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ARHGEF4 Rho guanine nucleotide exchange factor 4 [ Homo sapiens (human) ]

Gene ID: 50649, updated on 5-Mar-2024

Summary

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Official Symbol
ARHGEF4provided by HGNC
Official Full Name
Rho guanine nucleotide exchange factor 4provided by HGNC
Primary source
HGNC:HGNC:684
See related
Ensembl:ENSG00000136002 MIM:605216; AllianceGenome:HGNC:684
Gene type
protein coding
RefSeq status
REVIEWED
Organism
Homo sapiens
Lineage
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as
ASEF; GEF4; STM6; ASEF1; SMIM39
Summary
Rho GTPases play a fundamental role in numerous cellular processes that are initiated by extracellular stimuli that work through G protein coupled receptors. The protein encoded by this gene may form complex with G proteins and stimulate Rho-dependent signals. Multiple alternatively spliced transcript variants encoding different isoforms have been found, but the full-length nature of some variants has not been determined. [provided by RefSeq, Jun 2013]
Expression
Biased expression in brain (RPKM 13.8), skin (RPKM 13.1) and 11 other tissues See more
Orthologs
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Genomic context

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Location:
2q21.1
Exon count:
17
Annotation release Status Assembly Chr Location
RS_2023_10 current GRCh38.p14 (GCF_000001405.40) 2 NC_000002.12 (130836914..131047253)
RS_2023_10 current T2T-CHM13v2.0 (GCF_009914755.1) 2 NC_060926.1 (131271158..131481546)
105.20220307 previous assembly GRCh37.p13 (GCF_000001405.25) 2 NC_000002.11 (131594487..131804826)

Chromosome 2 - NC_000002.12Genomic Context describing neighboring genes Neighboring gene uncharacterized LOC124907891 Neighboring gene H3K27ac hESC enhancer GRCh37_chr2:131543220-131543720 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 11962 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 11963 Neighboring gene CYCS pseudogene 8 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr2:131571909-131572408 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr2:131577629-131578232 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr2:131580955-131581530 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr2:131581531-131582108 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 16530 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr2:131583263-131583838 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr2:131583839-131584416 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr2:131584417-131584994 Neighboring gene ARHGEF4 antisense RNA 1 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr2:131603815-131604349 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr2:131605209-131605886 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr2:131607901-131608435 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr2:131639059-131639560 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr2:131654824-131655422 Neighboring gene small Cajal body-specific RNA 4 Neighboring gene ReSE screen-validated silencer GRCh37_chr2:131706954-131707281 Neighboring gene OCT4-NANOG hESC enhancer GRCh37_chr2:131724236-131724855 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr2:131743536-131744354 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr2:131799328-131800200 Neighboring gene small integral membrane protein 39 Neighboring gene family with sequence similarity 168 member B Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 11964 Neighboring gene ReSE screen-validated silencer GRCh37_chr2:131855480-131855651 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr2:131856285-131856785 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 16531 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr2:131871473-131872062 Neighboring gene pleckstrin homology domain containing B2

Genomic regions, transcripts, and products

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Go to nucleotide: Graphics FASTA GenBank

Expression

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  • Project title: HPA RNA-seq normal tissues
  • Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
  • BioProject: PRJEB4337
  • Publication: PMID 24309898
  • Analysis date: Wed Apr 4 07:08:55 2018

Bibliography

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Related articles in PubMed

  1. ARHGEF4 predicts poor prognosis and promotes cell invasion by influencing ERK1/2 and GSK-3α/β signaling in pancreatic cancer. Taniuchi K, et al. Int J Oncol, 2018 Nov. PMID 30226582
  2. The RAC specific guanine nucleotide exchange factor Asef functions downstream from TEL-AML1 to promote leukaemic transformation. Lyons R, et al. Leuk Res, 2010 Jan. PMID 19628279
  3. Mutated APC and Asef are involved in the migration of colorectal tumour cells. Kawasaki Y, et al. Nat Cell Biol, 2003 Mar. PMID 12598901
  4. Conformational Selection Mechanism Provides Structural Insights into the Optimization of APC-Asef Inhibitors. He X, et al. Molecules, 2021 Feb 11. PMID 33670371, Free PMC Article
  5. Association of Asef and Cdc42 expression to tubular injury in diseased human kidney. Cheng HT, et al. J Investig Med, 2013 Oct. PMID 23941980

See all (37) citations in PubMed

GeneRIFs: Gene References Into Functions

What's a GeneRIF?
  1. Conformational Selection Mechanism Provides Structural Insights into the Optimization of APC-Asef Inhibitors.
    Title: Conformational Selection Mechanism Provides Structural Insights into the Optimization of APC-Asef Inhibitors.
  2. The armadillo repeats in full-length APC interact with the APC residues 1362 to 1540 (APC-2,3 repeats), and this interaction competes off and inhibits Asef. Deletion of APC-2,3 repeats permits Asef interactions leading to downstream signaling events, including the induction of Golgi fragmentation through the activation of the Asef-ROCK-MLC2.
    Title: Truncated Adenomatous Polyposis Coli Mutation Induces Asef-Activated Golgi Fragmentation.
  3. Evaluation of an immunohistochemical staining of 102 resected pancreatic cancer samples demonstrated that high ARHGEF4 expression was correlated with an independent predictor of worse overall survival. ARHGEF4 induces the formation of cell protrusions by increasing phosphorylated ERK1/2 and GSK-3alpha/beta, resulting in an increase in motility and invasiveness in pancreatic ductal adenocarcinoma cells.
    Title: ARHGEF4 predicts poor prognosis and promotes cell invasion by influencing ERK1/2 and GSK-3α/β signaling in pancreatic cancer.
  4. Our results indicate a possible contribution of CNVs in LEPR, NEGR1, ARHGEF4, and CPXCR1 and the intergenic regions 12q15c, 15q21.1a, and 22q11.21d to the development of obesity, particularly abdominal obesity in Mexican children.
    Title: Copy Number Variations in Candidate Genes and Intergenic Regions Affect Body Mass Index and Abdominal Obesity in Mexican Children.
  5. Although inappropriate promoter methylation was not invariantly associated with reduced transcript expression, a significant association was apparent for the ARHGEF4, PON3, STAT5a, and VAX2 gene transcripts (P<0.05). Herein, we present the first genome-wide DNA methylation analysis in a unique HG-NMIBC cohort, showing extensive and discrete methylation changes relative to normal bladder and low-intermediate-grade tumor
    Title: Quantitative genome-wide methylation analysis of high-grade non-muscle invasive bladder cancer.
  6. These data demonstrate, that in addition to microtubule-independent Tiam1 activation, HGF engages additional microtubule- and APC-dependent pathway of Asef activation.
    Title: Hepatocyte growth factor triggers distinct mechanisms of Asef and Tiam1 activation to induce endothelial barrier enhancement.
  7. these results demonstrate potent anti-inflammatory effects by HGF and delineate a key role of Asef in the mediation of the HGF barrier protective and anti-inflammatory effects.
    Title: Asef mediates HGF protective effects against LPS-induced lung injury and endothelial barrier dysfunction.
  8. Expression of Asef was associated with lower estimated glomerular filtration rate in kidney disease.
    Title: Association of Asef and Cdc42 expression to tubular injury in diseased human kidney.
  9. Expression of ARHGEF4 (Rho guanine nucleotide exchange factor 4) is restricted to the brain and may regulate the actin cytoskeletal network, cell morphology and migration, and neuronal function
    Title: Small rare recurrent deletions and reciprocal duplications in 2q21.1, including brain-specific ARHGEF4 and GPR148.
  10. structures thus elucidate the molecular mechanism of Asef recognition by APC
    Title: Structural basis for the recognition of Asef by adenomatous polyposis coli.
Submit: New GeneRIF Correction See all GeneRIFs (13)

Phenotypes

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Find tests for this gene in the NIH Genetic Testing Registry (GTR)

Review eQTL and phenotype association data in this region using PheGenI

Copy number response

Description
Copy number response
Haploinsufficency

No evidence available (Last evaluated 2018-04-05)

ClinGen Genome Curation Page
Triplosensitivity

No evidence available (Last evaluated 2018-04-05)

ClinGen Genome Curation Page

Variation

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See variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

See Variation Viewer (GRCh38)

Genotypes

Pathways from PubChem

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Interactions

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Products Interactant Other Gene Complex Source Pubs Description

General gene information

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Markers

Homology

Gene Ontology Provided by GOA

Function Evidence Code Pubs
enables guanyl-nucleotide exchange factor activity IMP
Inferred from Mutant Phenotype
more info
 PubMed 
enables guanyl-nucleotide exchange factor activity TAS
Traceable Author Statement
more info
  
enables protein binding IPI
Inferred from Physical Interaction
more info
 PubMed 
enables protein domain specific binding IPI
Inferred from Physical Interaction
more info
 PubMed 
Process Evidence Code Pubs
involved_in filopodium assembly IMP
Inferred from Mutant Phenotype
more info
 PubMed 
involved_in intracellular signal transduction IEA
Inferred from Electronic Annotation
more info
  
involved_in lamellipodium assembly IMP
Inferred from Mutant Phenotype
more info
 PubMed 
involved_in regulation of small GTPase mediated signal transduction TAS
Traceable Author Statement
more info
  
Component Evidence Code Pubs
located_in cytosol TAS
Traceable Author Statement
more info
  
located_in ruffle membrane IEA
Inferred from Electronic Annotation
more info
  

General protein information

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Preferred Names
rho guanine nucleotide exchange factor 4
Names
APC-stimulated guanine nucleotide exchange factor 1
Rho guanine nucleotide exchange factor (GEF) 4

NCBI Reference Sequences (RefSeq)

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RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

mRNA and Protein(s)

  1. NM_001367493.1 → NP_001354422.1  rho guanine nucleotide exchange factor 4 isoform c

    Status: REVIEWED

    Description
    Transcript Variant: This variant (3) represents the longest transcript and encodes the longest isoform (c).
    Source sequence(s)
    AB042199, AC009477, AC112786, AC133785, BC139742
    Consensus CDS
    CCDS92866.1
    UniProtKB/TrEMBL
    E7EV07
    Related
    ENSP00000386794.3, ENST00000409359.7

  2. NM_001375900.1 → NP_001362829.1  rho guanine nucleotide exchange factor 4 isoform d

    Status: REVIEWED

    Source sequence(s)
    AC009477, AC112786, AC133785
    UniProtKB/TrEMBL
    A0A2X0SFW4
    Related
    ENSP00000376680.5, ENST00000392953.8
    Conserved Domains (3) summary
    cd11973
    Location:195 → 267
    SH3_ASEF; Src homology 3 domain of APC-Stimulated guanine nucleotide Exchange Factor
    smart00325
    Location:303 → 482
    RhoGEF; Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases
    cd01224
    Location:487 → 626
    PH_Collybistin_ASEF; Collybistin/APC-stimulated guanine nucleotide exchange factor pleckstrin homology (PH) domain

  3. NM_001375901.1 → NP_001362830.1  rho guanine nucleotide exchange factor 4 isoform e

    Status: REVIEWED

    Source sequence(s)
    AC009477, AC112786, AC133785
    UniProtKB/TrEMBL
    A0A2X0SFW4
    Conserved Domains (3) summary
    cd11973
    Location:143 → 215
    SH3_ASEF; Src homology 3 domain of APC-Stimulated guanine nucleotide Exchange Factor
    smart00325
    Location:251 → 430
    RhoGEF; Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases
    cd01224
    Location:435 → 574
    PH_Collybistin_ASEF; Collybistin/APC-stimulated guanine nucleotide exchange factor pleckstrin homology (PH) domain

  4. NM_001375902.1 → NP_001362831.1  rho guanine nucleotide exchange factor 4 isoform f

    Status: REVIEWED

    Source sequence(s)
    AC009477, AC112786
    Conserved Domains (3) summary
    cd11973
    Location:138 → 201
    SH3_ASEF; Src homology 3 domain of APC-Stimulated guanine nucleotide Exchange Factor
    smart00325
    Location:237 → 416
    RhoGEF; Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases
    cd01224
    Location:421 → 560
    PH_Collybistin_ASEF; Collybistin/APC-stimulated guanine nucleotide exchange factor pleckstrin homology (PH) domain

  5. NM_001375903.1 → NP_001362832.1  rho guanine nucleotide exchange factor 4 isoform g

    Status: REVIEWED

    Source sequence(s)
    AC009477, AC112786
    UniProtKB/TrEMBL
    Q9NTG0
    Conserved Domains (3) summary
    cd11973
    Location:120 → 182
    SH3_ASEF; Src homology 3 domain of APC-Stimulated guanine nucleotide Exchange Factor
    smart00325
    Location:218 → 397
    RhoGEF; Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases
    cd01224
    Location:402 → 541
    PH_Collybistin_ASEF; Collybistin/APC-stimulated guanine nucleotide exchange factor pleckstrin homology (PH) domain

  6. NM_001375904.1 → NP_001362833.1  rho guanine nucleotide exchange factor 4 isoform h

    Status: REVIEWED

    Source sequence(s)
    AC009477, AC112786
    UniProtKB/TrEMBL
    Q53TH6
    Related
    ENSP00000387285.2, ENST00000409303.6
    Conserved Domains (3) summary
    cd11973
    Location:57 → 129
    SH3_ASEF; Src homology 3 domain of APC-Stimulated guanine nucleotide Exchange Factor
    smart00325
    Location:165 → 344
    RhoGEF; Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases
    cd01224
    Location:349 → 488
    PH_Collybistin_ASEF; Collybistin/APC-stimulated guanine nucleotide exchange factor pleckstrin homology (PH) domain

  7. NM_001395416.1 → NP_001382345.1  rho guanine nucleotide exchange factor 4 isoform i

    Status: REVIEWED

    Source sequence(s)
    AC009477
    UniProtKB/TrEMBL
    Q9NTG0
    Related
    ENST00000528247.2
    Conserved Domains (3) summary
    smart00325
    Location:81 → 260
    RhoGEF; Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases
    cd01224
    Location:265 → 404
    PH_Collybistin_ASEF; Collybistin/APC-stimulated guanine nucleotide exchange factor pleckstrin homology (PH) domain
    cl17036
    Location:1 → 45
    SH3; Src Homology 3 domain superfamily

  8. NM_015320.4 → NP_056135.2  rho guanine nucleotide exchange factor 4 isoform a

    See identical proteins and their annotated locations for NP_056135.2

    Status: REVIEWED

    Source sequence(s)
    AB042199, AC112786, AC133785, AF249745, AL137289
    Consensus CDS
    CCDS2165.1
    UniProtKB/Swiss-Prot
    Q9HDC6, Q9NR80, Q9UPP0
    UniProtKB/TrEMBL
    A0A2X0SFW4
    Related
    ENSP00000316845.5, ENST00000326016.10
    Conserved Domains (4) summary
    cd11973
    Location:180 → 252
    SH3_ASEF; Src homology 3 domain of APC-Stimulated guanine nucleotide Exchange Factor
    cd01224
    Location:472 → 611
    PH_Collybistin_ASEF; Collybistin/APC-stimulated guanine nucleotide exchange factor pleckstrin homology (PH) domain
    pfam00169
    Location:500 → 601
    PH; PH domain
    pfam00621
    Location:288 → 467
    RhoGEF; RhoGEF domain

RefSeqs of Annotated Genomes: GCF_000001405.40-RS_2023_10

The following sections contain reference sequences that belong to a specific genome build. Explain

Reference GRCh38.p14 Primary Assembly

Genomic

  1. NC_000002.12 Reference GRCh38.p14 Primary Assembly

    Range
    130836914..131047253
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)

Alternate T2T-CHM13v2.0

Genomic

  1. NC_060926.1 Alternate T2T-CHM13v2.0

    Range
    131271158..131481546
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)

Suppressed Reference Sequence(s)

The following Reference Sequences have been suppressed. Explain

  1. NM_032995.2: Suppressed sequence

    Description
    NM_032995.2: This RefSeq has been removed because currently there is insufficient support for the transcript and protein.
Nucleotide Protein
Heading Accession and Version
Protein Accession Links
GenPept Link UniProtKB Link
Q9NR80.3 GenPept UniProtKB/Swiss-Prot:Q9NR80

Gene LinkOut

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