ID   DOCK3_HUMAN             Reviewed;        2030 AA.
AC   Q8IZD9; O15017;
DT   03-JUL-2003, integrated into UniProtKB/Swiss-Prot.
DT   01-MAR-2003, sequence version 1.
DT   10-FEB-2021, entry version 150.
DE   RecName: Full=Dedicator of cytokinesis protein 3;
DE   AltName: Full=Modifier of cell adhesion;
DE   AltName: Full=Presenilin-binding protein;
DE            Short=PBP;
GN   Name=DOCK3; Synonyms=KIAA0299, MOCA;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RX   PubMed=10854253; DOI=10.1046/j.1471-4159.2000.0750109.x;
RA   Kashiwa A., Yoshida H., Lee S., Paladino T., Liu Y., Chen Q., Dargusch R.,
RA   Schubert D., Kimura H.;
RT   "Isolation and characterization of novel presenilin binding protein.";
RL   J. Neurochem. 75:109-116(2000).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA], AND CHROMOSOMAL REARRANGEMENT.
RX   PubMed=14569117; DOI=10.1136/jmg.40.10.733;
RA   De Silva M.G., Elliott K., Dahl H.-H.M., Fitzpatrick E., Wilcox S.,
RA   Delatycki M., Williamson R., Efron D., Lynch M., Forrest S.;
RT   "Disruption of a novel member of a sodium/hydrogen exchanger family and
RT   DOCK3 is associated with an attention deficit hyperactivity disorder-like
RT   phenotype.";
RL   J. Med. Genet. 40:733-740(2003).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 124-2030.
RC   TISSUE=Brain;
RX   PubMed=9205841; DOI=10.1093/dnares/4.2.141;
RA   Nagase T., Ishikawa K., Nakajima D., Ohira M., Seki N., Miyajima N.,
RA   Tanaka A., Kotani H., Nomura N., Ohara O.;
RT   "Prediction of the coding sequences of unidentified human genes. VII. The
RT   complete sequences of 100 new cDNA clones from brain which can code for
RT   large proteins in vitro.";
RL   DNA Res. 4:141-150(1997).
RN   [4]
RP   TISSUE SPECIFICITY.
RX   PubMed=11696419; DOI=10.1016/s0002-9440(10)63005-2;
RA   Chen Q., Yoshida H., Schubert D., Maher P., Mallory M., Masliah E.;
RT   "Presenilin binding protein is associated with neurofibrillary alterations
RT   in Alzheimer's disease and stimulates tau phosphorylation.";
RL   Am. J. Pathol. 159:1597-1602(2001).
RN   [5]
RP   NOMENCLATURE.
RX   PubMed=12432077; DOI=10.1242/jcs.00219;
RA   Cote J.-F., Vuori K.;
RT   "Identification of an evolutionarily conserved superfamily of DOCK180-
RT   related proteins with guanine nucleotide exchange activity.";
RL   J. Cell Sci. 115:4901-4913(2002).
RN   [6]
RP   INVOLVEMENT IN NEDIDHA, AND VARIANT NEDIDHA 128-GLN--GLN-2030 DEL.
RX   PubMed=28195318; DOI=10.1111/cge.12995;
RA   Helbig K.L., Mroske C., Moorthy D., Sajan S.A., Velinov M.;
RT   "Biallelic loss-of-function variants in DOCK3 cause muscle hypotonia,
RT   ataxia, and intellectual disability.";
RL   Clin. Genet. 92:430-433(2017).
RN   [7]
RP   INVOLVEMENT IN NEDIDHA.
RX   PubMed=29130632; DOI=10.1002/ajmg.a.38517;
RA   Iwata-Otsubo A., Ritter A.L., Weckselbatt B., Ryan N.R., Burgess D.,
RA   Conlin L.K., Izumi K.;
RT   "DOCK3-related neurodevelopmental syndrome: Biallelic intragenic deletion
RT   of DOCK3 in a boy with developmental delay and hypotonia.";
RL   Am. J. Med. Genet. A 176:241-245(2018).
RN   [8]
RP   INVOLVEMENT IN NEDIDHA, AND VARIANTS NEDIDHA GLN-392; ARG-1296 AND
RP   LEU-1674.
RX   PubMed=30976111; DOI=10.1038/s41431-019-0397-2;
RA   Wiltrout K., Ferrer A., van de Laar I., Namekata K., Harada T., Klee E.W.,
RA   Zimmerman M.T., Cousin M.A., Kempainen J.L., Babovic-Vuksanovic D.,
RA   van Slegtenhorst M.A., Aarts-Tesselaar C.D., Schnur R.E., Andrews M.,
RA   Shinawi M.;
RT   "Variants in DOCK3 cause developmental delay and hypotonia.";
RL   Eur. J. Hum. Genet. 0:0-0(2019).
CC   -!- FUNCTION: Potential guanine nucleotide exchange factor (GEF). GEF
CC       proteins activate some small GTPases by exchanging bound GDP for free
CC       GTP. Its interaction with presenilin proteins as well as its ability to
CC       stimulate Tau/MAPT phosphorylation suggest that it may be involved in
CC       Alzheimer disease. Ectopic expression in nerve cells decreases the
CC       secretion of amyloid-beta APBA1 protein and lowers the rate of cell-
CC       substratum adhesion, suggesting that it may affect the function of some
CC       small GTPase involved in the regulation of actin cytoskeleton or cell
CC       adhesion receptors (By similarity). {ECO:0000250}.
CC   -!- SUBUNIT: Interacts with presenilin proteins PSEN1 and PSEN2. Interacts
CC       with CRK (By similarity). {ECO:0000250}.
CC   -!- INTERACTION:
CC       Q8IZD9; Q13017-1: ARHGAP5; NbExp=2; IntAct=EBI-1752361, EBI-25409992;
CC       Q8IZD9; P49639: HOXA1; NbExp=3; IntAct=EBI-1752361, EBI-740785;
CC       Q8IZD9; P16333: NCK1; NbExp=3; IntAct=EBI-1752361, EBI-389883;
CC       Q8IZD9; Q9H8W4: PLEKHF2; NbExp=3; IntAct=EBI-1752361, EBI-742388;
CC   -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}.
CC   -!- TISSUE SPECIFICITY: In normal brains, it is localized in the neuropil,
CC       and occasionally in the pyramidal cells, while in Alzheimer disease
CC       brains, it is associated with neurofibrillary tangles.
CC       {ECO:0000269|PubMed:11696419}.
CC   -!- DOMAIN: The DOCKER domain may mediate some GEF activity. {ECO:0000250}.
CC   -!- DISEASE: Note=A chromosomal aberration involving DOCK3 has been found
CC       in a family with early-onset behavioral/developmental disorder with
CC       features of attention deficit-hyperactivity disorder and intellectual
CC       disability. Inversion inv(3)(p14:q21). The inversion disrupts DOCK3 and
CC       SLC9A9. {ECO:0000269|PubMed:14569117}.
CC   -!- DISEASE: Neurodevelopmental disorder with impaired intellectual
CC       development, hypotonia, and ataxia (NEDIDHA) [MIM:618292]: An autosomal
CC       recessive disease characterized by global developmental delay,
CC       hypotonia, ataxic gait, hyporeflexia, poor or absent speech, and
CC       variable and mild dysmorphic features. {ECO:0000269|PubMed:28195318,
CC       ECO:0000269|PubMed:29130632, ECO:0000269|PubMed:30976111}. Note=The
CC       disease is caused by variants affecting the gene represented in this
CC       entry.
CC   -!- SIMILARITY: Belongs to the DOCK family. {ECO:0000255|PROSITE-
CC       ProRule:PRU00983}.
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DR   EMBL; AY145303; AAN12301.1; -; mRNA.
DR   EMBL; AY254099; AAP80572.1; -; mRNA.
DR   EMBL; AB002297; BAA20759.1; -; mRNA.
DR   CCDS; CCDS46835.1; -.
DR   RefSeq; NP_004938.1; NM_004947.4.
DR   SMR; Q8IZD9; -.
DR   BioGRID; 108130; 11.
DR   IntAct; Q8IZD9; 36.
DR   STRING; 9606.ENSP00000266037; -.
DR   iPTMnet; Q8IZD9; -.
DR   PhosphoSitePlus; Q8IZD9; -.
DR   BioMuta; DOCK3; -.
DR   DMDM; 32469734; -.
DR   MassIVE; Q8IZD9; -.
DR   MaxQB; Q8IZD9; -.
DR   PaxDb; Q8IZD9; -.
DR   PeptideAtlas; Q8IZD9; -.
DR   PRIDE; Q8IZD9; -.
DR   ProteomicsDB; 71332; -.
DR   Antibodypedia; 46085; 76 antibodies.
DR   Ensembl; ENST00000266037; ENSP00000266037; ENSG00000088538.
DR   GeneID; 1795; -.
DR   KEGG; hsa:1795; -.
DR   UCSC; uc011bds.2; human.
DR   CTD; 1795; -.
DR   DisGeNET; 1795; -.
DR   GeneCards; DOCK3; -.
DR   HGNC; HGNC:2989; DOCK3.
DR   HPA; ENSG00000088538; Tissue enhanced (brain).
DR   MalaCards; DOCK3; -.
DR   MIM; 603123; gene.
DR   MIM; 618292; phenotype.
DR   neXtProt; NX_Q8IZD9; -.
DR   OpenTargets; ENSG00000088538; -.
DR   Orphanet; 528084; Non-specific syndromic intellectual disability.
DR   PharmGKB; PA27455; -.
DR   VEuPathDB; HostDB:ENSG00000088538.12; -.
DR   eggNOG; KOG1998; Eukaryota.
DR   GeneTree; ENSGT00940000155514; -.
DR   HOGENOM; CLU_000595_2_0_1; -.
DR   InParanoid; Q8IZD9; -.
DR   OMA; SMHFDAF; -.
DR   PhylomeDB; Q8IZD9; -.
DR   TreeFam; TF300423; -.
DR   PathwayCommons; Q8IZD9; -.
DR   Reactome; R-HSA-9032759; NTRK2 activates RAC1.
DR   Reactome; R-HSA-983231; Factors involved in megakaryocyte development and platelet production.
DR   SIGNOR; Q8IZD9; -.
DR   BioGRID-ORCS; 1795; 3 hits in 874 CRISPR screens.
DR   ChiTaRS; DOCK3; human.
DR   GeneWiki; Dock3; -.
DR   GenomeRNAi; 1795; -.
DR   Pharos; Q8IZD9; Tbio.
DR   PRO; PR:Q8IZD9; -.
DR   Proteomes; UP000005640; Chromosome 3.
DR   RNAct; Q8IZD9; protein.
DR   Bgee; ENSG00000088538; Expressed in frontal pole and 157 other tissues.
DR   Genevisible; Q8IZD9; HS.
DR   GO; GO:0005829; C:cytosol; IDA:HPA.
DR   GO; GO:0030676; F:Rac guanyl-nucleotide exchange factor activity; TAS:Reactome.
DR   GO; GO:0017124; F:SH3 domain binding; IEA:UniProtKB-KW.
DR   GO; GO:1903997; P:positive regulation of non-membrane spanning protein tyrosine kinase activity; TAS:Reactome.
DR   GO; GO:0007264; P:small GTPase mediated signal transduction; IEA:InterPro.
DR   CDD; cd08695; C2_Dock-B; 1.
DR   CDD; cd12048; SH3_DOCK3_B; 1.
DR   Gene3D; 1.20.1270.350; -; 1.
DR   Gene3D; 1.20.58.740; -; 1.
DR   Gene3D; 1.25.40.410; -; 1.
DR   Gene3D; 2.60.40.150; -; 1.
DR   InterPro; IPR016024; ARM-type_fold.
DR   InterPro; IPR037811; C2_Dock-B.
DR   InterPro; IPR035892; C2_domain_sf.
DR   InterPro; IPR027007; DHR-1_domain.
DR   InterPro; IPR027357; DHR-2.
DR   InterPro; IPR026791; DOCK.
DR   InterPro; IPR026800; DOCK3.
DR   InterPro; IPR035767; DOCK3_SH3.
DR   InterPro; IPR010703; DOCK_C.
DR   InterPro; IPR043161; DOCK_C_lobe_A.
DR   InterPro; IPR043162; DOCK_C_lobe_C.
DR   InterPro; IPR032376; DOCK_N.
DR   InterPro; IPR042455; DOCK_N_sub1.
DR   InterPro; IPR036028; SH3-like_dom_sf.
DR   InterPro; IPR001452; SH3_domain.
DR   PANTHER; PTHR45653; PTHR45653; 1.
DR   PANTHER; PTHR45653:SF4; PTHR45653:SF4; 1.
DR   Pfam; PF06920; DHR-2; 1.
DR   Pfam; PF14429; DOCK-C2; 1.
DR   Pfam; PF16172; DOCK_N; 1.
DR   Pfam; PF07653; SH3_2; 1.
DR   SMART; SM00326; SH3; 1.
DR   SUPFAM; SSF48371; SSF48371; 1.
DR   SUPFAM; SSF50044; SSF50044; 1.
DR   PROSITE; PS51650; C2_DOCK; 1.
DR   PROSITE; PS51651; DOCKER; 1.
DR   PROSITE; PS50002; SH3; 1.
PE   1: Evidence at protein level;
KW   Chromosomal rearrangement; Cytoplasm; Disease variant;
KW   Guanine-nucleotide releasing factor; Phosphoprotein; Reference proteome;
KW   SH3 domain; SH3-binding.
FT   CHAIN           1..2030
FT                   /note="Dedicator of cytokinesis protein 3"
FT                   /id="PRO_0000189988"
FT   DOMAIN          6..67
FT                   /note="SH3"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00192"
FT   DOMAIN          421..599
FT                   /note="C2 DOCK-type"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00983"
FT   DOMAIN          1228..1635
FT                   /note="DOCKER"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00984"
FT   MOTIF           1970..1976
FT                   /note="SH3-binding"
FT                   /evidence="ECO:0000255"
FT   COMPBIAS        1731..1768
FT                   /note="Ser-rich"
FT   MOD_RES         1658
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q8CIQ7"
FT   VARIANT         128..2030
FT                   /note="Missing (in NEDIDHA)"
FT                   /evidence="ECO:0000269|PubMed:28195318"
FT                   /id="VAR_081831"
FT   VARIANT         392
FT                   /note="R -> Q (in NEDIDHA; unknown pathological
FT                   significance; dbSNP:rs199600118)"
FT                   /evidence="ECO:0000269|PubMed:30976111"
FT                   /id="VAR_081832"
FT   VARIANT         1296
FT                   /note="K -> R (in NEDIDHA; unknown pathological
FT                   significance; dbSNP:rs201184598)"
FT                   /evidence="ECO:0000269|PubMed:30976111"
FT                   /id="VAR_081833"
FT   VARIANT         1674
FT                   /note="M -> L (in NEDIDHA; unknown pathological
FT                   significance; dbSNP:rs142515812)"
FT                   /evidence="ECO:0000269|PubMed:30976111"
FT                   /id="VAR_081834"
SQ   SEQUENCE   2030 AA;  233103 MW;  FF87E874B926C1C7 CRC64;
     MWTPTEEEKY GVVICSFRGS VPQGLVLEIG ETVQILEKCE GWYRGVSTKK PNVKGIFPAN
     YIHLKKAIVS NRGQYETVVP LEDSIVTEVT ATLQEWASLW KQLYVKHKVD LFYKLRHVMN
     ELIDLRRQLL SGHLTQDQVR EVKRHITVRL DWGNEHLGLD LVPRKDFEVV DSDQISVSDL
     YKMHLSSRQS VQQSTSQVDT MRPRHGETCR MPVPHHFFLS LKSFTYNTIG EDTDVFFSLY
     DMREGKQISE RFLVRLNKNG GPRNPEKIER MCALFTDLSS KDMKRDLYIV AHVIRIGRML
     LNDSKKGPPH LHYRRPYGCA VLSILDVLQS LTEVKEEKDF VLKVYTCNNE SEWSQIHENI
     IRKSSAKYSA PSASHGLIIS LQLLRGDMEQ IRRENPMIFN RGLAITRKLG FPDVIMPGDI
     RNDLYLTLEK GDFERGGKSV QKNIEVTMYV LYADGEILKD CISLGSGEPN RSSYHSFVLY
     HSNSPRWGEI IKLPIPIDRF RGSHLRFEFR HCSTKDKGEK KLFGFAFSTL MRDDGTTLSD
     DIHELYVYKC DENSTFNNHA LYLGLPCCKE DYNGCPNIPS SLIFQRSTKE SFFISTQLSS
     TKLTQNVDLL ALLKWKAFPD RIMDVLGRLR HVSGEEIVKF LQDILDTLFV ILDDNTEKYG
     LLVFQSLVFI INLLRDIKYF HFRPVMDTYI QKHFAGALAY KELIRCLKWY MDCSAELIRQ
     DHIQEAMRAL EYLFKFIVQS RILYSRATCG MEEEQFRSSI QELFQSIRFV LSLDSRNSET
     LLFTQAALLN SFPTIFDELL QMFTVQEVAE FVRGTLGSMP STVHIGQSMD VVKLQSIART
     VDSRLFSFSE SRRILLPVVL HHIHLHLRQQ KELLICSGIL GSIFSIVKTS SLEADVMEEV
     EMMVESLLDV LLQTLLTIMS KSHAQEAVRG QRCPQCTAEI TGEYVSCLLS LLRQMCDTHF
     QHLLDNFQSK DELKEFLLKI FCVFRNLMKM SVFPRDWMVM RLLTSNIIVT TVQYLSSALH
     KNFTETDFDF KVWNSYFSLA VLFINQPSLQ LEIITSAKRK KILDKYGDMR VMMAYELFSM
     WQNLGEHKIH FIPGMIGPFL GVTLVPQPEV RNIMIPIFHD MMDWEQRKNG NFKQVEAELI
     DKLDSMVSEG KGDESYRELF SLLTQLFGPY PSLLEKVEQE TWRETGISFV TSVTRLMERL
     LDYRDCMKGE ETENKKIGCT VNLMNFYKSE INKEEMYIRY IHKLCDMHLQ AENYTEAAFT
     LLLYCELLQW EDRPLREFLH YPSQTEWQRK EGLCRKIIHY FNKGKSWEFG IPLCRELACQ
     YESLYDYQSL SWIRKMEASY YDNIMEQQRL EPEFFRVGFY GRKFPFFLRN KEYVCRGHDY
     ERLEAFQQRM LSEFPQAVAM QHPNHPDDAI LQCDAQYLQI YAVTPIPDYV DVLQMDRVPD
     RVKSFYRVNN VRKFRYDRPF HKGPKDKENE FKSLWIERTT LTLTHSLPGI SRWFEVERRE
     LVEVSPLENA IQVVENKNQE LRSLISQYQH KQVHGNINLL SMCLNGVIDA AVNGGIARYQ
     EAFFDKDYIN KHPGDAEKIT QLKELMQEQV HVLGVGLAVH EKFVHPEMRP LHKKLIDQFQ
     MMRASLYHEF PGLDKLSPAC SGTSTPRGNV LASHSPMSPE SIKMTHRHSP MNLMGTGRHS
     SSSLSSHASS EAGNMVMLGD GSMGDAPEDL YHHMQLAYPN PRYQGSVTNV SVLSSSQASP
     SSSSLSSTHS APSQMITSAP SSARGSPSLP DKYRHAREMM LLLPTYRDRP SSAMYPAAIL
     ENGQPPNFQR ALFQQVVGAC KPCSDPNLSV AEKGHYSLHF DAFHHPLGDT PPALPARTLR
     KSPLHPIPAS PTSPQSGLDG SNSTLSGSAS SGVSSLSESN FGHSSEAPPR TDTMDSMPSQ
     AWNADEDLEP PYLPVHYSLS ESAVLDSIKA QPCRSHSAPG CVIPQDPMDP PALPPKPYHP
     RLPALEHDEG VLLREETERP RGLHRKAPLP PGSAKEEQAR MAWEHGRGEQ
//