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Dual specificity protein phosphatase 6 (EC 3.1.3.16) (EC 3.1.3.48) (Dual specificity protein phosphatase PYST1) (Mitogen-activated protein kinase phosphatase 3) (MAP kinase phosphatase 3) (MKP-3)

 DUS6_HUMAN              Reviewed;         381 AA.
Q16828; O75109; Q53Y75; Q9BSH6;
01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
30-MAY-2006, sequence version 2.
25-OCT-2017, entry version 178.
RecName: Full=Dual specificity protein phosphatase 6;
EC=3.1.3.16;
EC=3.1.3.48;
AltName: Full=Dual specificity protein phosphatase PYST1;
AltName: Full=Mitogen-activated protein kinase phosphatase 3;
Short=MAP kinase phosphatase 3;
Short=MKP-3;
Name=DUSP6; Synonyms=MKP3, PYST1;
Homo sapiens (Human).
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
Catarrhini; Hominidae; Homo.
NCBI_TaxID=9606;
[1]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, SUBCELLULAR
LOCATION, AND VARIANT LEU-114.
TISSUE=Foreskin;
PubMed=8670865;
Groom L.A., Sneddon A.A., Alessi D.R., Dowd S., Keyse S.M.;
"Differential regulation of the MAP, SAP and RK/p38 kinases by Pyst1,
a novel cytosolic dual-specificity phosphatase.";
EMBO J. 15:3621-3632(1996).
[2]
NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORMS 1 AND 2), AND
VARIANT LEU-114.
TISSUE=Liver;
PubMed=9858808;
Furukawa T., Yatsuoka T., Youssef E.M., 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.";
Cytogenet. Cell Genet. 82:156-159(1998).
[3]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT
LEU-114.
Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
Phelan M., Farmer A.;
"Cloning of human full-length CDSs in BD Creator(TM) system donor
vector.";
Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
[4]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
TISSUE=Colon, Kidney, Skin, and Stomach;
PubMed=15489334; DOI=10.1101/gr.2596504;
The MGC Project Team;
"The status, quality, and expansion of the NIH full-length cDNA
project: the Mammalian Gene Collection (MGC).";
Genome Res. 14:2121-2127(2004).
[5]
X-RAY CRYSTALLOGRAPHY (2.35 ANGSTROMS) OF 204-347, AND ACTIVE SITE.
PubMed=10048930; DOI=10.1038/5861;
Stewart A.E., Dowd S., Keyse S.M., McDonald N.Q.;
"Crystal structure of the MAPK phosphatase Pyst1 catalytic domain and
implications for regulated activation.";
Nat. Struct. Biol. 6:174-181(1999).
[6]
VARIANTS HH19 ILE-77; PHE-182; SER-189 AND MET-346.
PubMed=23643382; DOI=10.1016/j.ajhg.2013.04.008;
Miraoui H., Dwyer A.A., Sykiotis G.P., Plummer L., Chung W., Feng B.,
Beenken A., Clarke J., Pers T.H., Dworzynski P., Keefe K.,
Niedziela M., Raivio T., Crowley W.F. Jr., Seminara S.B., Quinton R.,
Hughes V.A., Kumanov P., Young J., Yialamas M.A., Hall J.E.,
Van Vliet G., Chanoine J.P., Rubenstein J., Mohammadi M., Tsai P.S.,
Sidis Y., Lage K., Pitteloud N.;
"Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in
individuals with congenital hypogonadotropic hypogonadism.";
Am. J. Hum. Genet. 92:725-743(2013).
-!- FUNCTION: Inactivates MAP kinases. Has a specificity for the ERK
family (PubMed:9858808). Plays an important role in alleviating
chronic postoperative pain. Necessary for the normal
dephosphorylation of the long-lasting phosphorylated forms of
spinal MAPK1/3 and MAP kinase p38 induced by peripheral surgery,
which drives the resolution of acute postoperative allodynia (By
similarity). {ECO:0000250|UniProtKB:Q9DBB1,
ECO:0000269|PubMed:8670865}.
-!- CATALYTIC ACTIVITY: Protein tyrosine phosphate + H(2)O = protein
tyrosine + phosphate.
-!- CATALYTIC ACTIVITY: [a protein]-serine/threonine phosphate + H(2)O
= [a protein]-serine/threonine + phosphate.
-!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:8670865}.
-!- ALTERNATIVE PRODUCTS:
Event=Alternative splicing; Named isoforms=2;
Name=1;
IsoId=Q16828-1; Sequence=Displayed;
Name=2; Synonyms=DUSP6-ALT;
IsoId=Q16828-2; Sequence=VSP_005137;
-!- DISEASE: Hypogonadotropic hypogonadism 19 with or without anosmia
(HH19) [MIM:615269]: A disorder characterized by absent or
incomplete sexual maturation by the age of 18 years, in
conjunction with low levels of circulating gonadotropins and
testosterone and no other abnormalities of the hypothalamic-
pituitary axis. In some cases, it is associated with non-
reproductive phenotypes, such as anosmia, cleft palate, and
sensorineural hearing loss. Anosmia or hyposmia is related to the
absence or hypoplasia of the olfactory bulbs and tracts.
Hypogonadism is due to deficiency in gonadotropin-releasing
hormone and probably results from a failure of embryonic migration
of gonadotropin-releasing hormone-synthesizing neurons. In the
presence of anosmia, idiopathic hypogonadotropic hypogonadism is
referred to as Kallmann syndrome, whereas in the presence of a
normal sense of smell, it has been termed normosmic idiopathic
hypogonadotropic hypogonadism (nIHH).
{ECO:0000269|PubMed:23643382}. Note=The disease is caused by
mutations affecting distinct genetic loci, including the gene
represented in this entry. Some patients carrying mutations in
DUSP6 also have a heterozygous mutation in another HH-associated
gene including FGFR1 and SPRY4 (PubMed:23643382).
{ECO:0000269|PubMed:23643382}.
-!- SIMILARITY: Belongs to the protein-tyrosine phosphatase family.
Non-receptor class dual specificity subfamily. {ECO:0000305}.
-!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
and Haematology;
URL="http://atlasgeneticsoncology.org/Genes/DUSP6ID46105ch12q21.html";
-----------------------------------------------------------------------
Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
Distributed under the Creative Commons Attribution-NoDerivs License
-----------------------------------------------------------------------
EMBL; X93920; CAA63813.1; -; mRNA.
EMBL; AB013601; BAA31968.1; -; Genomic_DNA.
EMBL; AB013382; BAA34369.1; -; mRNA.
EMBL; AB013602; BAA31969.1; -; mRNA.
EMBL; BT006895; AAP35541.1; -; mRNA.
EMBL; BC003143; AAH03143.1; -; mRNA.
EMBL; BC003562; AAH03562.1; -; mRNA.
EMBL; BC005047; AAH05047.1; -; mRNA.
EMBL; BC037236; AAH37236.1; -; mRNA.
CCDS; CCDS9033.1; -. [Q16828-1]
CCDS; CCDS9034.1; -. [Q16828-2]
RefSeq; NP_001937.2; NM_001946.3. [Q16828-1]
RefSeq; NP_073143.2; NM_022652.3. [Q16828-2]
UniGene; Hs.298654; -.
UniGene; Hs.718640; -.
PDB; 1HZM; NMR; -; A=1-154.
PDB; 1MKP; X-ray; 2.35 A; A=205-347.
PDBsum; 1HZM; -.
PDBsum; 1MKP; -.
ProteinModelPortal; Q16828; -.
SMR; Q16828; -.
BioGrid; 108181; 60.
ELM; Q16828; -.
IntAct; Q16828; 6.
MINT; MINT-1442837; -.
STRING; 9606.ENSP00000279488; -.
BindingDB; Q16828; -.
ChEMBL; CHEMBL1250381; -.
DEPOD; Q16828; -.
iPTMnet; Q16828; -.
PhosphoSitePlus; Q16828; -.
BioMuta; DUSP6; -.
DMDM; 108860971; -.
EPD; Q16828; -.
MaxQB; Q16828; -.
PaxDb; Q16828; -.
PeptideAtlas; Q16828; -.
PRIDE; Q16828; -.
DNASU; 1848; -.
Ensembl; ENST00000279488; ENSP00000279488; ENSG00000139318. [Q16828-1]
Ensembl; ENST00000308385; ENSP00000307835; ENSG00000139318. [Q16828-2]
GeneID; 1848; -.
KEGG; hsa:1848; -.
UCSC; uc001tay.5; human. [Q16828-1]
CTD; 1848; -.
DisGeNET; 1848; -.
EuPathDB; HostDB:ENSG00000139318.7; -.
GeneCards; DUSP6; -.
HGNC; HGNC:3072; DUSP6.
HPA; CAB017566; -.
HPA; HPA053188; -.
MalaCards; DUSP6; -.
MIM; 602748; gene.
MIM; 615269; phenotype.
neXtProt; NX_Q16828; -.
OpenTargets; ENSG00000139318; -.
Orphanet; 478; Kallmann syndrome.
Orphanet; 432; Normosmic congenital hypogonadotropic hypogonadism.
PharmGKB; PA27529; -.
eggNOG; KOG1717; Eukaryota.
eggNOG; COG2453; LUCA.
GeneTree; ENSGT00760000118902; -.
HOGENOM; HOG000294079; -.
HOVERGEN; HBG007347; -.
InParanoid; Q16828; -.
KO; K21946; -.
OMA; LLVMDCR; -.
OrthoDB; EOG091G0249; -.
PhylomeDB; Q16828; -.
TreeFam; TF105122; -.
BRENDA; 3.1.3.16; 2681.
BRENDA; 3.1.3.48; 2681.
Reactome; R-HSA-112409; RAF-independent MAPK1/3 activation.
Reactome; R-HSA-202670; ERKs are inactivated.
Reactome; R-HSA-5675221; Negative regulation of MAPK pathway.
SignaLink; Q16828; -.
SIGNOR; Q16828; -.
ChiTaRS; DUSP6; human.
EvolutionaryTrace; Q16828; -.
GeneWiki; DUSP6; -.
GenomeRNAi; 1848; -.
PRO; PR:Q16828; -.
Proteomes; UP000005640; Chromosome 12.
Bgee; ENSG00000139318; -.
CleanEx; HS_DUSP6; -.
ExpressionAtlas; Q16828; baseline and differential.
Genevisible; Q16828; HS.
GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
GO; GO:0005829; C:cytosol; TAS:Reactome.
GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
GO; GO:0017017; F:MAP kinase tyrosine/serine/threonine phosphatase activity; IDA:UniProtKB.
GO; GO:0004725; F:protein tyrosine phosphatase activity; TAS:Reactome.
GO; GO:0008138; F:protein tyrosine/serine/threonine phosphatase activity; TAS:Reactome.
GO; GO:0000187; P:activation of MAPK activity; TAS:Reactome.
GO; GO:0030154; P:cell differentiation; IEA:Ensembl.
GO; GO:0009953; P:dorsal/ventral pattern formation; IBA:GO_Central.
GO; GO:0000188; P:inactivation of MAPK activity; IDA:UniProtKB.
GO; GO:0000165; P:MAPK cascade; TAS:Reactome.
GO; GO:0070373; P:negative regulation of ERK1 and ERK2 cascade; IMP:UniProtKB.
GO; GO:0035335; P:peptidyl-tyrosine dephosphorylation; IDA:UniProtKB.
GO; GO:0043065; P:positive regulation of apoptotic process; IDA:UniProtKB.
GO; GO:0042663; P:regulation of endodermal cell fate specification; IBA:GO_Central.
GO; GO:0040036; P:regulation of fibroblast growth factor receptor signaling pathway; IBA:GO_Central.
GO; GO:0060420; P:regulation of heart growth; IBA:GO_Central.
GO; GO:0042493; P:response to drug; IEA:Ensembl.
GO; GO:0070848; P:response to growth factor; IEA:Ensembl.
GO; GO:0051409; P:response to nitrosative stress; IEP:UniProtKB.
GO; GO:0014070; P:response to organic cyclic compound; IEA:Ensembl.
CDD; cd00127; DSPc; 1.
Gene3D; 3.40.250.10; -; 1.
Gene3D; 3.90.190.10; -; 1.
InterPro; IPR000340; Dual-sp_phosphatase_cat-dom.
InterPro; IPR024950; DUSP.
InterPro; IPR008343; MKP.
InterPro; IPR029021; Prot-tyrosine_phosphatase-like.
InterPro; IPR001763; Rhodanese-like_dom.
InterPro; IPR036873; Rhodanese-like_dom_sf.
InterPro; IPR000387; TYR_PHOSPHATASE_dom.
InterPro; IPR020422; TYR_PHOSPHATASE_DUAL_dom.
PANTHER; PTHR10159; PTHR10159; 1.
Pfam; PF00782; DSPc; 1.
Pfam; PF00581; Rhodanese; 1.
PIRSF; PIRSF000939; MAPK_Ptase; 1.
PRINTS; PR01764; MAPKPHPHTASE.
SMART; SM00195; DSPc; 1.
SMART; SM00450; RHOD; 1.
SUPFAM; SSF52799; SSF52799; 1.
SUPFAM; SSF52821; SSF52821; 1.
PROSITE; PS50206; RHODANESE_3; 1.
PROSITE; PS50056; TYR_PHOSPHATASE_2; 1.
PROSITE; PS50054; TYR_PHOSPHATASE_DUAL; 1.
1: Evidence at protein level;
3D-structure; Alternative splicing; Complete proteome; Cytoplasm;
Disease mutation; Hydrolase; Hypogonadotropic hypogonadism;
Kallmann syndrome; Polymorphism; Protein phosphatase;
Reference proteome.
CHAIN 1 381 Dual specificity protein phosphatase 6.
/FTId=PRO_0000094804.
DOMAIN 30 148 Rhodanese. {ECO:0000255|PROSITE-
ProRule:PRU00173}.
DOMAIN 206 381 Tyrosine-protein phosphatase.
ACT_SITE 293 293 Phosphocysteine intermediate.
{ECO:0000269|PubMed:10048930}.
VAR_SEQ 134 279 Missing (in isoform 2).
{ECO:0000303|PubMed:9858808}.
/FTId=VSP_005137.
VARIANT 77 77 F -> I (in HH19; dbSNP:rs587776978).
{ECO:0000269|PubMed:23643382}.
/FTId=VAR_069943.
VARIANT 114 114 V -> L (in dbSNP:rs2279574).
{ECO:0000269|PubMed:8670865,
ECO:0000269|PubMed:9858808,
ECO:0000269|Ref.3}.
/FTId=VAR_015113.
VARIANT 144 144 S -> A (in dbSNP:rs770087).
/FTId=VAR_051750.
VARIANT 182 182 S -> F (in HH19; rare variant associated
with susceptibility to disease; the
patient carries a second mutation in the
HH-associated gene FGFR1;
dbSNP:rs139318648).
{ECO:0000269|PubMed:23643382}.
/FTId=VAR_069944.
VARIANT 189 189 N -> S (in HH19; dbSNP:rs143946794).
{ECO:0000269|PubMed:23643382}.
/FTId=VAR_069945.
VARIANT 313 313 N -> I (in dbSNP:rs12828557).
/FTId=VAR_051751.
VARIANT 346 346 T -> M (in HH19; rare variant associated
with susceptibility to disease; the
patient carries a second variant in the
HH-associated gene SPRY4;
dbSNP:rs146089505).
{ECO:0000269|PubMed:23643382}.
/FTId=VAR_069946.
STRAND 7 12 {ECO:0000244|PDB:1HZM}.
STRAND 15 18 {ECO:0000244|PDB:1HZM}.
HELIX 23 29 {ECO:0000244|PDB:1HZM}.
STRAND 31 33 {ECO:0000244|PDB:1HZM}.
STRAND 35 37 {ECO:0000244|PDB:1HZM}.
HELIX 43 48 {ECO:0000244|PDB:1HZM}.
STRAND 50 52 {ECO:0000244|PDB:1HZM}.
HELIX 61 64 {ECO:0000244|PDB:1HZM}.
TURN 73 76 {ECO:0000244|PDB:1HZM}.
HELIX 81 88 {ECO:0000244|PDB:1HZM}.
STRAND 95 97 {ECO:0000244|PDB:1HZM}.
STRAND 101 105 {ECO:0000244|PDB:1HZM}.
HELIX 114 124 {ECO:0000244|PDB:1HZM}.
HELIX 136 143 {ECO:0000244|PDB:1HZM}.
STRAND 149 152 {ECO:0000244|PDB:1HZM}.
STRAND 208 211 {ECO:0000244|PDB:1MKP}.
STRAND 214 217 {ECO:0000244|PDB:1MKP}.
HELIX 225 230 {ECO:0000244|PDB:1MKP}.
STRAND 233 238 {ECO:0000244|PDB:1MKP}.
STRAND 246 250 {ECO:0000244|PDB:1MKP}.
STRAND 253 257 {ECO:0000244|PDB:1MKP}.
HELIX 269 271 {ECO:0000244|PDB:1MKP}.
HELIX 272 284 {ECO:0000244|PDB:1MKP}.
STRAND 288 292 {ECO:0000244|PDB:1MKP}.
HELIX 298 312 {ECO:0000244|PDB:1MKP}.
HELIX 316 326 {ECO:0000244|PDB:1MKP}.
HELIX 337 345 {ECO:0000244|PDB:1MKP}.
SEQUENCE 381 AA; 42320 MW; 386612227F5D3B2A CRC64;
MIDTLRPVPF ASEMAISKTV AWLNEQLELG NERLLLMDCR PQELYESSHI ESAINVAIPG
IMLRRLQKGN LPVRALFTRG EDRDRFTRRC GTDTVVLYDE SSSDWNENTG GESVLGLLLK
KLKDEGCRAF YLEGGFSKFQ AEFSLHCETN LDGSCSSSSP PLPVLGLGGL RISSDSSSDI
ESDLDRDPNS ATDSDGSPLS NSQPSFPVEI LPFLYLGCAK DSTNLDVLEE FGIKYILNVT
PNLPNLFENA GEFKYKQIPI SDHWSQNLSQ FFPEAISFID EARGKNCGVL VHCLAGISRS
VTVTVAYLMQ KLNLSMNDAY DIVKMKKSNI SPNFNFMGQL LDFERTLGLS SPCDNRVPAQ
QLYFTTPSNQ NVYQVDSLQS T


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