Phosphatase Subfamily DSP1

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amoeba, and some basal eukaryotes, but is absent from ecdysozoa (nematodes and arthropods), most fungi and monosiga (unpublished data, DUSP1, DUSP2, DUSP4, DUSP5).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]).

(Note: It is worthy pointing out that DUSP1 expression is strictly regulated at low level in brain (see GTEx)).

(PS: more reading is needed).

DUSP2 (PAC1)

As a MKP, DUSP2 has preference toward ERK=p38 > JNK. 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].

DUSP4 (MKP2/TYP)

DUSP4 prefers ERK and JNK over p38 [7, 8, 9]. Further studies has shown the catalytic activity of DUSP4 was enhanced dramatically by ERK and JNK but was affected only minimally by p38. By contrast, p38 and ERK bound DUSP4 with comparably strong affinities, whereas JNK and DUSP2 interacted very weakly [10].

DUSP4's substrate in vivo is controversial. As reported in [11], DUSP4 selectively dephosphorylates JNK, or different DUSP4 isoforms have different substrate specificity as shown in [12].

DUSP4 is involved in cancer. For instance, it is a common epigenetically silenced gene in glioma [13].

DUSP4 dephosphorylates ERK, and on the other hand, ERK can phosphorylates DUSP4 (on Ser386 and Ser391 at its C-terminus) which leads to stabilization of DUSP4 protein, as blockage of ERK activation results in enhanced proteasomal degradation of DUSP4 protein [14]. (Note: Ser386 and Ser391 are also found in DUSP1, which preferential dephosphorylates p38 and JNK but NOT ERK. DUSP2 has Ser386 but position 391 is Ala; DUSP5 does not align at C-terminal region.)

(Note: look into the conservation of basic motif mentioned in [10, 15], which is supposed to mediate the interaction between DUSP4 (or even other DSP1 or MKPs) with ERK (or MAPKs in general).

References

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