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Protein

Rho guanine nucleotide exchange factor 4

Gene

ARHGEF4

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

Functioni

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.5 Publications

GO - Molecular functioni

  • guanyl-nucleotide exchange factor activity Source: UniProtKB
  • protein domain specific binding Source: UniProtKB
  • Rac guanyl-nucleotide exchange factor activity Source: UniProtKB
  • Rho guanyl-nucleotide exchange factor activity Source: Reactome

GO - Biological processi

  • filopodium assembly Source: UniProtKB
  • intracellular signal transduction Source: InterPro
  • lamellipodium assembly Source: UniProtKB
  • positive regulation of apoptotic process Source: Reactome
  • regulation of Rho protein signal transduction Source: InterPro
  • regulation of small GTPase mediated signal transduction Source: Reactome
Complete GO annotation...

Keywords - Molecular functioni

Guanine-nucleotide releasing factor

Enzyme and pathway databases

ReactomeiR-HSA-193648. NRAGE signals death through JNK.
R-HSA-194840. Rho GTPase cycle.
R-HSA-416482. G alpha (12/13) signalling events.
SIGNORiQ9NR80.

Names & Taxonomyi

Protein namesi
Recommended name:
Rho guanine nucleotide exchange factor 4
Alternative name(s):
APC-stimulated guanine nucleotide exchange factor 1
Short name:
Asef
Short name:
Asef1
Gene namesi
Name:ARHGEF4
Synonyms:KIAA1112
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 2

Organism-specific databases

HGNCiHGNC:684. ARHGEF4.

Subcellular locationi

Isoform 3 :

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Cell projection, Cytoplasm, Membrane

Pathology & Biotechi

Organism-specific databases

DisGeNETi50649.
OpenTargetsiENSG00000136002.
PharmGKBiPA24974.

Polymorphism and mutation databases

DMDMi229463003.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000809141 – 690Rho guanine nucleotide exchange factor 4Add BLAST690

Proteomic databases

MaxQBiQ9NR80.
PaxDbiQ9NR80.
PeptideAtlasiQ9NR80.
PRIDEiQ9NR80.

PTM databases

iPTMnetiQ9NR80.
PhosphoSitePlusiQ9NR80.

Expressioni

Tissue specificityi

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.3 Publications

Gene expression databases

BgeeiENSG00000136002.
CleanExiHS_ARHGEF4.
ExpressionAtlasiQ9NR80. baseline and differential.
GenevisibleiQ9NR80. HS.

Organism-specific databases

HPAiHPA018267.

Interactioni

Subunit structurei

Isoform 3 interacts with RHOA and RAC1, and (via ABR domain) with APC. Found in a complex consisting of ARHGEF4, APC and CTNNB1.1 Publication

GO - Molecular functioni

  • protein domain specific binding Source: UniProtKB

Protein-protein interaction databases

BioGridi119114. 7 interactors.
DIPiDIP-40814N.
IntActiQ9NR80. 4 interactors.
MINTiMINT-142950.
STRINGi9606.ENSP00000316845.

Structurei

Secondary structure

1690
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi187 – 191Combined sources5
Turni192 – 194Combined sources3
Beta strandi197 – 203Combined sources7
Beta strandi220 – 225Combined sources6
Beta strandi228 – 236Combined sources9
Beta strandi239 – 244Combined sources6
Helixi245 – 247Combined sources3
Beta strandi248 – 250Combined sources3
Helixi281 – 309Combined sources29
Helixi311 – 316Combined sources6
Turni318 – 320Combined sources3
Helixi323 – 330Combined sources8
Helixi333 – 350Combined sources18
Beta strandi353 – 355Combined sources3
Helixi356 – 358Combined sources3
Helixi362 – 367Combined sources6
Helixi369 – 372Combined sources4
Helixi375 – 393Combined sources19
Helixi396 – 409Combined sources14
Helixi416 – 439Combined sources24
Helixi448 – 484Combined sources37
Beta strandi485 – 487Combined sources3
Helixi493 – 496Combined sources4
Beta strandi500 – 509Combined sources10
Turni511 – 513Combined sources3
Beta strandi516 – 524Combined sources9
Beta strandi527 – 533Combined sources7
Beta strandi541 – 548Combined sources8
Turni549 – 551Combined sources3
Beta strandi553 – 556Combined sources4
Beta strandi559 – 561Combined sources3
Beta strandi571 – 576Combined sources6
Beta strandi578 – 580Combined sources3
Beta strandi583 – 590Combined sources8
Helixi591 – 609Combined sources19

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2DX1X-ray2.36A143-611[»]
2PZ1X-ray2.25A170-632[»]
3NMXX-ray2.30D/E/F170-194[»]
3NMZX-ray3.01C/D170-276[»]
ProteinModelPortaliQ9NR80.
SMRiQ9NR80.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiQ9NR80.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini194 – 253SH3PROSITE-ProRule annotationAdd BLAST60
Domaini284 – 468DHPROSITE-ProRule annotationAdd BLAST185
Domaini499 – 606PHPROSITE-ProRule annotationAdd BLAST108

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni73 – 126ABR (APC-binding region) domainAdd BLAST54

Domaini

In an autoinhibited form the SH3 domain binds intramolecularly to the DH domain, thus blocking the Rac-binding site.1 Publication

Sequence similaritiesi

Contains 1 DH (DBL-homology) domain.PROSITE-ProRule annotation
Contains 1 PH domain.PROSITE-ProRule annotation
Contains 1 SH3 domain.PROSITE-ProRule annotation

Keywords - Domaini

SH3 domain

Phylogenomic databases

eggNOGiKOG3519. Eukaryota.
ENOG410XT9S. LUCA.
GeneTreeiENSGT00760000118925.
HOGENOMiHOG000237363.
HOVERGENiHBG050568.
InParanoidiQ9NR80.
KOiK05769.
PhylomeDBiQ9NR80.
TreeFamiTF316832.

Family and domain databases

Gene3Di1.20.900.10. 1 hit.
2.30.29.30. 1 hit.
InterProiIPR000219. DH-domain.
IPR001331. GDS_CDC24_CS.
IPR011993. PH_dom-like.
IPR001849. PH_domain.
IPR001452. SH3_domain.
[Graphical view]
PfamiPF00169. PH. 1 hit.
PF00621. RhoGEF. 1 hit.
PF00018. SH3_1. 1 hit.
[Graphical view]
SMARTiSM00233. PH. 1 hit.
SM00325. RhoGEF. 1 hit.
SM00326. SH3. 1 hit.
[Graphical view]
SUPFAMiSSF48065. SSF48065. 1 hit.
SSF50044. SSF50044. 1 hit.
SSF50729. SSF50729. 1 hit.
PROSITEiPS00741. DH_1. 1 hit.
PS50010. DH_2. 1 hit.
PS50003. PH_DOMAIN. 1 hit.
PS50002. SH3. 1 hit.
[Graphical view]

Sequences (3)i

Sequence statusi: Complete.

This entry describes 3 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q9NR80-1) [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
MPWEEPAGEK PSCSHSQKAF HMEPAQKPCF TTDMVTWALL CISAETVRGE
60 70 80 90 100
APSQPRGIPH RSPVSVDDLW LEKTQRKKLQ KQAHVERRLH IGAVHKDGVK
110 120 130 140 150
CWRKTIITSP ESLNLPRRSH PLSQSAPTGL NHMGWPEHTP GTAMPDGALD
160 170 180 190 200
TAVCADEVGS EEDLYDDLHS SSHHYSHPGG GGEQLAINEL ISDGSVVCAE
210 220 230 240 250
ALWDHVTMDD QELGFKAGDV IEVMDATNRE WWWGRVADGE GWFPASFVRL
260 270 280 290 300
RVNQDEPADD DAPLAGNSGA EDGGAEAQSS KDQMRTNVIN EILSTERDYI
310 320 330 340 350
KHLRDICEGY VRQCRKRADM FSEEQLRTIF GNIEDIYRCQ KAFVKALEQR
360 370 380 390 400
FNRERPHLSE LGACFLEHQA DFQIYSEYCN NHPNACVELS RLTKLSKYVY
410 420 430 440 450
FFEACRLLQK MIDISLDGFL LTPVQKICKY PLQLAELLKY THPQHRDFKD
460 470 480 490 500
VEAALHAMKN VAQLINERKR RLENIDKIAQ WQSSIEDWEG EDLLVRSSEL
510 520 530 540 550
IYSGELTRVT QPQAKSQQRM FFLFDHQLIY CKKDLLRRDV LYYKGRLDMD
560 570 580 590 600
GLEVVDLEDG KDRDLHVSIK NAFRLHRGAT GDSHLLCTRK PEQKQRWLKA
610 620 630 640 650
FAREREQVQL DQETGFSITE LQRKQAMLNA SKQQVTGKPK AVGRPCYLTR
660 670 680 690
QKHPALPSNR PQQQVLVLAE PRRKPSTFWH SISRLAPFRK
Length:690
Mass (Da):79,067
Last modified:May 5, 2009 - v3
Checksum:i47E5B61C91950CD2
GO
Isoform 3 (identifier: Q9NR80-3) [UniParc]FASTAAdd to basket

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

Show »
Length:619
Mass (Da):71,130
Checksum:i2FEAB258AB1687C5
GO
Isoform 4 (identifier: Q9NR80-4) [UniParc]FASTAAdd to basket

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

Show »
Length:670
Mass (Da):76,420
Checksum:i90161166120CE37C
GO

Sequence cautioni

The sequence AAF79955 differs from that shown. Reason: Frameshift at positions 638 and 643.Curated
The sequence AAF79955 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated
The sequence BAA83064 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.Curated

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_05718733D → H.Corresponds to variant rs10188052dbSNPEnsembl.1
Natural variantiVAR_035970100K → R in a breast cancer sample; somatic mutation. 1 Publication1
Natural variantiVAR_035971441T → R in a breast cancer sample; somatic mutation. 1 Publication1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0116171 – 71Missing in isoform 3. 1 PublicationAdd BLAST71
Alternative sequenceiVSP_01161872 – 142EKTQR…HTPGT → MRPDGQQALDAVVRSFDCHS EAALRQRNDVIYCSLPRTAQ GIVQREDQLEVLVSLREVWG RRRGRDGTCTG in isoform 3. 1 PublicationAdd BLAST71
Alternative sequenceiVSP_037119641 – 690AVGRP…APFRK → GRRTAAPPPRLPGPYPADII PFSEPQSQAS in isoform 4. 1 PublicationAdd BLAST50

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF249745 mRNA. Translation: AAF79955.1. Sequence problems.
AB042199 mRNA. Translation: BAB11941.1.
AB029035 mRNA. Translation: BAA83064.1. Different initiation.
CCDSiCCDS2165.1. [Q9NR80-1]
CCDS42754.1. [Q9NR80-4]
RefSeqiNP_056135.2. NM_015320.3. [Q9NR80-1]
NP_127462.1. NM_032995.2. [Q9NR80-4]
UniGeneiHs.469935.

Genome annotation databases

EnsembliENST00000326016; ENSP00000316845; ENSG00000136002. [Q9NR80-1]
ENST00000355771; ENSP00000348017; ENSG00000136002. [Q9NR80-3]
ENST00000525839; ENSP00000432267; ENSG00000136002. [Q9NR80-4]
GeneIDi50649.
KEGGihsa:50649.
UCSCiuc002tsa.2. human. [Q9NR80-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF249745 mRNA. Translation: AAF79955.1. Sequence problems.
AB042199 mRNA. Translation: BAB11941.1.
AB029035 mRNA. Translation: BAA83064.1. Different initiation.
CCDSiCCDS2165.1. [Q9NR80-1]
CCDS42754.1. [Q9NR80-4]
RefSeqiNP_056135.2. NM_015320.3. [Q9NR80-1]
NP_127462.1. NM_032995.2. [Q9NR80-4]
UniGeneiHs.469935.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2DX1X-ray2.36A143-611[»]
2PZ1X-ray2.25A170-632[»]
3NMXX-ray2.30D/E/F170-194[»]
3NMZX-ray3.01C/D170-276[»]
ProteinModelPortaliQ9NR80.
SMRiQ9NR80.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi119114. 7 interactors.
DIPiDIP-40814N.
IntActiQ9NR80. 4 interactors.
MINTiMINT-142950.
STRINGi9606.ENSP00000316845.

PTM databases

iPTMnetiQ9NR80.
PhosphoSitePlusiQ9NR80.

Polymorphism and mutation databases

DMDMi229463003.

Proteomic databases

MaxQBiQ9NR80.
PaxDbiQ9NR80.
PeptideAtlasiQ9NR80.
PRIDEiQ9NR80.

Protocols and materials databases

DNASUi50649.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000326016; ENSP00000316845; ENSG00000136002. [Q9NR80-1]
ENST00000355771; ENSP00000348017; ENSG00000136002. [Q9NR80-3]
ENST00000525839; ENSP00000432267; ENSG00000136002. [Q9NR80-4]
GeneIDi50649.
KEGGihsa:50649.
UCSCiuc002tsa.2. human. [Q9NR80-1]

Organism-specific databases

CTDi50649.
DisGeNETi50649.
GeneCardsiARHGEF4.
HGNCiHGNC:684. ARHGEF4.
HPAiHPA018267.
MIMi605216. gene.
neXtProtiNX_Q9NR80.
OpenTargetsiENSG00000136002.
PharmGKBiPA24974.
HUGEiSearch...
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG3519. Eukaryota.
ENOG410XT9S. LUCA.
GeneTreeiENSGT00760000118925.
HOGENOMiHOG000237363.
HOVERGENiHBG050568.
InParanoidiQ9NR80.
KOiK05769.
PhylomeDBiQ9NR80.
TreeFamiTF316832.

Enzyme and pathway databases

ReactomeiR-HSA-193648. NRAGE signals death through JNK.
R-HSA-194840. Rho GTPase cycle.
R-HSA-416482. G alpha (12/13) signalling events.
SIGNORiQ9NR80.

Miscellaneous databases

ChiTaRSiARHGEF4. human.
EvolutionaryTraceiQ9NR80.
GeneWikiiARHGEF4.
GenomeRNAii50649.
PROiQ9NR80.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000136002.
CleanExiHS_ARHGEF4.
ExpressionAtlasiQ9NR80. baseline and differential.
GenevisibleiQ9NR80. HS.

Family and domain databases

Gene3Di1.20.900.10. 1 hit.
2.30.29.30. 1 hit.
InterProiIPR000219. DH-domain.
IPR001331. GDS_CDC24_CS.
IPR011993. PH_dom-like.
IPR001849. PH_domain.
IPR001452. SH3_domain.
[Graphical view]
PfamiPF00169. PH. 1 hit.
PF00621. RhoGEF. 1 hit.
PF00018. SH3_1. 1 hit.
[Graphical view]
SMARTiSM00233. PH. 1 hit.
SM00325. RhoGEF. 1 hit.
SM00326. SH3. 1 hit.
[Graphical view]
SUPFAMiSSF48065. SSF48065. 1 hit.
SSF50044. SSF50044. 1 hit.
SSF50729. SSF50729. 1 hit.
PROSITEiPS00741. DH_1. 1 hit.
PS50010. DH_2. 1 hit.
PS50003. PH_DOMAIN. 1 hit.
PS50002. SH3. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiARHG4_HUMAN
AccessioniPrimary (citable) accession number: Q9NR80
Secondary accession number(s): Q9HDC6, Q9UPP0
Entry historyi
Integrated into UniProtKB/Swiss-Prot: September 27, 2004
Last sequence update: May 5, 2009
Last modified: November 30, 2016
This is version 143 of the entry and version 3 of the sequence. [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

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 2
    Human chromosome 2: 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. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.