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Q9NR80 (ARHG4_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 119. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Rho guanine nucleotide exchange factor 4
Alternative name(s):
APC-stimulated guanine nucleotide exchange factor 1
Short name=Asef
Short name=Asef1
Gene names
Name:ARHGEF4
Synonyms:KIAA1112
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length690 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Acts as guanine nucleotide exchange factor (GEF) for RHOA, RAC1 and CDC42 GTPases. Binding of APC may activate RAC1 GEF activity. The APC-ARHGEF4 complex seems to be involved in cell migration as well as in E-cadherin-mediated cell-cell adhesion. Required for MMP9 up-regulation via the JNK signaling pathway in colorectal tumor cells. Involved in tumor angiogenesis and may play a role in intestinal adenoma formation and tumor progression. Ref.2 Ref.5 Ref.6 Ref.7 Ref.8

Subunit structure

Isoform 3 interacts with RHOA and RAC1, and (via ABR domain) with APC. Found in a complex consisting of ARHGEF4, APC and CTNNB1. Ref.2

Subcellular location

Isoform 3: Cytoplasm. Cell projectionruffle membrane; Peripheral membrane protein; Cytoplasmic side Probable. Note: Associated with membrane ruffles Probable. Ref.2

Tissue specificity

Expressed at high levels in the brain, skeletal muscle and testis and at low levels in the kidney, lung, small intestine, ovary and prostate. Expression is aberrantly enhanced in most colorectal tumors. Ref.1 Ref.6 Ref.8

Domain

In an autoinhibited form the SH3 domain binds intramolecularly to the DH domain, thus blocking the Rac-binding site (Ref.9). Ref.9

Sequence similarities

Contains 1 DH (DBL-homology) domain.

Contains 1 PH domain.

Contains 1 SH3 domain.

Sequence caution

The sequence AAF79955.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.

The sequence AAF79955.1 differs from that shown. Reason: Frameshift at positions 638 and 643.

The sequence BAA83064.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.

Ontologies

Keywords
   Cellular componentCell membrane
Cell projection
Cytoplasm
Membrane
   Coding sequence diversityAlternative splicing
Polymorphism
   DomainSH3 domain
   Molecular functionGuanine-nucleotide releasing factor
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processapoptotic signaling pathway

Traceable author statement. Source: Reactome

filopodium assembly

Inferred from mutant phenotype Ref.7. Source: UniProtKB

lamellipodium assembly

Inferred from mutant phenotype Ref.7. Source: UniProtKB

neurotrophin TRK receptor signaling pathway

Traceable author statement. Source: Reactome

positive regulation of apoptotic process

Traceable author statement. Source: Reactome

regulation of GTPase activity

Inferred from mutant phenotype Ref.7. Source: GOC

regulation of Rac GTPase activity

Inferred from mutant phenotype Ref.7. Source: GOC

regulation of small GTPase mediated signal transduction

Traceable author statement. Source: Reactome

small GTPase mediated signal transduction

Traceable author statement. Source: Reactome

   Cellular_componentcytosol

Traceable author statement. Source: Reactome

ruffle membrane

Inferred from electronic annotation. Source: UniProtKB-SubCell

   Molecular_functionRac guanyl-nucleotide exchange factor activity

Inferred from mutant phenotype Ref.7. Source: UniProtKB

guanyl-nucleotide exchange factor activity

Inferred from mutant phenotype Ref.7. Source: UniProtKB

protein domain specific binding

Inferred from physical interaction Ref.2. Source: UniProtKB

Complete GO annotation...

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: Q9NR80-1)

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.
Isoform 3 (identifier: Q9NR80-3)

The sequence of this isoform differs from the canonical sequence as follows:
     1-71: Missing.
     72-142: EKTQRKKLQK...MGWPEHTPGT → MRPDGQQALD...RRGRDGTCTG
Isoform 4 (identifier: Q9NR80-4)

The sequence of this isoform differs from the canonical sequence as follows:
     641-690: AVGRPCYLTR...SISRLAPFRK → GRRTAAPPPRLPGPYPADIIPFSEPQSQAS

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 690690Rho guanine nucleotide exchange factor 4
PRO_0000080914

Regions

Domain194 – 25360SH3
Domain284 – 468185DH
Domain499 – 606108PH
Region73 – 12654ABR (APC-binding region) domain

Natural variations

Alternative sequence1 – 7171Missing in isoform 3.
VSP_011617
Alternative sequence72 – 14271EKTQR…HTPGT → MRPDGQQALDAVVRSFDCHS EAALRQRNDVIYCSLPRTAQ GIVQREDQLEVLVSLREVWG RRRGRDGTCTG in isoform 3.
VSP_011618
Alternative sequence641 – 69050AVGRP…APFRK → GRRTAAPPPRLPGPYPADII PFSEPQSQAS in isoform 4.
VSP_037119
Natural variant331D → H.
Corresponds to variant rs10188052 [ dbSNP | Ensembl ].
VAR_057187
Natural variant1001K → R in a breast cancer sample; somatic mutation. Ref.10
VAR_035970
Natural variant4411T → R in a breast cancer sample; somatic mutation. Ref.10
VAR_035971

Secondary structure

................................................................ 690
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified May 5, 2009. Version 3.
Checksum: 47E5B61C91950CD2

FASTA69079,067
        10         20         30         40         50         60 
MPWEEPAGEK PSCSHSQKAF HMEPAQKPCF TTDMVTWALL CISAETVRGE APSQPRGIPH 

        70         80         90        100        110        120 
RSPVSVDDLW LEKTQRKKLQ KQAHVERRLH IGAVHKDGVK CWRKTIITSP ESLNLPRRSH 

       130        140        150        160        170        180 
PLSQSAPTGL NHMGWPEHTP GTAMPDGALD TAVCADEVGS EEDLYDDLHS SSHHYSHPGG 

       190        200        210        220        230        240 
GGEQLAINEL ISDGSVVCAE ALWDHVTMDD QELGFKAGDV IEVMDATNRE WWWGRVADGE 

       250        260        270        280        290        300 
GWFPASFVRL RVNQDEPADD DAPLAGNSGA EDGGAEAQSS KDQMRTNVIN EILSTERDYI 

       310        320        330        340        350        360 
KHLRDICEGY VRQCRKRADM FSEEQLRTIF GNIEDIYRCQ KAFVKALEQR FNRERPHLSE 

       370        380        390        400        410        420 
LGACFLEHQA DFQIYSEYCN NHPNACVELS RLTKLSKYVY FFEACRLLQK MIDISLDGFL 

       430        440        450        460        470        480 
LTPVQKICKY PLQLAELLKY THPQHRDFKD VEAALHAMKN VAQLINERKR RLENIDKIAQ 

       490        500        510        520        530        540 
WQSSIEDWEG EDLLVRSSEL IYSGELTRVT QPQAKSQQRM FFLFDHQLIY CKKDLLRRDV 

       550        560        570        580        590        600 
LYYKGRLDMD GLEVVDLEDG KDRDLHVSIK NAFRLHRGAT GDSHLLCTRK PEQKQRWLKA 

       610        620        630        640        650        660 
FAREREQVQL DQETGFSITE LQRKQAMLNA SKQQVTGKPK AVGRPCYLTR QKHPALPSNR 

       670        680        690 
PQQQVLVLAE PRRKPSTFWH SISRLAPFRK 

« Hide

Isoform 3 [UniParc].

Checksum: 2FEAB258AB1687C5
Show »

FASTA61971,130
Isoform 4 [UniParc].

Checksum: 90161166120CE37C
Show »

FASTA67076,420

References

« Hide 'large scale' references
[1]"Isolation of two novel human RhoGEFs, ARHGEF3 and ARHGEF4, in 3p13-21 and 2q22."
Thiesen S., Kuebart S., Ropers H.-H., Nothwang H.G.
Biochem. Biophys. Res. Commun. 273:364-369(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY.
[2]"Asef, a link between the tumor suppressor APC and G-protein signaling."
Kawasaki Y., Senda T., Ishidate T., Koyama R., Morishita T., Iwayama Y., Higuchi O., Akiyama T.
Science 289:1194-1197(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3), FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH APC; RHOA AND RAC1, IDENTIFICATION IN A COMPLEX WITH APC AND CTNNB1.
Tissue: Fetal brain.
[3]"Prediction of the coding sequences of unidentified human genes. XIV. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro."
Kikuno R., Nagase T., Ishikawa K., Hirosawa M., Miyajima N., Tanaka A., Kotani H., Nomura N., Ohara O.
DNA Res. 6:197-205(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 4).
Tissue: Brain.
[4]"Construction of expression-ready cDNA clones for KIAA genes: manual curation of 330 KIAA cDNA clones."
Nakajima D., Okazaki N., Yamakawa H., Kikuno R., Ohara O., Nagase T.
DNA Res. 9:99-106(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: SEQUENCE REVISION.
[5]"Mutated APC and Asef are involved in the migration of colorectal tumour cells."
Kawasaki Y., Sato R., Akiyama T.
Nat. Cell Biol. 5:211-215(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[6]"Asef2 functions as a Cdc42 exchange factor and is stimulated by the release of an autoinhibitory module from a concealed C-terminal activation element."
Hamann M.J., Lubking C.M., Luchini D.N., Billadeau D.D.
Mol. Cell. Biol. 27:1380-1393(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, TISSUE SPECIFICITY.
[7]"Identification and characterization of Asef2, a guanine-nucleotide exchange factor specific for Rac1 and Cdc42."
Kawasaki Y., Sagara M., Shibata Y., Shirouzu M., Yokoyama S., Akiyama T.
Oncogene 26:7620-7627(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[8]"The adenomatous polyposis coli-associated exchange factors Asef and Asef2 are required for adenoma formation in Apc(Min/+)mice."
Kawasaki Y., Tsuji S., Muroya K., Furukawa S., Shibata Y., Okuno M., Ohwada S., Akiyama T.
EMBO Rep. 10:1355-1362(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, TISSUE SPECIFICITY.
[9]"Crystal structure of the rac activator, Asef, reveals its autoinhibitory mechanism."
Murayama K., Shirouzu M., Kawasaki Y., Kato-Murayama M., Hanawa-Suetsugu K., Sakamoto A., Katsura Y., Suenaga A., Toyama M., Terada T., Taiji M., Akiyama T., Yokoyama S.
J. Biol. Chem. 282:4238-4242(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.36 ANGSTROMS) OF 143-611, SH3 DOMAIN.
[10]"The consensus coding sequences of human breast and colorectal cancers."
Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V. expand/collapse author list , Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W., Velculescu V.E.
Science 314:268-274(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS [LARGE SCALE ANALYSIS] ARG-100 AND ARG-441.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AF249745 mRNA. Translation: AAF79955.1. Sequence problems.
AB042199 mRNA. Translation: BAB11941.1.
AB029035 mRNA. Translation: BAA83064.1. Different initiation.
RefSeqNP_056135.2. NM_015320.3.
NP_127462.1. NM_032995.2.
XP_005263743.1. XM_005263686.1.
XP_005275988.2. XM_005275931.2.
UniGeneHs.469935.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
2DX1X-ray2.36A143-611[»]
2PZ1X-ray2.25A170-632[»]
3NMXX-ray2.30D/E/F170-194[»]
3NMZX-ray3.01C/D170-276[»]
ProteinModelPortalQ9NR80.
SMRQ9NR80. Positions 171-611.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid119114. 5 interactions.
DIPDIP-40814N.
IntActQ9NR80. 3 interactions.
MINTMINT-142950.
STRING9606.ENSP00000316845.

PTM databases

PhosphoSiteQ9NR80.

Polymorphism databases

DMDM229463003.

Proteomic databases

PaxDbQ9NR80.
PRIDEQ9NR80.

Protocols and materials databases

DNASU50649.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000326016; ENSP00000316845; ENSG00000136002. [Q9NR80-1]
ENST00000355771; ENSP00000348017; ENSG00000136002. [Q9NR80-3]
ENST00000392953; ENSP00000376680; ENSG00000136002. [Q9NR80-4]
ENST00000525839; ENSP00000432267; ENSG00000136002. [Q9NR80-4]
GeneID101930241.
50649.
KEGGhsa:50649.
UCSCuc002tsa.1. human. [Q9NR80-1]
uc002tsb.1. human. [Q9NR80-4]

Organism-specific databases

CTD50649.
GeneCardsGC02P131595.
HGNCHGNC:684. ARHGEF4.
HPAHPA018267.
MIM605216. gene.
neXtProtNX_Q9NR80.
PharmGKBPA24974.
HUGESearch...
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG5422.
HOGENOMHOG000237363.
HOVERGENHBG050568.
KOK05769.
PhylomeDBQ9NR80.
TreeFamTF316832.

Enzyme and pathway databases

ReactomeREACT_111102. Signal Transduction.

Gene expression databases

ArrayExpressQ9NR80.
BgeeQ9NR80.
CleanExHS_ARHGEF4.
GenevestigatorQ9NR80.

Family and domain databases

Gene3D1.20.900.10. 1 hit.
2.30.29.30. 1 hit.
InterProIPR000219. DH-domain.
IPR001331. GDS_CDC24_CS.
IPR011993. PH_like_dom.
IPR001849. Pleckstrin_homology.
IPR001452. SH3_domain.
[Graphical view]
PfamPF00169. PH. 1 hit.
PF00621. RhoGEF. 1 hit.
[Graphical view]
SMARTSM00233. PH. 1 hit.
SM00325. RhoGEF. 1 hit.
SM00326. SH3. 1 hit.
[Graphical view]
SUPFAMSSF48065. SSF48065. 1 hit.
SSF50044. SSF50044. 1 hit.
PROSITEPS00741. DH_1. 1 hit.
PS50010. DH_2. 1 hit.
PS50003. PH_DOMAIN. 1 hit.
PS50002. SH3. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

EvolutionaryTraceQ9NR80.
GeneWikiARHGEF4.
GenomeRNAi50649.
NextBio53194.
PROQ9NR80.
SOURCESearch...

Entry information

Entry nameARHG4_HUMAN
AccessionPrimary (citable) accession number: Q9NR80
Secondary accession number(s): Q9HDC6, Q9UPP0
Entry history
Integrated into UniProtKB/Swiss-Prot: September 27, 2004
Last sequence update: May 5, 2009
Last modified: April 16, 2014
This is version 119 of the entry and version 3 of the sequence. [Complete history]
Entry statusReviewed (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.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 2

Human chromosome 2: entries, gene names and cross-references to MIM