DUSP3

Dual specificity protein phosphatase 3 is an enzyme that in humans is encoded by the DUSP3 gene.[5][6]

DUSP3
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1J4X, 1VHR, 3F81
Identifiers
Aliases	DUSP3, VHR, dual specificity phosphatase 3
External IDs	OMIM: 600183 MGI: 1919599 HomoloGene: 20870 GeneCards: DUSP3
Gene location (Human) Chr. Chromosome 17 (human)[1] Band 17q21.31 Start 43,766,125 bp[1] End 43,778,977 bp[1]
Gene location (Mouse) Chr. Chromosome 11 (mouse)[2] Band 11|11 D Start 101,971,143 bp[2] End 101,987,013 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • phosphoprotein phosphatase activity • MAP kinase phosphatase activity • hydrolase activity • protein kinase binding • protein tyrosine/serine/threonine phosphatase activity • phosphatase activity • protein tyrosine phosphatase activity • cytoskeletal protein binding • receptor tyrosine kinase binding • protein tyrosine kinase binding Cellular component • cytosol • nucleoplasm • immunological synapse • cell nucleus Biological process • inactivation of MAPK activity • protein dephosphorylation • positive regulation of mitotic cell cycle • negative regulation of T cell receptor signaling pathway • negative regulation of JNK cascade • negative regulation of MAPK cascade • negative regulation of ERK1 and ERK2 cascade • peptidyl-tyrosine dephosphorylation • negative regulation of T cell activation • in utero embryonic development • dephosphorylation • negative regulation of cell migration • negative regulation of epidermal growth factor receptor signaling pathway • negative regulation of chemotaxis • regulation of focal adhesion assembly • cellular response to epidermal growth factor stimulus • positive regulation of focal adhesion disassembly • peptidyl-tyrosine dephosphorylation involved in inactivation of protein kinase activity Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	1845	72349
Ensembl	ENSG00000108861	ENSMUSG00000003518
UniProt	P51452	Q9D7X3
RefSeq (mRNA)	NM_004090	NM_028207
RefSeq (protein)	NP_004081	NP_082483
Location (UCSC)	Chr 17: 43.77 – 43.78 Mb	Chr 11: 101.97 – 101.99 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

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 maps in a region that contains the BRCA1 locus which confers susceptibility to breast and ovarian cancer. Although DUSP3 is expressed in both breast and ovarian tissues, mutation screening in breast cancer pedigrees and in sporadic tumors was negative, leading to the conclusion that this gene is not BRCA1.[6]

Model organisms

Dusp3 knockout mouse phenotype

Characteristic	Phenotype
Homozygote viability	Normal
Fertility	Normal
Body weight	Normal
Anxiety	Normal
Neurological assessment	Normal
Grip strength	Normal
Hot plate	Normal
Dysmorphology	Normal
Indirect calorimetry	Normal
Glucose tolerance test	Normal
Auditory brainstem response	Normal
DEXA	Abnormal[7]
Radiography	Abnormal[8]
Body temperature	Normal
Eye morphology	Normal
Clinical chemistry	Normal
Plasma immunoglobulins	Normal
Haematology	Normal[9]
Peripheral blood lymphocytes	Normal
Micronucleus test	Normal
Heart weight	Normal
Skin Histopathology	Normal
Brain histopathology	Abnormal
Salmonella infection	Abnormal[10]
Citrobacter infection	Normal[11]
All tests and analysis from[12][13]

Model organisms have been used in the study of DUSP3 function. A conditional knockout mouse line, called Dusp3^{tm1a(KOMP)Wtsi}[14][15] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[16][17][18]

Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[12][19] Twenty five tests were carried out on mutant mice and four significant abnormalities were observed.[12] Homozygous mutants had an increased percent of body fat, abnormal humerus morphology and an increased susceptibility to bacterial infection. Corpus callosum area, hippocampus area and total brain section area was increased, while length of pyramidal cell layer was reduced.[12]

Interactions

DUSP3 has been shown to interact with MAPK3[20] and MAPK1.[20]

References

1. GRCh38: Ensembl release 89: ENSG00000108861 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000003518 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Folander K, Douglass J, Swanson R (Feb 1995). "Confirmation of the assignment of the gene encoding Kv1.3, a voltage-gated potassium channel (KCNA3) to the proximal short arm of human chromosome 1". Genomics. 23 (1): 295–6. doi:10.1006/geno.1994.1500. PMID 7829094.
6. "Entrez Gene: DUSP3 dual specificity phosphatase 3 (vaccinia virus phosphatase VH1-related)".
7. "DEXA data for Dusp3". Wellcome Trust Sanger Institute.
8. "Radiography data for Dusp3". Wellcome Trust Sanger Institute.
9. "Haematology data for Dusp3". Wellcome Trust Sanger Institute.
10. "Salmonella infection data for Dusp3". Wellcome Trust Sanger Institute.
11. "Citrobacter infection data for Dusp3". Wellcome Trust Sanger Institute.
12. Gerdin AK (2010). "The Sanger Mouse Genetics Programme: High throughput characterisation of knockout mice". Acta Ophthalmologica. 88: 925–7. doi:10.1111/j.1755-3768.2010.4142.x.
13. Mouse Resources Portal, Wellcome Trust Sanger Institute.
14. "International Knockout Mouse Consortium".
15. "Mouse Genome Informatics".
16. Skarnes, W. C.; Rosen, B.; West, A. P.; Koutsourakis, M.; Bushell, W.; Iyer, V.; Mujica, A. O.; Thomas, M.; Harrow, J.; Cox, T.; Jackson, D.; Severin, J.; Biggs, P.; Fu, J.; Nefedov, M.; De Jong, P. J.; Stewart, A. F.; Bradley, A. (2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature. 474 (7351): 337–342. doi:10.1038/nature10163. PMC 3572410. PMID 21677750.
17. Dolgin E (2011). "Mouse library set to be knockout". Nature. 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718.
18. Collins FS, Rossant J, Wurst W (2007). "A Mouse for All Reasons". Cell. 128 (1): 9–13. doi:10.1016/j.cell.2006.12.018. PMID 17218247.
19. van der Weyden L, White JK, Adams DJ, Logan DW (2011). "The mouse genetics toolkit: revealing function and mechanism". Genome Biol. 12 (6): 224. doi:10.1186/gb-2011-12-6-224. PMC 3218837. PMID 21722353.
20. Todd, J L; Tanner K G; Denu J M (May 1999). "Extracellular regulated kinases (ERK) 1 and ERK2 are authentic substrates for the dual-specificity protein-tyrosine phosphatase VHR. A novel role in down-regulating the ERK pathway". J. Biol. Chem. UNITED STATES. 274 (19): 13271–80. doi:10.1074/jbc.274.19.13271. ISSN 0021-9258. PMID 10224087.

Further reading

• Ishibashi T, Bottaro DP, Chan A, et al. (1993). "Expression cloning of a human dual-specificity phosphatase". Proc. Natl. Acad. Sci. U.S.A. 89 (24): 12170–4. Bibcode:1992PNAS...8912170I. doi:10.1073/pnas.89.24.12170. PMC 50720. PMID 1281549.
• Kamb A, Futreal PA, Rosenthal J, et al. (1995). "Localization of the VHR phosphatase gene and its analysis as a candidate for BRCA1". Genomics. 23 (1): 163–7. doi:10.1006/geno.1994.1473. PMID 7829067.
• Jones KA, Black DM, Brown MA, et al. (1995). "The detailed characterisation of a 400 kb cosmid walk in the BRCA1 region: identification and localisation of 10 genes including a dual-specificity phosphatase". Hum. Mol. Genet. 3 (11): 1927–34. doi:10.1093/hmg/3.11.1927. PMID 7874108.
• Yuvaniyama J, Denu JM, Dixon JE, Saper MA (1996). "Crystal structure of the dual specificity protein phosphatase VHR". Science. 272 (5266): 1328–31. Bibcode:1996Sci...272.1328Y. doi:10.1126/science.272.5266.1328. PMID 8650541.
• Todd JL, Tanner KG, Denu JM (1999). "Extracellular regulated kinases (ERK) 1 and ERK2 are authentic substrates for the dual-specificity protein-tyrosine phosphatase VHR. A novel role in down-regulating the ERK pathway". J. Biol. Chem. 274 (19): 13271–80. doi:10.1074/jbc.274.19.13271. PMID 10224087.
• Alonso A, Saxena M, Williams S, Mustelin T (2001). "Inhibitory role for dual specificity phosphatase VHR in T cell antigen receptor and CD28-induced Erk and Jnk activation". J. Biol. Chem. 276 (7): 4766–71. doi:10.1074/jbc.M006497200. PMID 11085983.
• Najarro P, Traktman P, Lewis JA (2001). "Vaccinia virus blocks gamma interferon signal transduction: viral VH1 phosphatase reverses Stat1 activation". J. Virol. 75 (7): 3185–96. doi:10.1128/JVI.75.7.3185-3196.2001. PMC 114112. PMID 11238845.
• Alonso A, Rahmouni S, Williams S, et al. (2003). "Tyrosine phosphorylation of VHR phosphatase by ZAP-70". Nat. Immunol. 4 (1): 44–8. doi:10.1038/ni856. PMID 12447358.
• Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. Bibcode:2002PNAS...9916899M. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
• Kim HS, Song MC, Kwak IH, et al. (2003). "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" (PDF). J. Biol. Chem. 278 (39): 37497–510. doi:10.1074/jbc.M211739200. PMID 12840032.
• Ota T, Suzuki Y, Nishikawa T, et al. (2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs". Nat. Genet. 36 (1): 40–5. doi:10.1038/ng1285. PMID 14702039.
• Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)". Genome Res. 14 (10B): 2121–7. doi:10.1101/gr.2596504. PMC 528928. PMID 15489334.
• Rual JF, Venkatesan K, Hao T, et al. (2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature. 437 (7062): 1173–8. Bibcode:2005Natur.437.1173R. doi:10.1038/nature04209. PMID 16189514.
• Rahmouni S, Cerignoli F, Alonso A, et al. (2006). "Loss of the VHR dual-specific phosphatase causes cell-cycle arrest and senescence". Nat. Cell Biol. 8 (5): 524–31. doi:10.1038/ncb1398. PMID 16604064.
• Hao L, ElShamy WM (2007). "BRCA1-IRIS activates cyclin D1 expression in breast cancer cells by downregulating the JNK phosphatase DUSP3/VHR". Int. J. Cancer. 121 (1): 39–46. doi:10.1002/ijc.22597. PMID 17278098.
• Hoyt R, Zhu W, Cerignoli F, et al. (2007). "Cutting edge: selective tyrosine dephosphorylation of interferon-activated nuclear STAT5 by the VHR phosphatase". J. Immunol. 179 (6): 3402–6. doi:10.4049/jimmunol.179.6.3402. PMC 2770724. PMID 17785772.