase is a transcription target of p53 in signalling apoptosis and growth suppression. Nature. 2003 Apr 3;422(6931):527-31. DOI:10.1038/nature01519 | PubMed ID:12673251 | HubMed [Yin03]
5. Lin SC, Chien CW, Lee JC, Yeh YC, Hsu KF, Lai YY, Lin SC, and Tsai SJ. Suppression of dual-specificity phosphatase-2 by hypoxia increases chemoresistance and malignancy in human cancer cells. J Clin Invest. 2011 May;121(5):1905-16. DOI:10.1172/JCI44362 | PubMed ID:21490398 | HubMed [Lin11]
6. Wu MH, Lin SC, Hsiao KY, and Tsai SJ. Hypoxia-inhibited dual-specificity phosphatase-2 expression in endometriotic cells regulates cyclooxygenase-2 expression. J Pathol. 2011 Nov;225(3):390-400. DOI:10.1002/path.2963 | PubMed ID:21984126 | HubMed [Wu11]