ARHG4_HUMAN
ID ARHG4_HUMAN Reviewed; 690 AA.
AC Q9NR80; Q9HDC6; Q9UPP0;
DT 27-SEP-2004, integrated into UniProtKB/Swiss-Prot.
DT 05-MAY-2009, sequence version 3.
DT 03-AUG-2022, entry version 178.
DE RecName: Full=Rho guanine nucleotide exchange factor 4;
DE AltName: Full=APC-stimulated guanine nucleotide exchange factor 1;
DE Short=Asef;
DE Short=Asef1;
GN Name=ARHGEF4; Synonyms=KIAA1112;
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] (ISOFORM 1), AND TISSUE SPECIFICITY.
RX PubMed=10873612; DOI=10.1006/bbrc.2000.2925;
RA Thiesen S., Kuebart S., Ropers H.-H., Nothwang H.G.;
RT "Isolation of two novel human RhoGEFs, ARHGEF3 and ARHGEF4, in 3p13-21 and
RT 2q22.";
RL Biochem. Biophys. Res. Commun. 273:364-369(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3), FUNCTION, SUBCELLULAR LOCATION,
RP INTERACTION WITH APC; RHOA AND RAC1, AND IDENTIFICATION IN A COMPLEX WITH
RP APC AND CTNNB1.
RC TISSUE=Fetal brain;
RX PubMed=10947987; DOI=10.1126/science.289.5482.1194;
RA Kawasaki Y., Senda T., Ishidate T., Koyama R., Morishita T., Iwayama Y.,
RA Higuchi O., Akiyama T.;
RT "Asef, a link between the tumor suppressor APC and G-protein signaling.";
RL Science 289:1194-1197(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 4).
RC TISSUE=Brain;
RX PubMed=10470851; DOI=10.1093/dnares/6.3.197;
RA Kikuno R., Nagase T., Ishikawa K., Hirosawa M., Miyajima N., Tanaka A.,
RA Kotani H., Nomura N., Ohara O.;
RT "Prediction of the coding sequences of unidentified human genes. XIV. The
RT complete sequences of 100 new cDNA clones from brain which code for large
RT proteins in vitro.";
RL DNA Res. 6:197-205(1999).
RN [4]
RP SEQUENCE REVISION.
RX PubMed=12168954; DOI=10.1093/dnares/9.3.99;
RA Nakajima D., Okazaki N., Yamakawa H., Kikuno R., Ohara O., Nagase T.;
RT "Construction of expression-ready cDNA clones for KIAA genes: manual
RT curation of 330 KIAA cDNA clones.";
RL DNA Res. 9:99-106(2002).
RN [5]
RP FUNCTION.
RX PubMed=12598901; DOI=10.1038/ncb937;
RA Kawasaki Y., Sato R., Akiyama T.;
RT "Mutated APC and Asef are involved in the migration of colorectal tumour
RT cells.";
RL Nat. Cell Biol. 5:211-215(2003).
RN [6]
RP FUNCTION, AND TISSUE SPECIFICITY.
RX PubMed=17145773; DOI=10.1128/mcb.01608-06;
RA Hamann M.J., Lubking C.M., Luchini D.N., Billadeau D.D.;
RT "Asef2 functions as a Cdc42 exchange factor and is stimulated by the
RT release of an autoinhibitory module from a concealed C-terminal activation
RT element.";
RL Mol. Cell. Biol. 27:1380-1393(2007).
RN [7]
RP FUNCTION.
RX PubMed=17599059; DOI=10.1038/sj.onc.1210574;
RA Kawasaki Y., Sagara M., Shibata Y., Shirouzu M., Yokoyama S., Akiyama T.;
RT "Identification and characterization of Asef2, a guanine-nucleotide
RT exchange factor specific for Rac1 and Cdc42.";
RL Oncogene 26:7620-7627(2007).
RN [8]
RP FUNCTION, AND TISSUE SPECIFICITY.
RX PubMed=19893577; DOI=10.1038/embor.2009.233;
RA Kawasaki Y., Tsuji S., Muroya K., Furukawa S., Shibata Y., Okuno M.,
RA Ohwada S., Akiyama T.;
RT "The adenomatous polyposis coli-associated exchange factors Asef and Asef2
RT are required for adenoma formation in Apc(Min/+)mice.";
RL EMBO Rep. 10:1355-1362(2009).
RN [9]
RP X-RAY CRYSTALLOGRAPHY (2.36 ANGSTROMS) OF 143-611, AND SH3 DOMAIN.
RX PubMed=17190834; DOI=10.1074/jbc.c600234200;
RA Murayama K., Shirouzu M., Kawasaki Y., Kato-Murayama M.,
RA Hanawa-Suetsugu K., Sakamoto A., Katsura Y., Suenaga A., Toyama M.,
RA Terada T., Taiji M., Akiyama T., Yokoyama S.;
RT "Crystal structure of the rac activator, Asef, reveals its autoinhibitory
RT mechanism.";
RL J. Biol. Chem. 282:4238-4242(2007).
RN [10]
RP VARIANTS [LARGE SCALE ANALYSIS] ARG-100 AND ARG-441.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P.,
RA Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V.,
RA Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H.,
RA Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W.,
RA Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal cancers.";
RL Science 314:268-274(2006).
CC -!- FUNCTION: Acts as guanine nucleotide exchange factor (GEF) for RHOA,
CC RAC1 and CDC42 GTPases. Binding of APC may activate RAC1 GEF activity.
CC The APC-ARHGEF4 complex seems to be involved in cell migration as well
CC as in E-cadherin-mediated cell-cell adhesion. Required for MMP9 up-
CC regulation via the JNK signaling pathway in colorectal tumor cells.
CC Involved in tumor angiogenesis and may play a role in intestinal
CC adenoma formation and tumor progression. {ECO:0000269|PubMed:10947987,
CC ECO:0000269|PubMed:12598901, ECO:0000269|PubMed:17145773,
CC ECO:0000269|PubMed:17599059, ECO:0000269|PubMed:19893577}.
CC -!- SUBUNIT: Isoform 3 interacts with RHOA and RAC1, and (via ABR domain)
CC with APC. Found in a complex consisting of ARHGEF4, APC and CTNNB1.
CC {ECO:0000269|PubMed:10947987}.
CC -!- INTERACTION:
CC Q9NR80; O75031: HSF2BP; NbExp=3; IntAct=EBI-3389984, EBI-7116203;
CC Q9NR80-3; P25054: APC; NbExp=5; IntAct=EBI-13639160, EBI-727707;
CC -!- SUBCELLULAR LOCATION: [Isoform 3]: Cytoplasm. Cell projection, ruffle
CC membrane {ECO:0000305}; Peripheral membrane protein {ECO:0000305};
CC Cytoplasmic side {ECO:0000305}. Note=Associated with membrane ruffles.
CC {ECO:0000305}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=Q9NR80-1; Sequence=Displayed;
CC Name=3;
CC IsoId=Q9NR80-3; Sequence=VSP_011617, VSP_011618;
CC Name=4;
CC IsoId=Q9NR80-4; Sequence=VSP_037119;
CC -!- TISSUE SPECIFICITY: Expressed at high levels in the brain, skeletal
CC muscle and testis and at low levels in the kidney, lung, small
CC intestine, ovary and prostate. Expression is aberrantly enhanced in
CC most colorectal tumors. {ECO:0000269|PubMed:10873612,
CC ECO:0000269|PubMed:17145773, ECO:0000269|PubMed:19893577}.
CC -!- DOMAIN: In an autoinhibited form the SH3 domain binds intramolecularly
CC to the DH domain, thus blocking the Rac-binding site.
CC {ECO:0000269|PubMed:17190834}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAF79955.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
CC Sequence=AAF79955.1; Type=Frameshift; Evidence={ECO:0000305};
CC Sequence=BAA83064.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
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DR EMBL; AF249745; AAF79955.1; ALT_SEQ; mRNA.
DR EMBL; AB042199; BAB11941.1; -; mRNA.
DR EMBL; AB029035; BAA83064.1; ALT_INIT; mRNA.
DR CCDS; CCDS2165.1; -. [Q9NR80-1]
DR RefSeq; NP_056135.2; NM_015320.3. [Q9NR80-1]
DR RefSeq; NP_127462.1; NM_032995.2.
DR PDB; 2DX1; X-ray; 2.36 A; A=143-611.
DR PDB; 2PZ1; X-ray; 2.25 A; A=170-632.
DR PDB; 3NMX; X-ray; 2.30 A; D/E/F=170-194.
DR PDB; 3NMZ; X-ray; 3.01 A; C/D=170-276.
DR PDBsum; 2DX1; -.
DR PDBsum; 2PZ1; -.
DR PDBsum; 3NMX; -.
DR PDBsum; 3NMZ; -.
DR AlphaFoldDB; Q9NR80; -.
DR SMR; Q9NR80; -.
DR BioGRID; 119114; 70.
DR DIP; DIP-40814N; -.
DR IntAct; Q9NR80; 23.
DR MINT; Q9NR80; -.
DR STRING; 9606.ENSP00000316845; -.
DR ChEMBL; CHEMBL4296093; -.
DR iPTMnet; Q9NR80; -.
DR PhosphoSitePlus; Q9NR80; -.
DR BioMuta; ARHGEF4; -.
DR DMDM; 229463003; -.
DR EPD; Q9NR80; -.
DR jPOST; Q9NR80; -.
DR MassIVE; Q9NR80; -.
DR MaxQB; Q9NR80; -.
DR PaxDb; Q9NR80; -.
DR PeptideAtlas; Q9NR80; -.
DR PRIDE; Q9NR80; -.
DR ProteomicsDB; 82293; -. [Q9NR80-1]
DR ProteomicsDB; 82294; -. [Q9NR80-3]
DR ProteomicsDB; 82295; -. [Q9NR80-4]
DR ABCD; Q9NR80; 2 sequenced antibodies.
DR Antibodypedia; 18611; 186 antibodies from 31 providers.
DR DNASU; 50649; -.
DR Ensembl; ENST00000326016.10; ENSP00000316845.5; ENSG00000136002.20. [Q9NR80-1]
DR Ensembl; ENST00000355771.7; ENSP00000348017.3; ENSG00000136002.20. [Q9NR80-3]
DR GeneID; 50649; -.
DR KEGG; hsa:50649; -.
DR UCSC; uc002tsa.2; human. [Q9NR80-1]
DR CTD; 50649; -.
DR DisGeNET; 50649; -.
DR GeneCards; ARHGEF4; -.
DR HGNC; HGNC:684; ARHGEF4.
DR HPA; ENSG00000136002; Tissue enhanced (brain, skin).
DR MIM; 605216; gene.
DR neXtProt; NX_Q9NR80; -.
DR OpenTargets; ENSG00000136002; -.
DR PharmGKB; PA24974; -.
DR VEuPathDB; HostDB:ENSG00000136002; -.
DR eggNOG; KOG3519; Eukaryota.
DR GeneTree; ENSGT00940000164741; -.
DR HOGENOM; CLU_008436_2_0_1; -.
DR InParanoid; Q9NR80; -.
DR OMA; ERETQKH; -.
DR OrthoDB; 55078at2759; -.
DR PhylomeDB; Q9NR80; -.
DR TreeFam; TF316832; -.
DR PathwayCommons; Q9NR80; -.
DR Reactome; R-HSA-193648; NRAGE signals death through JNK.
DR Reactome; R-HSA-416482; G alpha (12/13) signalling events.
DR Reactome; R-HSA-8980692; RHOA GTPase cycle.
DR Reactome; R-HSA-9013148; CDC42 GTPase cycle.
DR Reactome; R-HSA-9013149; RAC1 GTPase cycle.
DR SignaLink; Q9NR80; -.
DR SIGNOR; Q9NR80; -.
DR BioGRID-ORCS; 50649; 11 hits in 1067 CRISPR screens.
DR ChiTaRS; ARHGEF4; human.
DR EvolutionaryTrace; Q9NR80; -.
DR GeneWiki; ARHGEF4; -.
DR GenomeRNAi; 50649; -.
DR Pharos; Q9NR80; Tbio.
DR PRO; PR:Q9NR80; -.
DR Proteomes; UP000005640; Chromosome 2.
DR RNAct; Q9NR80; protein.
DR Bgee; ENSG00000136002; Expressed in right frontal lobe and 163 other tissues.
DR ExpressionAtlas; Q9NR80; baseline and differential.
DR Genevisible; Q9NR80; HS.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0032587; C:ruffle membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005085; F:guanyl-nucleotide exchange factor activity; IMP:UniProtKB.
DR GO; GO:0019904; F:protein domain specific binding; IPI:UniProtKB.
DR GO; GO:0046847; P:filopodium assembly; IMP:UniProtKB.
DR GO; GO:0035556; P:intracellular signal transduction; IEA:InterPro.
DR GO; GO:0030032; P:lamellipodium assembly; IMP:UniProtKB.
DR GO; GO:0051056; P:regulation of small GTPase mediated signal transduction; TAS:Reactome.
DR CDD; cd00160; RhoGEF; 1.
DR Gene3D; 1.20.900.10; -; 1.
DR Gene3D; 2.30.29.30; -; 1.
DR IDEAL; IID00606; -.
DR InterPro; IPR035899; DBL_dom_sf.
DR InterPro; IPR000219; DH-domain.
DR InterPro; IPR001331; GDS_CDC24_CS.
DR InterPro; IPR011993; PH-like_dom_sf.
DR InterPro; IPR001849; PH_domain.
DR InterPro; IPR036028; SH3-like_dom_sf.
DR InterPro; IPR001452; SH3_domain.
DR Pfam; PF00169; PH; 1.
DR Pfam; PF00621; RhoGEF; 1.
DR Pfam; PF00018; SH3_1; 1.
DR SMART; SM00233; PH; 1.
DR SMART; SM00325; RhoGEF; 1.
DR SMART; SM00326; SH3; 1.
DR SUPFAM; SSF48065; SSF48065; 1.
DR SUPFAM; SSF50044; SSF50044; 1.
DR PROSITE; PS00741; DH_1; 1.
DR PROSITE; PS50010; DH_2; 1.
DR PROSITE; PS50003; PH_DOMAIN; 1.
DR PROSITE; PS50002; SH3; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cell membrane; Cell projection;
KW Cytoplasm; Guanine-nucleotide releasing factor; Membrane;
KW Reference proteome; SH3 domain.
FT CHAIN 1..690
FT /note="Rho guanine nucleotide exchange factor 4"
FT /id="PRO_0000080914"
FT DOMAIN 194..253
FT /note="SH3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00192"
FT DOMAIN 284..468
FT /note="DH"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00062"
FT DOMAIN 499..606
FT /note="PH"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00145"
FT REGION 73..126
FT /note="ABR (APC-binding region) domain"
FT REGION 113..145
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 257..282
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 113..130
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT VAR_SEQ 1..71
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:10947987"
FT /id="VSP_011617"
FT VAR_SEQ 72..142
FT /note="EKTQRKKLQKQAHVERRLHIGAVHKDGVKCWRKTIITSPESLNLPRRSHPLS
FT QSAPTGLNHMGWPEHTPGT -> MRPDGQQALDAVVRSFDCHSEAALRQRNDVIYCSLP
FT RTAQGIVQREDQLEVLVSLREVWGRRRGRDGTCTG (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:10947987"
FT /id="VSP_011618"
FT VAR_SEQ 641..690
FT /note="AVGRPCYLTRQKHPALPSNRPQQQVLVLAEPRRKPSTFWHSISRLAPFRK
FT -> GRRTAAPPPRLPGPYPADIIPFSEPQSQAS (in isoform 4)"
FT /evidence="ECO:0000303|PubMed:10470851"
FT /id="VSP_037119"
FT VARIANT 33
FT /note="D -> H (in dbSNP:rs10188052)"
FT /id="VAR_057187"
FT VARIANT 100
FT /note="K -> R (in a breast cancer sample; somatic
FT mutation)"
FT /evidence="ECO:0000269|PubMed:16959974"
FT /id="VAR_035970"
FT VARIANT 441
FT /note="T -> R (in a breast cancer sample; somatic
FT mutation)"
FT /evidence="ECO:0000269|PubMed:16959974"
FT /id="VAR_035971"
FT HELIX 187..191
FT /evidence="ECO:0007829|PDB:2PZ1"
FT TURN 192..194
FT /evidence="ECO:0007829|PDB:2PZ1"
FT STRAND 197..203
FT /evidence="ECO:0007829|PDB:2PZ1"
FT STRAND 220..225
FT /evidence="ECO:0007829|PDB:2PZ1"
FT STRAND 228..236
FT /evidence="ECO:0007829|PDB:2PZ1"
FT STRAND 239..244
FT /evidence="ECO:0007829|PDB:2PZ1"
FT HELIX 245..247
FT /evidence="ECO:0007829|PDB:2PZ1"
FT STRAND 248..250
FT /evidence="ECO:0007829|PDB:2PZ1"
FT HELIX 281..309
FT /evidence="ECO:0007829|PDB:2PZ1"
FT HELIX 311..316
FT /evidence="ECO:0007829|PDB:2PZ1"
FT TURN 318..320
FT /evidence="ECO:0007829|PDB:2PZ1"
FT HELIX 323..330
FT /evidence="ECO:0007829|PDB:2PZ1"
FT HELIX 333..350
FT /evidence="ECO:0007829|PDB:2PZ1"
FT STRAND 353..355
FT /evidence="ECO:0007829|PDB:2DX1"
FT HELIX 356..358
FT /evidence="ECO:0007829|PDB:2PZ1"
FT HELIX 362..367
FT /evidence="ECO:0007829|PDB:2PZ1"
FT HELIX 369..372
FT /evidence="ECO:0007829|PDB:2PZ1"
FT HELIX 375..393
FT /evidence="ECO:0007829|PDB:2PZ1"
FT HELIX 396..409
FT /evidence="ECO:0007829|PDB:2PZ1"
FT HELIX 416..439
FT /evidence="ECO:0007829|PDB:2PZ1"
FT HELIX 448..484
FT /evidence="ECO:0007829|PDB:2PZ1"
FT STRAND 485..487
FT /evidence="ECO:0007829|PDB:2DX1"
FT HELIX 493..496
FT /evidence="ECO:0007829|PDB:2PZ1"
FT STRAND 500..509
FT /evidence="ECO:0007829|PDB:2PZ1"
FT TURN 511..513
FT /evidence="ECO:0007829|PDB:2PZ1"
FT STRAND 516..524
FT /evidence="ECO:0007829|PDB:2PZ1"
FT STRAND 527..533
FT /evidence="ECO:0007829|PDB:2PZ1"
FT STRAND 541..548
FT /evidence="ECO:0007829|PDB:2PZ1"
FT TURN 549..551
FT /evidence="ECO:0007829|PDB:2PZ1"
FT STRAND 553..556
FT /evidence="ECO:0007829|PDB:2PZ1"
FT STRAND 559..561
FT /evidence="ECO:0007829|PDB:2PZ1"
FT STRAND 571..576
FT /evidence="ECO:0007829|PDB:2PZ1"
FT STRAND 578..580
FT /evidence="ECO:0007829|PDB:2PZ1"
FT STRAND 583..590
FT /evidence="ECO:0007829|PDB:2PZ1"
FT HELIX 591..609
FT /evidence="ECO:0007829|PDB:2PZ1"
SQ SEQUENCE 690 AA; 79067 MW; 47E5B61C91950CD2 CRC64;
MPWEEPAGEK PSCSHSQKAF HMEPAQKPCF TTDMVTWALL CISAETVRGE APSQPRGIPH
RSPVSVDDLW LEKTQRKKLQ KQAHVERRLH IGAVHKDGVK CWRKTIITSP ESLNLPRRSH
PLSQSAPTGL NHMGWPEHTP GTAMPDGALD TAVCADEVGS EEDLYDDLHS SSHHYSHPGG
GGEQLAINEL ISDGSVVCAE ALWDHVTMDD QELGFKAGDV IEVMDATNRE WWWGRVADGE
GWFPASFVRL RVNQDEPADD DAPLAGNSGA EDGGAEAQSS KDQMRTNVIN EILSTERDYI
KHLRDICEGY VRQCRKRADM FSEEQLRTIF GNIEDIYRCQ KAFVKALEQR FNRERPHLSE
LGACFLEHQA DFQIYSEYCN NHPNACVELS RLTKLSKYVY FFEACRLLQK MIDISLDGFL
LTPVQKICKY PLQLAELLKY THPQHRDFKD VEAALHAMKN VAQLINERKR RLENIDKIAQ
WQSSIEDWEG EDLLVRSSEL IYSGELTRVT QPQAKSQQRM FFLFDHQLIY CKKDLLRRDV
LYYKGRLDMD GLEVVDLEDG KDRDLHVSIK NAFRLHRGAT GDSHLLCTRK PEQKQRWLKA
FAREREQVQL DQETGFSITE LQRKQAMLNA SKQQVTGKPK AVGRPCYLTR QKHPALPSNR
PQQQVLVLAE PRRKPSTFWH SISRLAPFRK
