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Protein

Rho guanine nucleotide exchange factor 4

Gene

ARHGEF4

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -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

Keywordsi

Molecular functionGuanine-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

EuPathDBiHostDB:ENSG00000136002.16
HGNCiHGNC:684 ARHGEF4
MIMi605216 gene
neXtProtiNX_Q9NR80

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

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

EPDiQ9NR80
MaxQBiQ9NR80
PaxDbiQ9NR80
PeptideAtlasiQ9NR80
PRIDEiQ9NR80
ProteomicsDBi82293
82294 [Q9NR80-3]
82295 [Q9NR80-4]

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 Expressed in 179 organ(s), highest expression level in right frontal lobe
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

Binary interactionsi

WithEntry#Exp.IntActNotes
APCP250545EBI-13639160,EBI-727707

GO - Molecular functioni

Protein-protein interaction databases

BioGridi119114, 9 interactors
DIPiDIP-40814N
IntActiQ9NR80, 7 interactors
MINTiQ9NR80
STRINGi9606.ENSP00000316845

Structurei

Secondary structure

1690
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

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

Keywords - Domaini

SH3 domain

Phylogenomic databases

eggNOGiKOG3519 Eukaryota
ENOG410XT9S LUCA
GeneTreeiENSGT00930000150835
HOGENOMiHOG000237363
HOVERGENiHBG050568
InParanoidiQ9NR80
KOiK05769
PhylomeDBiQ9NR80
TreeFamiTF316832

Family and domain databases

CDDicd00160 RhoGEF, 1 hit
Gene3Di1.20.900.10, 1 hit
2.30.29.30, 1 hit
InterProiView protein in InterPro
IPR035899 DBL_dom_sf
IPR000219 DH-domain
IPR001331 GDS_CDC24_CS
IPR011993 PH-like_dom_sf
IPR001849 PH_domain
IPR036028 SH3-like_dom_sf
IPR001452 SH3_domain
PfamiView protein in Pfam
PF00169 PH, 1 hit
PF00621 RhoGEF, 1 hit
PF00018 SH3_1, 1 hit
SMARTiView protein in SMART
SM00233 PH, 1 hit
SM00325 RhoGEF, 1 hit
SM00326 SH3, 1 hit
SUPFAMiSSF48065 SSF48065, 1 hit
SSF50044 SSF50044, 1 hit
PROSITEiView protein in PROSITE
PS00741 DH_1, 1 hit
PS50010 DH_2, 1 hit
PS50003 PH_DOMAIN, 1 hit
PS50002 SH3, 1 hit

Sequences (3+)i

Sequence statusi: Complete.

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

This entry has 3 described isoforms and 8 potential isoforms that are computationally mapped.Show allAlign All

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

Computationally mapped potential isoform sequencesi

There are 8 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
E7EV07E7EV07_HUMAN
Rho guanine nucleotide exchange fac...
ARHGEF4
1,816Annotation score:
H0YCT6H0YCT6_HUMAN
Rho guanine nucleotide exchange fac...
ARHGEF4
287Annotation score:
E9PEM0E9PEM0_HUMAN
Rho guanine nucleotide exchange fac...
ARHGEF4
517Annotation score:
A0A087X0P1A0A087X0P1_HUMAN
Rho guanine nucleotide exchange fac...
ARHGEF4
630Annotation score:
A0A0C4DFY6A0A0C4DFY6_HUMAN
Rho guanine nucleotide exchange fac...
ARHGEF4
695Annotation score:
H0Y451H0Y451_HUMAN
Rho guanine nucleotide exchange fac...
ARHGEF4
372Annotation score:
A4QPB6A4QPB6_HUMAN
ARHGEF4 protein
ARHGEF4
192Annotation score:
A0A1B0GW00A0A1B0GW00_HUMAN
Rho guanine nucleotide exchange fac...
ARHGEF4
142Annotation score:

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 dbSNP:rs10188052Ensembl.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

Similar proteinsi

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, 9 interactors
DIPiDIP-40814N
IntActiQ9NR80, 7 interactors
MINTiQ9NR80
STRINGi9606.ENSP00000316845

PTM databases

iPTMnetiQ9NR80
PhosphoSitePlusiQ9NR80

Polymorphism and mutation databases

DMDMi229463003

Proteomic databases

EPDiQ9NR80
MaxQBiQ9NR80
PaxDbiQ9NR80
PeptideAtlasiQ9NR80
PRIDEiQ9NR80
ProteomicsDBi82293
82294 [Q9NR80-3]
82295 [Q9NR80-4]

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
EuPathDBiHostDB:ENSG00000136002.16
GeneCardsiARHGEF4
HGNCiHGNC:684 ARHGEF4
HPAiHPA018267
MIMi605216 gene
neXtProtiNX_Q9NR80
OpenTargetsiENSG00000136002
PharmGKBiPA24974
HUGEiSearch...
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG3519 Eukaryota
ENOG410XT9S LUCA
GeneTreeiENSGT00930000150835
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
PROiPR:Q9NR80
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000136002 Expressed in 179 organ(s), highest expression level in right frontal lobe
CleanExiHS_ARHGEF4
ExpressionAtlasiQ9NR80 baseline and differential
GenevisibleiQ9NR80 HS

Family and domain databases

CDDicd00160 RhoGEF, 1 hit
Gene3Di1.20.900.10, 1 hit
2.30.29.30, 1 hit
InterProiView protein in InterPro
IPR035899 DBL_dom_sf
IPR000219 DH-domain
IPR001331 GDS_CDC24_CS
IPR011993 PH-like_dom_sf
IPR001849 PH_domain
IPR036028 SH3-like_dom_sf
IPR001452 SH3_domain
PfamiView protein in Pfam
PF00169 PH, 1 hit
PF00621 RhoGEF, 1 hit
PF00018 SH3_1, 1 hit
SMARTiView protein in SMART
SM00233 PH, 1 hit
SM00325 RhoGEF, 1 hit
SM00326 SH3, 1 hit
SUPFAMiSSF48065 SSF48065, 1 hit
SSF50044 SSF50044, 1 hit
PROSITEiView protein in PROSITE
PS00741 DH_1, 1 hit
PS50010 DH_2, 1 hit
PS50003 PH_DOMAIN, 1 hit
PS50002 SH3, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiARHG4_HUMAN
AccessioniPrimary (citable) accession number: Q9NR80
Secondary accession number(s): Q9HDC6, Q9UPP0
Entry historyiIntegrated into UniProtKB/Swiss-Prot: September 27, 2004
Last sequence update: May 5, 2009
Last modified: November 7, 2018
This is version 156 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

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
UniProt is an ELIXIR core data resource
Main funding by: National Institutes of Health

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