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Protein

Dedicator of cytokinesis protein 8

Gene

DOCK8

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Guanine nucleotide exchange factor (GEF) which specifically activates small GTPase CDC42 by exchanging bound GDP for free GTP (PubMed:28028151, PubMed:22461490). During immune responses, required for interstitial dendritic cell (DC) migration by locally activating CDC42 at the leading edge membrane of DC (By similarity). Required for CD4+ T-cell migration in response to chemokine stimulation by promoting CDC42 activation at T cell leading edge membrane (PubMed:28028151). Is involved in NK cell cytotoxicity by controlling polarization of microtubule-organizing center (MTOC), and possibly regulating CCDC88B-mediated lytic granule transport to MTOC during cell killing (PubMed:25762780).By similarity3 Publications

GO - Molecular functioni

  • guanyl-nucleotide exchange factor activity Source: UniProtKB

GO - Biological processi

  • blood coagulation Source: Reactome
  • cellular response to chemokine Source: UniProtKB
  • dendritic cell migration Source: Ensembl
  • immunological synapse formation Source: Ensembl
  • memory T cell proliferation Source: MGI
  • negative regulation of T cell apoptotic process Source: Ensembl
  • positive regulation of establishment of T cell polarity Source: UniProtKB
  • positive regulation of GTPase activity Source: UniProtKB
  • positive regulation of T cell migration Source: UniProtKB
  • small GTPase mediated signal transduction Source: InterPro

Keywordsi

Molecular functionGuanine-nucleotide releasing factor

Enzyme and pathway databases

ReactomeiR-HSA-983231. Factors involved in megakaryocyte development and platelet production.

Names & Taxonomyi

Protein namesi
Recommended name:
Dedicator of cytokinesis protein 8
Gene namesi
Name:DOCK8
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 9

Organism-specific databases

EuPathDBiHostDB:ENSG00000107099.15.
HGNCiHGNC:19191. DOCK8.

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cell membrane, Cell projection, Cytoplasm, Membrane

Pathology & Biotechi

Involvement in diseasei

Hyperimmunoglobulin E recurrent infection syndrome, autosomal recessive (AR-HIES)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA rare disorder characterized by immunodeficiency, recurrent infections, eczema, increased serum IgE, eosinophilia and lack of connective tissue and skeletal involvement.
See also OMIM:243700
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_063753473K → R in AR-HIES. 1 PublicationCorresponds to variant dbSNP:rs112321280Ensembl.1
Mental retardation, autosomal dominant 2 (MRD2)1 Publication
The gene represented in this entry is involved in disease pathogenesis. A chromosomal aberration disrupting DOCK8 has been found in a patient with mental retardation and ectodermal dysplasia. A balanced translocation, t(X;9) (q13.1;p24). A genomic deletion of approximately 230 kb in subtelomeric 9p has been detected in a patient with mental retardation.
Disease descriptionA disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period.
See also OMIM:614113

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi2077S → A: Abolishes phosphorylation. No migration in response to chemokine CXCL12/SDF-1-alpha stimulation; when associated with A-2082 and A-2087. 1 Publication1
Mutagenesisi2077S → E: Phosphomimetic mutant. Enhances migration in response to chemokine CXCL12/SDF-1-alpha stimulation and reduces interaction with LRCH1; when associated with E-2082 and E-2087. 1 Publication1
Mutagenesisi2082S → A: Abolishes phosphorylation. No migration in response to chemokine CXCL12/SDF-1-alpha stimulation; when associated with A-2077 and A-2087. 1 Publication1
Mutagenesisi2082S → E: Phosphomimetic mutant. Enhances migration in response to chemokine CXCL12/SDF-1-alpha stimulation and reduces interaction with LRCH1; when associated with E-2077 and E-2087. 1 Publication1
Mutagenesisi2087S → A: Abolishes phosphorylation. No migration in response to chemokine CXCL12/SDF-1-alpha stimulation; when associated with A-2077 and A-2082. 1 Publication1
Mutagenesisi2087S → E: Phosphomimetic mutant. Enhances migration in response to chemokine CXCL12/SDF-1-alpha stimulation and reduces interaction with LRCH1; when associated with E-2077 and E-2082. 1 Publication1

Keywords - Diseasei

Disease mutation, Mental retardation

Organism-specific databases

DisGeNETi81704.
MalaCardsiDOCK8.
MIMi243700. phenotype.
614113. phenotype.
OpenTargetsiENSG00000107099.
Orphaneti178469. Autosomal dominant non-syndromic intellectual disability.
169446. Autosomal recessive hyper-IgE syndrome.
217390. Combined immunodeficiency due to DOCK8 deficiency.
PharmGKBiPA134918866.

Polymorphism and mutation databases

BioMutaiDOCK8.
DMDMi158937439.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00001899971 – 2099Dedicator of cytokinesis protein 8Add BLAST2099

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei20PhosphoserineCombined sources1
Modified residuei139PhosphoserineCombined sources1
Modified residuei451PhosphoserineCombined sources1
Modified residuei904PhosphoserineBy similarity1
Modified residuei936PhosphoserineCombined sources1
Modified residuei1145PhosphoserineCombined sources1
Modified residuei1243PhosphoserineBy similarity1
Modified residuei2087PhosphoserineCombined sources1

Post-translational modificationi

In response to chemokine CXCL12/SDF-1-alpha stimulation, phosphorylated by PRKCA/PKC-alpha which promotes DOCK8 dissociation from LRCH1.1 Publication

Keywords - PTMi

Phosphoprotein

Proteomic databases

EPDiQ8NF50.
MaxQBiQ8NF50.
PaxDbiQ8NF50.
PeptideAtlasiQ8NF50.
PRIDEiQ8NF50.

PTM databases

iPTMnetiQ8NF50.
PhosphoSitePlusiQ8NF50.

Expressioni

Tissue specificityi

Expressed in peripheral blood mononuclear cells (PBMCs).1 Publication

Gene expression databases

BgeeiENSG00000107099.
ExpressionAtlasiQ8NF50. baseline and differential.
GenevisibleiQ8NF50. HS.

Organism-specific databases

HPAiHPA003218.

Interactioni

Subunit structurei

Interacts (via DHR-2 domain) with GTPase CDC42; the interaction activates CDC42 by exchanging GDP for GTP (PubMed:22461490, PubMed:28028151). The unphosphorylated form interacts (via DHR-2 domain) with LRCH1 (via LRR repeats); the interaction prevents the association between DOCK8 and CDC42 (PubMed:28028151). Interacts with CCDC88B (PubMed:25762780).3 Publications

Binary interactionsi

Show more details

Protein-protein interaction databases

BioGridi123577. 39 interactors.
CORUMiQ8NF50.
IntActiQ8NF50. 45 interactors.
MINTiMINT-1189381.
STRINGi9606.ENSP00000408464.

Structurei

3D structure databases

ProteinModelPortaliQ8NF50.
SMRiQ8NF50.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini560 – 729DHR-1PROSITE-ProRule annotationAdd BLAST170
Domaini1632 – 2066DHR-2PROSITE-ProRule annotationAdd BLAST435

Domaini

The DHR-2 domain is necessary and sufficient for the GEF activity.2 Publications

Sequence similaritiesi

Belongs to the DOCK family.PROSITE-ProRule annotation

Phylogenomic databases

eggNOGiKOG1997. Eukaryota.
ENOG410ZJ2S. LUCA.
GeneTreeiENSGT00760000119234.
HOGENOMiHOG000230910.
HOVERGENiHBG051390.
InParanoidiQ8NF50.
KOiK21852.
OMAiFNLRRFM.
OrthoDBiEOG091G0067.
PhylomeDBiQ8NF50.
TreeFamiTF313629.

Family and domain databases

Gene3Di1.25.10.10. 1 hit.
InterProiView protein in InterPro
IPR011989. ARM-like.
IPR016024. ARM-type_fold.
IPR027007. DHR-1_domain.
IPR027357. DHR-2.
IPR026791. DOCK.
IPR010703. DOCK_C.
IPR021816. DOCK_C/D_N.
PANTHERiPTHR23317. PTHR23317. 1 hit.
PfamiView protein in Pfam
PF06920. DHR-2. 1 hit.
PF14429. DOCK-C2. 1 hit.
PF11878. DUF3398. 1 hit.
SUPFAMiSSF48371. SSF48371. 1 hit.
PROSITEiView protein in PROSITE
PS51650. DHR_1. 1 hit.
PS51651. DHR_2. 1 hit.

Sequences (4)i

Sequence statusi: Complete.

This entry describes 4 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q8NF50-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MATLPSAERR AFALKINRYS SAEIRKQFTL PPNLGQYHRQ SISTSGFPSL
60 70 80 90 100
QLPQFYDPVE PVDFEGLLMT HLNSLDVQLA QELGDFTDDD LDVVFTPKEC
110 120 130 140 150
RTLQPSLPEE GVELDPHVRD CVQTYIREWL IVNRKNQGSP EICGFKKTGS
160 170 180 190 200
RKDFHKTLPK QTFESETLEC SEPAAQAGPR HLNVLCDVSG KGPVTACDFD
210 220 230 240 250
LRSLQPDKRL ENLLQQVSAE DFEKQNEEAR RTNRQAELFA LYPSVDEEDA
260 270 280 290 300
VEIRPVPECP KEHLGNRILV KLLTLKFEIE IEPLFASIAL YDVKERKKIS
310 320 330 340 350
ENFHCDLNSD QFKGFLRAHT PSVAASSQAR SAVFSVTYPS SDIYLVVKIE
360 370 380 390 400
KVLQQGEIGD CAEPYTVIKE SDGGKSKEKI EKLKLQAESF CQRLGKYRMP
410 420 430 440 450
FAWAPISLSS FFNVSTLERE VTDVDSVVGR SSVGERRTLA QSRRLSERAL
460 470 480 490 500
SLEENGVGSN FKTSTLSVSS FFKQEGDRLS DEDLFKFLAD YKRSSSLQRR
510 520 530 540 550
VKSIPGLLRL EISTAPEIIN CCLTPEMLPV KPFPENRTRP HKEILEFPTR
560 570 580 590 600
EVYVPHTVYR NLLYVYPQRL NFVNKLASAR NITIKIQFMC GEDASNAMPV
610 620 630 640 650
IFGKSSGPEF LQEVYTAVTY HNKSPDFYEE VKIKLPAKLT VNHHLLFTFY
660 670 680 690 700
HISCQQKQGA SVETLLGYSW LPILLNERLQ TGSYCLPVAL EKLPPNYSMH
710 720 730 740 750
SAEKVPLQNP PIKWAEGHKG VFNIEVQAVS SVHTQDNHLE KFFTLCHSLE
760 770 780 790 800
SQVTFPIRVL DQKISEMALE HELKLSIICL NSSRLEPLVL FLHLVLDKLF
810 820 830 840 850
QLSVQPMVIA GQTANFSQFA FESVVAIANS LHNSKDLSKD QHGRNCLLAS
860 870 880 890 900
YVHYVFRLPE VQRDVPKSGA PTALLDPRSY HTYGRTSAAA VSSKLLQARV
910 920 930 940 950
MSSSNPDLAG THSAADEEVK NIMSSKIADR NCSRMSYYCS GSSDAPSSPA
960 970 980 990 1000
APRPASKKHF HEELALQMVV STGMVRETVF KYAWFFFELL VKSMAQHVHN
1010 1020 1030 1040 1050
MDKRDSFRRT RFSDRFMDDI TTIVNVVTSE IAALLVKPQK ENEQAEKMNI
1060 1070 1080 1090 1100
SLAFFLYDLL SLMDRGFVFN LIRHYCSQLS AKLSNLPTLI SMRLEFLRIL
1110 1120 1130 1140 1150
CSHEHYLNLN LFFMNADTAP TSPCPSISSQ NSSSCSSFQD QKIASMFDLT
1160 1170 1180 1190 1200
SEYRQQHFLT GLLFTELAAA LDAEGEGISK VQRKAVSAIH SLLSSHDLDP
1210 1220 1230 1240 1250
RCVKPEVKVK IAALYLPLVG IILDALPQLC DFTVADTRRY RTSGSDEEQE
1260 1270 1280 1290 1300
GAGAINQNVA LAIAGNNFNL KTSGIVLSSL PYKQYNMLNA DTTRNLMICF
1310 1320 1330 1340 1350
LWIMKNADQS LIRKWIADLP STQLNRILDL LFICVLCFEY KGKQSSDKVS
1360 1370 1380 1390 1400
TQVLQKSRDV KARLEEALLR GEGARGEMMR RRAPGNDRFP GLNENLRWKK
1410 1420 1430 1440 1450
EQTHWRQANE KLDKTKAELD QEALISGNLA TEAHLIILDM QENIIQASSA
1460 1470 1480 1490 1500
LDCKDSLLGG VLRVLVNSLN CDQSTTYLTH CFATLRALIA KFGDLLFEEE
1510 1520 1530 1540 1550
VEQCFDLCHQ VLHHCSSSMD VTRSQACATL YLLMRFSFGA TSNFARVKMQ
1560 1570 1580 1590 1600
VTMSLASLVG RAPDFNEEHL RRSLRTILAY SEEDTAMQMT PFPTQVEELL
1610 1620 1630 1640 1650
CNLNSILYDT VKMREFQEDP EMLMDLMYRI AKSYQASPDL RLTWLQNMAE
1660 1670 1680 1690 1700
KHTKKKCYTE AAMCLVHAAA LVAEYLSMLE DHSYLPVGSV SFQNISSNVL
1710 1720 1730 1740 1750
EESVVSEDTL SPDEDGVCAG QYFTESGLVG LLEQAAELFS TGGLYETVNE
1760 1770 1780 1790 1800
VYKLVIPILE AHREFRKLTL THSKLQRAFD SIVNKDHKRM FGTYFRVGFF
1810 1820 1830 1840 1850
GSKFGDLDEQ EFVYKEPAIT KLPEISHRLE AFYGQCFGAE FVEVIKDSTP
1860 1870 1880 1890 1900
VDKTKLDPNK AYIQITFVEP YFDEYEMKDR VTYFEKNFNL RRFMYTTPFT
1910 1920 1930 1940 1950
LEGRPRGELH EQYRRNTVLT TMHAFPYIKT RISVIQKEEF VLTPIEVAIE
1960 1970 1980 1990 2000
DMKKKTLQLA VAINQEPPDA KMLQMVLQGS VGATVNQGPL EVAQVFLAEI
2010 2020 2030 2040 2050
PADPKLYRHH NKLRLCFKEF IMRCGEAVEK NKRLITADQR EYQQELKKNY
2060 2070 2080 2090
NKLKENLRPM IERKIPELYK PIFRVESQKR DSFHRSSFRK CETQLSQGS
Length:2,099
Mass (Da):238,529
Last modified:August 21, 2007 - v3
Checksum:iAF651C26E2D8E73E
GO
Isoform 2 (identifier: Q8NF50-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     927-958: Missing.

Note: No experimental confirmation available.
Show »
Length:2,067
Mass (Da):235,185
Checksum:i63FB02FCA204E1C8
GO
Isoform 3 (identifier: Q8NF50-3) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-68: Missing.

Show »
Length:2,031
Mass (Da):230,820
Checksum:i4BDDA98A79349281
GO
Isoform 4 (identifier: Q8NF50-4) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-68: Missing.
     927-958: Missing.

Note: No experimental confirmation available.
Show »
Length:1,999
Mass (Da):227,477
Checksum:i9D0A9F61AD502256
GO

Sequence cautioni

Q8NF50: The sequence AAG42221 differs from that shown. Reason: Frameshift at positions 2067 and 2083.Curated
Q8NF50: The sequence BAB84907 differs from that shown. Reason: Frameshift at position 1956.Curated
Q8NF50: The sequence CAI46160 differs from that shown. Reason: Erroneous initiation.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti22A → V in BAE45254 (Ref. 1) Curated1
Sequence conflicti470S → I in AAI30519 (PubMed:15489334).Curated1
Sequence conflicti470S → I in AAI43930 (PubMed:15489334).Curated1
Sequence conflicti600V → VV in CAI46160 (PubMed:17974005).Curated1
Sequence conflicti1751V → F in BAB84907 (Ref. 6) Curated1
Sequence conflicti1755V → F in BAB84907 (Ref. 6) Curated1
Sequence conflicti1927Y → F in AAI30519 (PubMed:15489334).Curated1
Sequence conflicti1927Y → F in AAI43930 (PubMed:15489334).Curated1
Sequence conflicti2029E → K in AAG42221 (PubMed:10729223).Curated1
Sequence conflicti2046L → F in AAG42221 (PubMed:10729223).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_03388897P → T1 PublicationCorresponds to variant dbSNP:rs529208Ensembl.1
Natural variantiVAR_059972169E → K. Corresponds to variant dbSNP:rs11789099Ensembl.1
Natural variantiVAR_033889237E → K. Corresponds to variant dbSNP:rs11789099Ensembl.1
Natural variantiVAR_033890413N → S1 PublicationCorresponds to variant dbSNP:rs10970979Ensembl.1
Natural variantiVAR_063753473K → R in AR-HIES. 1 PublicationCorresponds to variant dbSNP:rs112321280Ensembl.1
Natural variantiVAR_033891597A → V. Corresponds to variant dbSNP:rs17673268Ensembl.1
Natural variantiVAR_071964652I → V1 Publication1
Natural variantiVAR_0338921008R → W. Corresponds to variant dbSNP:rs16937932Ensembl.1
Natural variantiVAR_0338931970A → P1 PublicationCorresponds to variant dbSNP:rs34908836Ensembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0398381 – 68Missing in isoform 3 and isoform 4. 1 PublicationAdd BLAST68
Alternative sequenceiVSP_027373927 – 958Missing in isoform 2 and isoform 4. 1 PublicationAdd BLAST32

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AB191037 mRNA. Translation: BAE45254.1.
AL158832, AL161725 Genomic DNA. Translation: CAM22536.1.
AL161725, AL158832 Genomic DNA. Translation: CAM13234.1.
BC019102 mRNA. Translation: AAH19102.2.
BC112894 mRNA. Translation: AAI12895.1.
BC130518 mRNA. Translation: AAI30519.1.
BC143929 mRNA. Translation: AAI43930.1.
AL583913 mRNA. Translation: CAC29497.1.
AL832270 mRNA. Translation: CAI46160.1. Different initiation.
AK090429 mRNA. Translation: BAC03410.1.
AK074081 mRNA. Translation: BAB84907.1. Frameshift.
AK024436 mRNA. Translation: BAB15726.1.
AF194407 mRNA. Translation: AAG42221.1. Frameshift.
CCDSiCCDS55283.1. [Q8NF50-3]
CCDS55284.1. [Q8NF50-4]
CCDS6440.2. [Q8NF50-1]
RefSeqiNP_001177387.1. NM_001190458.1. [Q8NF50-4]
NP_001180465.1. NM_001193536.1. [Q8NF50-3]
NP_982272.2. NM_203447.3. [Q8NF50-1]
XP_011516347.1. XM_011518045.2. [Q8NF50-4]
XP_011516349.1. XM_011518047.2. [Q8NF50-3]
XP_011516350.1. XM_011518048.2. [Q8NF50-3]
XP_016870662.1. XM_017015173.1. [Q8NF50-3]
UniGeneiHs.132599.

Genome annotation databases

EnsembliENST00000432829; ENSP00000394888; ENSG00000107099. [Q8NF50-1]
ENST00000453981; ENSP00000408464; ENSG00000107099. [Q8NF50-3]
ENST00000469391; ENSP00000419438; ENSG00000107099. [Q8NF50-4]
GeneIDi81704.
KEGGihsa:81704.
UCSCiuc003zgf.2. human. [Q8NF50-1]

Keywords - Coding sequence diversityi

Alternative splicing, Chromosomal rearrangement, Polymorphism

Similar proteinsi

Entry informationi

Entry nameiDOCK8_HUMAN
AccessioniPrimary (citable) accession number: Q8NF50
Secondary accession number(s): A2A350
, A2BDF2, A4FU78, B7ZLP0, E9PH09, Q3MV16, Q5JPJ1, Q8TEP1, Q8WUY2, Q9BYJ5, Q9H1Q2, Q9H1Q3, Q9H308, Q9H7P2
Entry historyiIntegrated into UniProtKB/Swiss-Prot: July 3, 2003
Last sequence update: August 21, 2007
Last modified: October 25, 2017
This is version 143 of the entry and version 3 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. Human chromosome 9
    Human chromosome 9: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. SIMILARITY comments
    Index of protein domains and families