Q9NR80 (ARHG4_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

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 names

Name:	ARHGEF4
Synonyms:	KIAA1112

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	690 AA.
Sequence status	Complete.
Protein existence	Evidence 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 projection › ruffle 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
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 component	Cell membrane Cell projection Cytoplasm Membrane
Coding sequence diversity	Alternative splicing Polymorphism
Domain	SH3 domain
Molecular function	Guanine-nucleotide releasing factor
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	apoptotic process 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 nerve growth factor receptor signaling pathway Traceable author statement. Source: Reactome regulation of Rho protein signal transduction Inferred from electronic annotation. Source: InterPro regulation of small GTPase mediated signal transduction Traceable author statement. Source: Reactome small GTPase mediated signal transduction Traceable author statement. Source: Reactome
Cellular_component	cytosol Traceable author statement. Source: Reactome ruffle membrane Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	Rac guanyl-nucleotide exchange factor activity Inferred from mutant phenotype Ref.7. Source: UniProtKB phospholipid binding Inferred from electronic annotation. Source: InterPro
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 key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 690

690

Rho guanine nucleotide exchange factor 4

PRO_0000080914

Regions

Domain

194 – 253

60

SH3

Domain

284 – 468

185

DH

Domain

499 – 606

108

PH

Region

73 – 126

54

ABR (APC-binding region) domain

Natural variations

Alternative sequence

1 – 71

71

Missing in isoform 3.

VSP_011617

Alternative sequence

72 – 142

71

EKTQR…HTPGT → MRPDGQQALDAVVRSFDCHS EAALRQRNDVIYCSLPRTAQ GIVQREDQLEVLVSLREVWG RRRGRDGTCTG in isoform 3.

VSP_011618

Alternative sequence

641 – 690

50

AVGRP…APFRK → GRRTAAPPPRLPGPYPADII PFSEPQSQAS in isoform 4.

VSP_037119

Natural variant

33

1

D → H.
Corresponds to variant rs10188052 [ dbSNP | Ensembl ].

VAR_057187

Natural variant

100

1

K → R in a breast cancer sample; somatic mutation. Ref.9

VAR_035970

Natural variant

441

1

T → R in a breast cancer sample; somatic mutation. Ref.9

VAR_035971

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

690

Helix Strand Turn

Details...

Helix

187 – 191

5

Turn

192 – 194

3

Beta strand

197 – 203

7

Beta strand

220 – 225

6

Beta strand

228 – 236

9

Beta strand

239 – 244

6

Helix

245 – 247

3

Beta strand

248 – 250

3

Helix

281 – 309

29

Helix

311 – 316

6

Turn

318 – 320

3

Helix

323 – 330

8

Helix

333 – 350

18

Beta strand

353 – 355

3

Helix

356 – 358

3

Helix

362 – 367

6

Helix

369 – 372

4

Helix

375 – 393

19

Helix

396 – 409

14

Helix

416 – 439

24

Helix

448 – 484

37

Beta strand

485 – 487

3

Helix

493 – 496

4

Beta strand

500 – 509

10

Turn

511 – 513

3

Beta strand

516 – 524

9

Beta strand

527 – 533

7

Beta strand

541 – 548

8

Turn

549 – 551

3

Beta strand

553 – 556

4

Beta strand

559 – 561

3

Beta strand

571 – 576

6

Beta strand

578 – 580

3

Beta strand

583 – 590

8

Helix

591 – 609

19

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified May 5, 2009. Version 3. Checksum: 47E5B61C91950CD2	FASTA	690	79,067
	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
	Isoform 3 [UniParc]. Checksum: 2FEAB258AB1687C5	FASTA	619	71,130
	10 20 30 40 50 60 MRPDGQQALD AVVRSFDCHS EAALRQRNDV IYCSLPRTAQ GIVQREDQLE VLVSLREVWG 70 80 90 100 110 120 RRRGRDGTCT GAMPDGALDT AVCADEVGSE EDLYDDLHSS SHHYSHPGGG GEQLAINELI 130 140 150 160 170 180 SDGSVVCAEA LWDHVTMDDQ ELGFKAGDVI EVMDATNREW WWGRVADGEG WFPASFVRLR 190 200 210 220 230 240 VNQDEPADDD APLAGNSGAE DGGAEAQSSK DQMRTNVINE ILSTERDYIK HLRDICEGYV 250 260 270 280 290 300 RQCRKRADMF SEEQLRTIFG NIEDIYRCQK AFVKALEQRF NRERPHLSEL GACFLEHQAD 310 320 330 340 350 360 FQIYSEYCNN HPNACVELSR LTKLSKYVYF FEACRLLQKM IDISLDGFLL TPVQKICKYP 370 380 390 400 410 420 LQLAELLKYT HPQHRDFKDV EAALHAMKNV AQLINERKRR LENIDKIAQW QSSIEDWEGE 430 440 450 460 470 480 DLLVRSSELI YSGELTRVTQ PQAKSQQRMF FLFDHQLIYC KKDLLRRDVL YYKGRLDMDG 490 500 510 520 530 540 LEVVDLEDGK DRDLHVSIKN AFRLHRGATG DSHLLCTRKP EQKQRWLKAF AREREQVQLD 550 560 570 580 590 600 QETGFSITEL QRKQAMLNAS KQQVTGKPKA VGRPCYLTRQ KHPALPSNRP QQQVLVLAEP 610 RRKPSTFWHS ISRLAPFRK
	Isoform 4 [UniParc]. Checksum: 90161166120CE37C	FASTA	670	76,420
	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 GRRTAAPPPR LPGPYPADII 670 PFSEPQSQAS

References

	« Hide 'large scale' referencesShow '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]	"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. , 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.

IPI

IPI00022186.
IPI00154201.
IPI00470754.

RefSeq

NP_056135.2. NM_015320.2.
NP_127462.1. NM_032995.1.

UniGene

Hs.469935.

3D structure databases

PDBe
RCSB PDB
PDBj

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	[»]

ProteinModelPortal

Q9NR80.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-40814N.

IntAct

Q9NR80. 2 interactions.

STRING

9606.ENSP00000316845.

PTM databases

PhosphoSite

Q9NR80.

Polymorphism databases

DMDM

229463003.

Proteomic databases

PaxDb

Q9NR80.

PRIDE

Q9NR80.

Protocols and materials databases

DNASU

50649.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000326016; ENSP00000316845; ENSG00000136002.
ENST00000355771; ENSP00000348017; ENSG00000136002.
ENST00000392953; ENSP00000376680; ENSG00000136002.
ENST00000525839; ENSP00000432267; ENSG00000136002.

GeneID

50649.

KEGG

hsa:50649.

UCSC

uc002tsa.1. human.
uc002tsb.1. human.

Organism-specific databases

CTD

50649.

GeneCards

GC02P131595.

HGNC

HGNC:684. ARHGEF4.

HPA

HPA018267.

MIM

605216. gene.

neXtProt

NX_Q9NR80.

PharmGKB

PA24974.

HUGE

Search...

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG5422.

HOGENOM

HOG000237363.

HOVERGEN

HBG050568.

KO

K05769.

Enzyme and pathway databases

Reactome

REACT_111102. Signal Transduction.

Gene expression databases

ArrayExpress

Q9NR80.

Bgee

Q9NR80.

CleanEx

HS_ARHGEF4.

Genevestigator

Q9NR80.

GermOnline

ENSG00000136002. Homo sapiens.

Family and domain databases

Gene3D

1.20.900.10. 1 hit.
2.30.29.30. 1 hit.

InterPro

IPR000219. DH-domain.
IPR001331. GDS_CDC24_CS.
IPR011993. PH_like_dom.
IPR001849. Pleckstrin_homology.
IPR001452. SH3_domain.
[Graphical view]

Pfam

PF00169. PH. 1 hit.
PF00621. RhoGEF. 1 hit.
PF00018. SH3_1. 1 hit.
[Graphical view]

SMART

SM00233. PH. 1 hit.
SM00325. RhoGEF. 1 hit.
SM00326. SH3. 1 hit.
[Graphical view]

SUPFAM

SSF48065. DH-domain. 1 hit.
SSF50044. SH3. 1 hit.

PROSITE

PS00741. DH_1. 1 hit.
PS50010. DH_2. 1 hit.
PS50003. PH_DOMAIN. 1 hit.
PS50002. SH3. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

EvolutionaryTrace

Q9NR80.

GenomeRNAi

50649.

NextBio

53194.

SOURCE

Search...

Entry information

Entry name

ARHG4_HUMAN

Accession

Primary (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:	May 1, 2013
This is version 110 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.