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

    Gene ID: 50649, updated on 27-Nov-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
    mouse all
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    Genomic context

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    See ARHGEF4 in Genome Data Viewer
    Location:
    2q21.1
    Exon count:
    17
    Annotation release Status Assembly Chr Location
    RS_2024_08 current GRCh38.p14 (GCF_000001405.40) 2 NC_000002.12 (130836914..131047253)
    RS_2024_08 current T2T-CHM13v2.0 (GCF_009914755.1) 2 NC_060926.1 (131271158..131481546)
    RS_2024_09 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. 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
    2. 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
    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. Phosphorylation and activation of the Rac1 and Cdc42 GEF Asef in A431 cells stimulated by EGF. Itoh RE, et al. J Cell Sci, 2008 Aug 15. PMID 18653540
    5. Isolation of two novel human RhoGEFs, ARHGEF3 and ARHGEF4, in 3p13-21 and 2q22. Thiesen S, et al. Biochem Biophys Res Commun, 2000 Jun 24. PMID 10873612

    See all (40) 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)

    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_2024_08

    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

    The following LinkOut resources are supplied by external providers. These providers are responsible for maintaining the links.

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