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Q9NR80

- ARHG4_HUMAN

UniProt

Q9NR80 - ARHG4_HUMAN

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Protein
Rho guanine nucleotide exchange factor 4
Gene
ARHGEF4, KIAA1112
Organism
Homo sapiens (Human)
Status
Reviewed - 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

  1. Rac guanyl-nucleotide exchange factor activity Source: UniProtKB
  2. guanyl-nucleotide exchange factor activity Source: UniProtKB
  3. protein binding Source: UniProtKB
  4. protein domain specific binding Source: UniProtKB

GO - Biological processi

  1. apoptotic signaling pathway Source: Reactome
  2. filopodium assembly Source: UniProtKB
  3. lamellipodium assembly Source: UniProtKB
  4. neurotrophin TRK receptor signaling pathway Source: Reactome
  5. positive regulation of apoptotic process Source: Reactome
  6. regulation of GTPase activity Source: GOC
  7. regulation of Rac GTPase activity Source: GOC
  8. regulation of small GTPase mediated signal transduction Source: Reactome
  9. small GTPase mediated signal transduction Source: Reactome
Complete GO annotation...

Keywords - Molecular functioni

Guanine-nucleotide releasing factor

Enzyme and pathway databases

ReactomeiREACT_11051. Rho GTPase cycle.
REACT_13638. NRAGE signals death through JNK.
REACT_18407. G alpha (12/13) signalling events.

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
ProteomesiUP000005640: Chromosome 2

Organism-specific databases

HGNCiHGNC:684. ARHGEF4.

Subcellular locationi

Isoform 3 : Cytoplasm. Cell projectionruffle membrane; Peripheral membrane protein; Cytoplasmic side Inferred
Note: Associated with membrane ruffles Inferred.1 Publication

GO - Cellular componenti

  1. cytosol Source: Reactome
  2. ruffle membrane Source: UniProtKB-SubCell
Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Cell projection, Cytoplasm, Membrane

Pathology & Biotechi

Organism-specific databases

PharmGKBiPA24974.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 690690Rho guanine nucleotide exchange factor 4
PRO_0000080914Add
BLAST

Proteomic databases

PaxDbiQ9NR80.
PRIDEiQ9NR80.

PTM databases

PhosphoSiteiQ9NR80.

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

ArrayExpressiQ9NR80.
BgeeiQ9NR80.
CleanExiHS_ARHGEF4.
GenevestigatoriQ9NR80.

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

Protein-protein interaction databases

BioGridi119114. 5 interactions.
DIPiDIP-40814N.
IntActiQ9NR80. 3 interactions.
MINTiMINT-142950.
STRINGi9606.ENSP00000316845.

Structurei

Secondary structure

Legend: HelixTurnBeta strand
Show more details
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Helixi187 – 1915
Turni192 – 1943
Beta strandi197 – 2037
Beta strandi220 – 2256
Beta strandi228 – 2369
Beta strandi239 – 2446
Helixi245 – 2473
Beta strandi248 – 2503
Helixi281 – 30929
Helixi311 – 3166
Turni318 – 3203
Helixi323 – 3308
Helixi333 – 35018
Beta strandi353 – 3553
Helixi356 – 3583
Helixi362 – 3676
Helixi369 – 3724
Helixi375 – 39319
Helixi396 – 40914
Helixi416 – 43924
Helixi448 – 48437
Beta strandi485 – 4873
Helixi493 – 4964
Beta strandi500 – 50910
Turni511 – 5133
Beta strandi516 – 5249
Beta strandi527 – 5337
Beta strandi541 – 5488
Turni549 – 5513
Beta strandi553 – 5564
Beta strandi559 – 5613
Beta strandi571 – 5766
Beta strandi578 – 5803
Beta strandi583 – 5908
Helixi591 – 60919

3D structure databases

Select the link destinations:
PDBe
RCSB PDB
PDBj
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
2DX1X-ray2.36A143-611[»]
2PZ1X-ray2.25A170-632[»]
3NMXX-ray2.30D/E/F170-194[»]
3NMZX-ray3.01C/D170-276[»]
ProteinModelPortaliQ9NR80.
SMRiQ9NR80. Positions 171-611.

Miscellaneous databases

EvolutionaryTraceiQ9NR80.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini194 – 25360SH3
Add
BLAST
Domaini284 – 468185DH
Add
BLAST
Domaini499 – 606108PH
Add
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni73 – 12654ABR (APC-binding region) domain
Add
BLAST

Domaini

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

Sequence similaritiesi

Contains 1 PH domain.
Contains 1 SH3 domain.

Keywords - Domaini

SH3 domain

Phylogenomic databases

eggNOGiCOG5422.
HOGENOMiHOG000237363.
HOVERGENiHBG050568.
KOiK05769.
OMAiINILIRP.
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.
IPR001849. PH_domain.
IPR011993. PH_like_dom.
IPR001452. SH3_domain.
[Graphical view]
PfamiPF00169. PH. 1 hit.
PF00621. RhoGEF. 1 hit.
PF14604. SH3_9. 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.
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. Align

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

MPWEEPAGEK PSCSHSQKAF HMEPAQKPCF TTDMVTWALL CISAETVRGE    50
APSQPRGIPH RSPVSVDDLW LEKTQRKKLQ KQAHVERRLH IGAVHKDGVK 100
CWRKTIITSP ESLNLPRRSH PLSQSAPTGL NHMGWPEHTP GTAMPDGALD 150
TAVCADEVGS EEDLYDDLHS SSHHYSHPGG GGEQLAINEL ISDGSVVCAE 200
ALWDHVTMDD QELGFKAGDV IEVMDATNRE WWWGRVADGE GWFPASFVRL 250
RVNQDEPADD DAPLAGNSGA EDGGAEAQSS KDQMRTNVIN EILSTERDYI 300
KHLRDICEGY VRQCRKRADM FSEEQLRTIF GNIEDIYRCQ KAFVKALEQR 350
FNRERPHLSE LGACFLEHQA DFQIYSEYCN NHPNACVELS RLTKLSKYVY 400
FFEACRLLQK MIDISLDGFL LTPVQKICKY PLQLAELLKY THPQHRDFKD 450
VEAALHAMKN VAQLINERKR RLENIDKIAQ WQSSIEDWEG EDLLVRSSEL 500
IYSGELTRVT QPQAKSQQRM FFLFDHQLIY CKKDLLRRDV LYYKGRLDMD 550
GLEVVDLEDG KDRDLHVSIK NAFRLHRGAT GDSHLLCTRK PEQKQRWLKA 600
FAREREQVQL DQETGFSITE LQRKQAMLNA SKQQVTGKPK AVGRPCYLTR 650
QKHPALPSNR PQQQVLVLAE PRRKPSTFWH SISRLAPFRK 690
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 AAF79955.1 differs from that shown. Reason: Frameshift at positions 638 and 643.
The sequence AAF79955.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.
The sequence BAA83064.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.

Natural variant

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti33 – 331D → H.
Corresponds to variant rs10188052 [ dbSNP | Ensembl ].
VAR_057187
Natural varianti100 – 1001K → R in a breast cancer sample; somatic mutation. 1 Publication
VAR_035970
Natural varianti441 – 4411T → R in a breast cancer sample; somatic mutation. 1 Publication
VAR_035971

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei1 – 7171Missing in isoform 3.
VSP_011617Add
BLAST
Alternative sequencei72 – 14271EKTQR…HTPGT → MRPDGQQALDAVVRSFDCHS EAALRQRNDVIYCSLPRTAQ GIVQREDQLEVLVSLREVWG RRRGRDGTCTG in isoform 3.
VSP_011618Add
BLAST
Alternative sequencei641 – 69050AVGRP…APFRK → GRRTAAPPPRLPGPYPADII PFSEPQSQAS in isoform 4.
VSP_037119Add
BLAST

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
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]
XP_005263743.1. XM_005263686.1. [Q9NR80-3]
XP_005275988.2. XM_005275931.2. [Q9NR80-3]
UniGeneiHs.469935.

Genome annotation databases

EnsembliENST00000326016; ENSP00000316845; ENSG00000136002. [Q9NR80-1]
ENST00000355771; ENSP00000348017; ENSG00000136002. [Q9NR80-3]
ENST00000392953; ENSP00000376680; ENSG00000136002. [Q9NR80-4]
ENST00000525839; ENSP00000432267; ENSG00000136002. [Q9NR80-4]
GeneIDi101930241.
50649.
KEGGihsa:101930241.
hsa:50649.
UCSCiuc002tsa.1. human. [Q9NR80-1]
uc002tsb.1. human. [Q9NR80-4]

Polymorphism databases

DMDMi229463003.

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
AF249745 mRNA. Translation: AAF79955.1 . Sequence problems.
AB042199 mRNA. Translation: BAB11941.1 .
AB029035 mRNA. Translation: BAA83064.1 . Different initiation.
CCDSi CCDS2165.1. [Q9NR80-1 ]
CCDS42754.1. [Q9NR80-4 ]
RefSeqi NP_056135.2. NM_015320.3. [Q9NR80-1 ]
NP_127462.1. NM_032995.2. [Q9NR80-4 ]
XP_005263743.1. XM_005263686.1. [Q9NR80-3 ]
XP_005275988.2. XM_005275931.2. [Q9NR80-3 ]
UniGenei Hs.469935.

3D structure databases

Select the link destinations:
PDBe
RCSB PDB
PDBj
Links Updated
Entry Method Resolution (Å) Chain Positions PDBsum
2DX1 X-ray 2.36 A 143-611 [» ]
2PZ1 X-ray 2.25 A 170-632 [» ]
3NMX X-ray 2.30 D/E/F 170-194 [» ]
3NMZ X-ray 3.01 C/D 170-276 [» ]
ProteinModelPortali Q9NR80.
SMRi Q9NR80. Positions 171-611.
ModBasei Search...
MobiDBi Search...

Protein-protein interaction databases

BioGridi 119114. 5 interactions.
DIPi DIP-40814N.
IntActi Q9NR80. 3 interactions.
MINTi MINT-142950.
STRINGi 9606.ENSP00000316845.

PTM databases

PhosphoSitei Q9NR80.

Polymorphism databases

DMDMi 229463003.

Proteomic databases

PaxDbi Q9NR80.
PRIDEi Q9NR80.

Protocols and materials databases

DNASUi 50649.
Structural Biology Knowledgebase Search...

Genome annotation databases

Ensembli ENST00000326016 ; ENSP00000316845 ; ENSG00000136002 . [Q9NR80-1 ]
ENST00000355771 ; ENSP00000348017 ; ENSG00000136002 . [Q9NR80-3 ]
ENST00000392953 ; ENSP00000376680 ; ENSG00000136002 . [Q9NR80-4 ]
ENST00000525839 ; ENSP00000432267 ; ENSG00000136002 . [Q9NR80-4 ]
GeneIDi 101930241.
50649.
KEGGi hsa:101930241.
hsa:50649.
UCSCi uc002tsa.1. human. [Q9NR80-1 ]
uc002tsb.1. human. [Q9NR80-4 ]

Organism-specific databases

CTDi 50649.
GeneCardsi GC02P131595.
HGNCi HGNC:684. ARHGEF4.
HPAi HPA018267.
MIMi 605216. gene.
neXtProti NX_Q9NR80.
PharmGKBi PA24974.
HUGEi Search...
GenAtlasi Search...

Phylogenomic databases

eggNOGi COG5422.
HOGENOMi HOG000237363.
HOVERGENi HBG050568.
KOi K05769.
OMAi INILIRP.
PhylomeDBi Q9NR80.
TreeFami TF316832.

Enzyme and pathway databases

Reactomei REACT_11051. Rho GTPase cycle.
REACT_13638. NRAGE signals death through JNK.
REACT_18407. G alpha (12/13) signalling events.

Miscellaneous databases

EvolutionaryTracei Q9NR80.
GeneWikii ARHGEF4.
GenomeRNAii 50649.
NextBioi 53194.
PROi Q9NR80.
SOURCEi Search...

Gene expression databases

ArrayExpressi Q9NR80.
Bgeei Q9NR80.
CleanExi HS_ARHGEF4.
Genevestigatori Q9NR80.

Family and domain databases

Gene3Di 1.20.900.10. 1 hit.
2.30.29.30. 1 hit.
InterProi IPR000219. DH-domain.
IPR001331. GDS_CDC24_CS.
IPR001849. PH_domain.
IPR011993. PH_like_dom.
IPR001452. SH3_domain.
[Graphical view ]
Pfami PF00169. PH. 1 hit.
PF00621. RhoGEF. 1 hit.
PF14604. SH3_9. 1 hit.
[Graphical view ]
SMARTi SM00233. PH. 1 hit.
SM00325. RhoGEF. 1 hit.
SM00326. SH3. 1 hit.
[Graphical view ]
SUPFAMi SSF48065. SSF48065. 1 hit.
SSF50044. SSF50044. 1 hit.
PROSITEi PS00741. DH_1. 1 hit.
PS50010. DH_2. 1 hit.
PS50003. PH_DOMAIN. 1 hit.
PS50002. SH3. 1 hit.
[Graphical view ]
ProtoNeti Search...

Publicationsi

« Hide 'large scale' publications
  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. Cited for: X-RAY CRYSTALLOGRAPHY (2.36 ANGSTROMS) OF 143-611, SH3 DOMAIN.
  10. Cited for: VARIANTS [LARGE SCALE ANALYSIS] ARG-100 AND ARG-441.

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: September 3, 2014
This is version 123 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

External Data

Dasty 3

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