Phosphatase Subfamily DSP6

Phosphatase Classification: Fold CC1: Superfamily CC1: Family DSP: Subfamily DSP6

Domain

DSP6 subfamily has two domains: rhodanese domain and phosphatase domain.

Rhodanese domain inhibit phosphatase domain activity in DUSP6 [1]. stabilizes the inactive conformation of the catalytic site and implies that the N-terminal domain functions as an allosteric inhibitor of phosphatase activity.

Rhodanese domain mediates interaction with MAP kinases (often ERK). Rhodanese domain of DSP6 also has two conserved Leu-rich nuclear export signals [2] (particular Figure 5 and Figure 11). Binding to MAP kinases induces conformation change in phosphatase domain, which can increase the phosphatase activity [3].

Function

DUSP6 (MKP3/PYST1)

DUSP6 preferentially dephosphorylates ERK [4, 5, 6], which resulted from that DUSP6 binds to ERK but not p38 or JNK. The interaction is mediated by rhodanese domain (or kinase interaction motif embedded in rhodanese domain?) [7]. Later study has shown DUSP6 is ERK1/2-specific, as it does not inactive ERK5 [8].

As a negative regulator of ERK, DUSP6 is proposed to be tumor suppressor. DUSP6 expression was down-regulated through hypermethylation at enhancer in some pancreatic cell lines and pancreatic cancer tissues [9, 10]. But, DUSP6 was up-regulated in endometrial adenocarcinomas [11], thyroid carcinoma [12, 13], and glioblastomas [14]. Meanwhile, DUSP6 upregulation induced by angiotensin II mediates endothelial cell apoptosis [15]. (note: DUSP6 upregulation in cancer may be the response to suppress carcinogenesis?)

Like DUSP2, DUSP4 and DUSP4 of DSP1 subfamily, DUSP6 is phosphorylated by ERK [16]. However, the phosphorylation sites are different. DUSP6 is phosphorylated at serines 159 and 197 [16], which are found in DUSP6 and DUSP7, but not DUSP9 or other DSPs.

Nitric oxide down-regulates MKP-3 mRNA levels [17].

DUSP7 (MKPX/PYST2)

DUSP7 is constitutively expressed in a wide variety of human cell lines. DUSP7 is predominantly cytosolic when expressed in COS-1 cells. In common with other members of DSP6 subfamily, DUSP7 shows substrate selectivity ERK > p38 = JNK. DUSP7 binds ERK in vivo. Both ERK and JNK activate DUSP7 phosphatase activity in vitro [18].

DUSP7 has at least two isoforms. The longer isoform is constitutively highly expressed in myeloid leukemia and other malignant cells [19, 20, 21].

DUSP9 (MKP4)

DUSP6 blocks activation of MAP kinases with the selectivity ERK > p38 = JNK. Same as other members in the subfamily, it locates in cytosol [22, 23]. DUSP9 is unique among these cytoplasmic MKPs in containing a conserved PKA consensus phosphorylation site (55)RRXSer-58 immediately adjacent to the kinase interaction motif. DUSP9 is phosphorylated on Ser-58 by PKA in vitro, and phosphorylation abrogates the binding of DUSP9 to both ERK2 and p38alpha MAP kinases [24].

Decreased expression of DUSP-9 is associated with poor prognosis in clear cell renal cell carcinomas [25].

References

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