DUSP6 explained

Dual specificity phosphatase 6 (DUSP6) is an enzyme that in humans is encoded by the DUSP6 gene.^{[1] [2] [3]}

Function

The protein encoded by this gene is a member of the dual specificity protein phosphatase subfamily. These phosphatases inactivate their target kinases by dephosphorylating both the phosphoserine/threonine and phosphotyrosine residues. They negatively regulate members of the mitogen-activated protein (MAP) kinase superfamily (MAPK/ERK, SAPK/JNK, p38), which are associated with cellular proliferation and differentiation. Different members of the family of dual specificity phosphatases show distinct substrate specificities for various MAP kinases, different tissue distribution and subcellular localization, and different modes of inducibility of their expression by extracellular stimuli. This gene product inactivates ERK2, is expressed in a variety of tissues with the highest levels in heart and pancreas and, unlike most other members of this family, is localized in the cytoplasm. Two transcript variants encoding different isoforms have been found for this gene. Upregulation of MKP-3 has been shown to alleviate chronic postoperative pain.^{[4] [5]}

Interactions

DUSP6 has been shown to interact with MAPK3.^[6]

Further reading

• Maruyama K, Sugano S . Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides . Gene . 138 . 1–2 . 171–4 . January 1994 . 8125298 . 10.1016/0378-1119(94)90802-8 .
• Groom LA, Sneddon AA, Alessi DR, Dowd S, Keyse SM . Differential regulation of the MAP, SAP and RK/p38 kinases by Pyst1, a novel cytosolic dual-specificity phosphatase . The EMBO Journal . 15 . 14 . 3621–32 . July 1996 . 8670865 . 451978 . 10.1002/j.1460-2075.1996.tb00731.x.
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S . Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library . Gene . 200 . 1–2 . 149–56 . October 1997 . 9373149 . 10.1016/S0378-1119(97)00411-3 .
• Furukawa T, Yatsuoka T, Youssef EM, Abe T, Yokoyama T, Fukushige S, Soeda E, Hoshi M, Hayashi Y, Sunamura M, Kobari M, Horii A . Genomic analysis of DUSP6, a dual specificity MAP kinase phosphatase, in pancreatic cancer . Cytogenetics and Cell Genetics . 82 . 3–4 . 156–9 . 1999 . 9858808 . 10.1159/000015091 . 46883904 .
• Stewart AE, Dowd S, Keyse SM, McDonald NQ . Crystal structure of the MAPK phosphatase Pyst1 catalytic domain and implications for regulated activation . Nature Structural Biology . 6 . 2 . 174–81 . February 1999 . 10048930 . 10.1038/5861 . 11373236 .
• Rössig L, Hermann C, Haendeler J, Assmus B, Zeiher AM, Dimmeler S . Angiotensin II-induced upregulation of MAP kinase phosphatase-3 mRNA levels mediates endothelial cell apoptosis . Basic Research in Cardiology . 97 . 1 . 1–8 . January 2002 . 11998972 . 10.1007/s395-002-8381-2 . 27714293 .
• Furukawa T, Sunamura M, Motoi F, Matsuno S, Horii A . Potential tumor suppressive pathway involving DUSP6/MKP-3 in pancreatic cancer . The American Journal of Pathology . 162 . 6 . 1807–15 . June 2003 . 12759238 . 1868131 . 10.1016/S0002-9440(10)64315-5 .
• Kim HS, Song MC, Kwak IH, Park TJ, Lim IK . Constitutive induction of p-Erk1/2 accompanied by reduced activities of protein phosphatases 1 and 2A and MKP3 due to reactive oxygen species during cellular senescence . The Journal of Biological Chemistry . 278 . 39 . 37497–510 . September 2003 . 12840032 . 10.1074/jbc.M211739200 . free .
• Kim Y, Rice AE, Denu JM . Intramolecular dephosphorylation of ERK by MKP3 . Biochemistry . 42 . 51 . 15197–207 . December 2003 . 14690430 . 10.1021/bi035346b .
• Karlsson M, Mathers J, Dickinson RJ, Mandl M, Keyse SM . Both nuclear-cytoplasmic shuttling of the dual specificity phosphatase MKP-3 and its ability to anchor MAP kinase in the cytoplasm are mediated by a conserved nuclear export signal . The Journal of Biological Chemistry . 279 . 40 . 41882–91 . October 2004 . 15269220 . 10.1074/jbc.M406720200 . free .
• Marchetti S, Gimond C, Chambard JC, Touboul T, Roux D, Pouysségur J, Pagès G . Extracellular signal-regulated kinases phosphorylate mitogen-activated protein kinase phosphatase 3/DUSP6 at serines 159 and 197, two sites critical for its proteasomal degradation . Molecular and Cellular Biology . 25 . 2 . 854–64 . January 2005 . 15632084 . 543408 . 10.1128/MCB.25.2.854-864.2005 .
• Kamata H, Honda S, Maeda S, Chang L, Hirata H, Karin M . Reactive oxygen species promote TNFalpha-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases . Cell . 120 . 5 . 649–61 . March 2005 . 15766528 . 10.1016/j.cell.2004.12.041 . 15009756 . free .
• Xu S, Furukawa T, Kanai N, Sunamura M, Horii A . Abrogation of DUSP6 by hypermethylation in human pancreatic cancer . Journal of Human Genetics . 50 . 4 . 159–67 . 2005 . 15824892 . 10.1007/s10038-005-0235-y . free .
• Furukawa T, Fujisaki R, Yoshida Y, Kanai N, Sunamura M, Abe T, Takeda K, Matsuno S, Horii A . Distinct progression pathways involving the dysfunction of DUSP6/MKP-3 in pancreatic intraepithelial neoplasia and intraductal papillary-mucinous neoplasms of the pancreas . Modern Pathology . 18 . 8 . 1034–42 . August 2005 . 15832194 . 10.1038/modpathol.3800383 . free .

Notes and References

1. Web site: Entrez Gene: DUSP6 dual specificity phosphatase 6.
2. Muda M, Boschert U, Dickinson R, Martinou JC, Martinou I, Camps M, Schlegel W, Arkinstall S . MKP-3, a novel cytosolic protein-tyrosine phosphatase that exemplifies a new class of mitogen-activated protein kinase phosphatase . The Journal of Biological Chemistry . 271 . 8 . 4319–26 . February 1996 . 8626780 . 10.1074/jbc.271.8.4319 . free .
3. Smith A, Price C, Cullen M, Muda M, King A, Ozanne B, Arkinstall S, Ashworth A . Chromosomal localization of three human dual specificity phosphatase genes (DUSP4, DUSP6, and DUSP7) . Genomics . 42 . 3 . 524–7 . June 1997 . 9205128 . 10.1006/geno.1997.4756 .
4. Saha M, Skopelja S, Martinez E, Alvarez DL, Liponis BS, Romero-Sandoval EA . Spinal mitogen-activated protein kinase phosphatase-3 (MKP-3) is necessary for the normal resolution of mechanical allodynia in a mouse model of acute postoperative pain . The Journal of Neuroscience . 33 . 43 . 17182–7 . October 2013 . 24155322 . 6618446 . 10.1523/JNEUROSCI.5605-12.2013 .
5. Skopelja-Gardner S, Saha M, Alvarado-Vazquez PA, Liponis BS, Martinez E, Romero-Sandoval EA . Mitogen-activated protein kinase phosphatase-3 (MKP-3) in the surgical wound is necessary for the resolution of postoperative pain in mice . Journal of Pain Research . 10 . 763–774 . 2017-03-28 . 28405172 . 10.2147/jpr.s129826 . 5378457 . free .
6. Muda M, Theodosiou A, Gillieron C, Smith A, Chabert C, Camps M, Boschert U, Rodrigues N, Davies K, Ashworth A, Arkinstall S . The mitogen-activated protein kinase phosphatase-3 N-terminal noncatalytic region is responsible for tight substrate binding and enzymatic specificity . The Journal of Biological Chemistry . 273 . 15 . 9323–9 . April 1998 . 9535927 . 10.1074/jbc.273.15.9323 . free .