Phosphatase Subfamily DSP3

The subfamily DSP3 consists of five genes in human, DUSP3, DUSP13, DUSP26 (chr 8, also called MKP8, DUSP24), DUSP27 (chr 1), DUPD1 (chr 10, it has an alias of DUSP27). It is found in eumetazoan but lost in nematodes.

Phosphatase Classification: Fold CC1: Superfamily CC1: Family DSP: Subfamily DSP3

summary

Function

DUSP3 (VHR, vaccinia H1-related)

DUSP3 (VHR, vaccinia H1-related) is constitutively expressed, localized to the nucleus. It is widely expressed in different tissues (see GTEx). It specifically dephosphorylates and inactivates ERK1 and ERK2 in vitro and in vivo. It does not dephosphorylate p38 or JNK [1]. Later study also suggested DUSP3 does not dephosphorylate p38, but probably dephosphorylate JNK in T cells [2]. By modulating MAP kinases ERKs and JNKs, DUSP3 is involved in cell-cycle progression as it modulates MAP kinase activation in a cell-cycle phase-dependent manner [3]. DUSP3 activity towards ERK2 is dependent on phosphorylation at Tyr138 by tyrosine kinase ZAP-70 of Syk family. The phosphorylation was required for DUSP3 to inhibit the Erk2-Elk-1 pathway [4].

DUSP3 selectively dephosphorylates IFN-alpha- and beta-activated, tyrosine-phosphorylated STAT5, leading to the subsequent inhibition of STAT5 function. DUSP3 activity towards STAT5 is also dependent on phosphorylation at Tyr138, but by tyrosine kinase Tyk2 of Jak family, which mediates the phosphorylation of STAT5. Besides phosphorylation at Tyr138 of DUSP3, Src homology 2 domain of STAT5 was required for the effective dephosphorylation of STAT5 [5] (note: SH2 domain of STAT5 binds to Tyr138 of DUSP3?).

DUSP3 dephosphorylates EGFR/ERBB1 and ERBB2. In particular, it probably dephosphorylates Tyr-992 [6]. DUSP3 dephosphorylated several activated growth factor receptors, as well as serine-phosphorylated casein, in vitro [7].

DUSP3 is regulated by dimerization. DUSP3 can dimerize inside cells, and its catalytic activity is reduced upon dimerization. Dimerization could occlude the active site, thereby blocking its accessibility to substrates. Transient self-association of DUSP3 may act as a means for the negative regulation of its catalytic activity [8].

DUSP3 is implicated in human cancer, but it has been alternatively described as having tumor suppressive and oncogenic properties. DUSP3 is upregulated in (pre) neoplastic lesions (squamous intraepithelial lesions; SILs) of the uterine cervix mainly in high grade SIL (H-SIL) compared to normal exocervix. In the invasive cancer, it is also highly expressed with nuclear localization in the majority of cells compared to normal tissue where it is always in the cytoplasm. DUSP3 is highly expressed in several cervix cancer cell lines such as HeLa, SiHa, CaSki, C33 and HT3 compared to primary keratinocytes [9]. DUSP3 inhibits apoptosis in prostate cancer cells and is overexpressed in prostate cancer. DUSP3 may therefore have a role in prostate cancer progression [10]. Expression of DUSP3 suppressed tumor formation in a mouse xenograft model. Its expression was significantly lower in non-small cell lung cancer tissues in comparison to that in normal lung tissues [6]. In addition, DUSP3 is a pro-angiogenic [11].

DUSP3 was one of the first phosphatases whose crystal structure was solved [12, 13].

References

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