DUSP6 (dual specificity phosphatase 6)

	The diagram depicts the structure of the DUSP6 gene (bottom) roughly aligned with its corresponding functional protein domains (middle and top). DUSP6 comprises a C-terminal catalytic domain and an N-terminal non-catalytic domain (middle). The 3 exons of DUSP6 (rectangles) are connected with lines representing introns.
Description	The human DUSP6 gene is located on chromosome 12q21.33 and consists of 3 exons. The full-length coding sequence of DUSP6 contains 1146 nucleotides. The functional phosphatase domain of DUSP6 is encoded by half of exon 2 and almost the entire sequence of exon 3.
Transcription	DUSP6 gene transcription can start from either the first ATG or alternatively the second ATG (Met14), and therefore two protein products are generated which usually demonstrate a double-band appearance in regular immunoblotting assays (Dowd et al., 1998; Zhang et al., 2010).

	The diagram depicts the structural features of DUSP6. The highly conserved C-terminal domain of DUSP6 contains the canonical tyrosine/threonine-specific phosphatase signature sequence HCXXXXXR at the active site, where the cysteine acts as the essential enzymatic nucleophile and arginine interacts directly with the phosphate group on phosphotyrosine or phosphothreonine (Farooq et al., 2001). The amino-terminal domain of DUSP6 contains a specific arginine-rich kinase interaction motif (KIM) (Tárrega et al., 2005) and a leucine-rich nuclear export signal (NES) necessary and sufficient for nuclear export of the phosphatase (Karlsson et al., 2004).
Description	The full-length DUSP6 protein contains 381 amino acids and has a molecular weight of 44 kDa. DUSPs are characterized by a common structure comprising a C-terminal phosphatase domain that are defined by the active-site signature motif HCXXXXXR. The structure of DUSP proteins confers phosphatase activity for both phosphoserine/threonine and phosphotyrosine residues. An enzyme-dead DUSP6 expression construct can be generated via a 293 Cysteine to Serine/Glycine (C293S/G) point mutation (Wishart et al., 1995; Zhang et al., 2010; Zhou et al., 2006).
Expression	DUSP6 is expressed usually at low level in resting, nonstimulated cells in a variety of tissues and is induced as an early response gene after activation of the ERK-MAPK signaling pathway.
Localisation	DUSP6 is a cytoplasmic dual specificity protein phosphatase.
Function	Mitogen-activated protein kinases (MAPK) constitute a highly conserved family of kinases that relay information from extracellular signals to downstream effectors that control diverse cellular processes such as proliferation, differentiation, migration, survival and apoptosis (Wada and Penninger, 2004). A balance between the activities of upstream activators and various negative regulatory mechanisms of MAPK signaling, which terminate its activation, determines its biological outcomes. DUSP6 is a prototypical member of a subfamily of cytoplasmic MKPs, which includes DUSP7 and DUSP9 as well. These enzymes all display a high degree of substrate selectivity for ERK1 and ERK2 (Keyse, 2008). DUSP6 has been shown to act as a central feedback regulator attenuating ERK levels in developmental programs (Echevarria et al., 2005; Li et al., 2007). The cytoplasmic localization of DUSP6 is mediated by a chromosome region maintenance-1-dependent nuclear export pathway. DUSP6 appears to play a role in determining the subcellular localization of ERK by serving as a cytoplasmic anchor for ERK, thereby mediating a spatio-temporal mechanism of ERK signaling regulation. Cytoplasmic retention of ERK requires both a functional kinase interaction motif and nuclear export site. Defects of these feedback regulation steps are thought to contribute to ERK-MAPK related oncogenesis. An in vivo study has identified DUSP6 as a negative feedback regulator of fibroblast growth factor-stimulated ERK signaling during murine development (Li et al., 2007). Several in vitro studies have demonstrated that DUSP6 acts as a negative regulator of fibroblast growth factor receptor signaling and endothelial cell platelet-derived growth factor receptor signaling via termination of ERK activation (Ekerot et al., 2008; Jurek et al., 2009).
Homology	DUSP6 belongs to a subfamily of ten more closely related dual-specificity MAPK phosphatases (MKPs) within the larger cysteine-dependent dual specificity phosphatase (DUSP) family (Keyse, 2008). While DUSP1 (MKP-1), DUSP4 (MKP-2), and DUSP9 (MKP4) dephosphorylate both ERKs, p38 and JNK, the phosphatases DUSP5 (Hvh-3), DUSP6 (MKP-3), and DUSP7 (MKP-X) exclusively target ERK1/2 MAPKs (Keyse, 2008). The N-terminal domain of all DUSPs has two regions of homology with the Cdc25 cell cycle regulatory phosphatase. The more conserved catalytic domain within DUSPs contains an active site sequence related to the prototypic VH-1 phosphatase encoded by the vaccinia virus. Specificity of MKPs toward MAPKs relies on the KIM domain. Although each MKP targets different subsets of MAPKs, there is an overlap between their specificities (Bermudez et al., 2010).

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