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RASGRP4 RAS guanyl releasing protein 4 [ Homo sapiens (human) ]

Gene ID: 115727, updated on 2-Nov-2024

Summary

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Official Symbol
RASGRP4provided by HGNC
Official Full Name
RAS guanyl releasing protein 4provided by HGNC
Primary source
HGNC:HGNC:18958
See related
Ensembl:ENSG00000171777 MIM:607320; AllianceGenome:HGNC:18958
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
Summary
The protein encoded by this gene is a member of the Ras guanyl nucleotide-releasing protein (RasGRP) family of Ras guanine nucleotide exchange factors. It contains a Ras exchange motif, a diacylglycerol-binding domain, and two calcium-binding EF hands. This protein was shown to activate H-Ras in a cation-dependent manner in vitro. Expression of this protein in myeloid cell lines was found to be correlated with elevated level of activated RAS protein, and the RAS activation can be greatly enhanced by phorbol ester treatment, which suggested a role of this protein in diacylglycerol regulated cell signaling pathways. Studies of a mast cell leukemia cell line expressing substantial amounts of abnormal transcripts of this gene indicated that this gene may play an important role in the final stages of mast cell development. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2009]
Expression
Biased expression in bone marrow (RPKM 11.0), appendix (RPKM 5.5) and 13 other tissues See more
Orthologs
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Genomic context

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See RASGRP4 in Genome Data Viewer
Location:
19q13.2
Exon count:
18
Annotation release Status Assembly Chr Location
RS_2024_08 current GRCh38.p14 (GCF_000001405.40) 19 NC_000019.10 (38409058..38426219, complement)
RS_2024_08 current T2T-CHM13v2.0 (GCF_009914755.1) 19 NC_060943.1 (41211234..41228392, complement)
RS_2024_09 previous assembly GRCh37.p13 (GCF_000001405.25) 19 NC_000019.9 (38899698..38916859, complement)

Chromosome 19 - NC_000019.10Genomic Context describing neighboring genes Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 10571 Neighboring gene Sharpr-MPRA regulatory region 13764 Neighboring gene ReSE screen-validated silencer GRCh37_chr19:38890799-38890957 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 10572 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 10573 Neighboring gene sprouty related EVH1 domain containing 3 Neighboring gene gametogenetin Neighboring gene family with sequence similarity 98 member C Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 10574 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr19:38917687-38918201 Neighboring gene MPRA-validated peak3471 silencer Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 10575 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr19:38925085-38925660 Neighboring gene ReSE screen-validated silencer GRCh37_chr19:38932363-38932538 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr19:38932982-38933942 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr19:38943427-38943954 Neighboring gene MPRA-validated peak3472 silencer Neighboring gene ryanodine receptor 1 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr19:38953733-38954234 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr19:38954745-38955341 Neighboring gene ReSE screen-validated silencer GRCh37_chr19:38969337-38969680 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr19:38986475-38987366 Neighboring gene BRD4-independent group 4 enhancer GRCh37_chr19:38995830-38997029 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 10576 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 14572 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 14573 Neighboring gene uncharacterized LOC124904710 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 14575 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 14574 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 14576 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 10577 Neighboring gene MPRA-validated peak3473 silencer Neighboring gene H3K4me1 hESC enhancer GRCh37_chr19:39070191-39070692 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 14578 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr19:39087374-39087874 Neighboring gene MAP4K1 antisense RNA 1 Neighboring gene mitogen-activated protein kinase kinase kinase kinase 1

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 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 critical role of RasGRP4 in the growth of diffuse large B cell lymphoma. Zhu L, et al. Cell Commun Signal, 2019 Aug 13. PMID 31409422, Free PMC Article
  2. Aberrant splicing of the hRasGRP4 transcript and decreased levels of this signaling protein in the peripheral blood mononuclear cells in a subset of patients with rheumatoid arthritis. Hashimoto T, et al. Arthritis Res Ther, 2011. PMID 21933395, Free PMC Article
  3. RasGRP4, a new mast cell-restricted Ras guanine nucleotide-releasing protein with calcium- and diacylglycerol-binding motifs. Identification of defective variants of this signaling protein in asthma, mastocytosis, and mast cell leukemia patients and demonstration of the importance of RasGRP4 in mast cell development and function. Yang Y, et al. J Biol Chem, 2002 Jul 12. PMID 11956218
  4. RasGRP4 regulates the expression of prostaglandin D2 in human and rat mast cell lines. Li L, et al. J Biol Chem, 2003 Feb 14. PMID 12493770
  5. The Diacylglycerol-dependent translocation of ras guanine nucleotide-releasing protein 4 inside a human mast cell line results in substantial phenotypic changes, including expression of interleukin 13 receptor alpha2. Katsoulotos GP, et al. J Biol Chem, 2008 Jan 18. PMID 18024961

See all (20) citations in PubMed

GeneRIFs: Gene References Into Functions

What's a GeneRIF?
  1. The findings indicate the oncogenic role of RasGRP4 in diffuse large B cell lymphoma (DLBCL), suggesting it as a prognostic biomarker and potential therapeutic target in DLBCL.
    Title: The critical role of RasGRP4 in the growth of diffuse large B cell lymphoma.
  2. Ras guanine nucleotide-releasing protein 4 is aberrantly expressed in the fibroblast-like synoviocytes of patients with rheumatoid arthritis and controls their proliferation.
    Title: Ras guanine nucleotide-releasing protein 4 is aberrantly expressed in the fibroblast-like synoviocytes of patients with rheumatoid arthritis and controls their proliferation.
  3. Identification of defective isoforms of hRasGRP4 transcripts in rheumatoid arthritis(RA) patients raises the possibility that dysregulated expression of hRasGRP4 in developing monocytes plays a pathogenic role in this subset of RA patients.
    Title: Aberrant splicing of the hRasGRP4 transcript and decreased levels of this signaling protein in the peripheral blood mononuclear cells in a subset of patients with rheumatoid arthritis.
  4. GPCR activation of Ras and PI3Kc in neutrophils depends on PLCb2/b3 and the RasGEF RasGRP4.
    Title: GPCR activation of Ras and PI3Kc in neutrophils depends on PLCb2/b3 and the RasGEF RasGRP4.
  5. RasGRP4 cooperates with AML1 mutations in T cell leukemogenesis as a class I mutation
    Title: Possible involvement of RasGRP4 in leukemogenesis.
  6. RasGRP4 translocates to varied intracellular compartments via its DAG/PMA-binding domain to regulate signaling pathways that control gene and protein expression in MCs, including the cell's ability to respond to IL-13.
    Title: The Diacylglycerol-dependent translocation of ras guanine nucleotide-releasing protein 4 inside a human mast cell line results in substantial phenotypic changes, including expression of interleukin 13 receptor alpha2.
  7. identification of defective variants of this signaling protein in asthma, mastocytosis, and mast cell leukemia patients and demonstration of the importance of RasGRP4 in mast cell development and function
    Title: RasGRP4, a new mast cell-restricted Ras guanine nucleotide-releasing protein with calcium- and diacylglycerol-binding motifs. Identification of defective variants of this signaling protein in asthma, mastocytosis, and mast cell leukemia patients and demonstration of the importance of RasGRP4 in mast cell development and function.
  8. RasGRP4 plays a role in myeloid cell signaling growth regulation pathways that are responsive to diacylglycerol levels
    Title: RasGRP4 is a novel Ras activator isolated from acute myeloid leukemia.
  9. RasGRP4 regulates the expression of prostaglandin D2 in mast cells
    Title: RasGRP4 regulates the expression of prostaglandin D2 in human and rat mast cell lines.
  10. RasGRP4 is a cation-dependent, guanine nucleotide exchange factor and diacylglycerol/phorbol ester receptor that is selectively expressed in mast cells and their progenitors. RasGRP4 regulates the final stages of mast cell development.
    Title: RasGRP4, a new mast cell-restricted Ras guanine nucleotide-releasing protein with calcium- and diacylglycerol-binding motifs. Identification of defective variants of this signaling protein in asthma, mastocytosis, and mast cell leukemia patients and demonstration of the importance of RasGRP4 in mast cell development and function.
Submit: New GeneRIF Correction

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

EBI GWAS Catalog

Description
Variants in several genomic regions associated with asperger disorder.
EBI GWAS Catalog

Variation

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See Variation Viewer (GRCh37.p13)

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 calcium ion binding IEA
Inferred from Electronic Annotation
more info
  
enables diacylglycerol binding ISS
Inferred from Sequence or Structural Similarity
more info
  
enables diacylglycerol binding TAS
Traceable Author Statement
more info
 PubMed 
enables guanyl-nucleotide exchange factor activity IBA
Inferred from Biological aspect of Ancestor
more info
  
enables guanyl-nucleotide exchange factor activity IDA
Inferred from Direct Assay
more info
 PubMed 
enables protein binding IPI
Inferred from Physical Interaction
more info
 PubMed 
Process Evidence Code Pubs
involved_in Ras protein signal transduction IBA
Inferred from Biological aspect of Ancestor
more info
  
involved_in antibacterial innate immune response ISS
Inferred from Sequence or Structural Similarity
more info
  
involved_in myeloid cell differentiation TAS
Traceable Author Statement
more info
 PubMed 
involved_in phospholipase C-activating G protein-coupled receptor signaling pathway ISS
Inferred from Sequence or Structural Similarity
more info
  
involved_in positive regulation of natural killer cell mediated immunity ISS
Inferred from Sequence or Structural Similarity
more info
  
Component Evidence Code Pubs
located_in cytoplasmic side of plasma membrane IDA
Inferred from Direct Assay
more info
 PubMed 
located_in cytosol IDA
Inferred from Direct Assay
more info
 PubMed 
located_in cytosol TAS
Traceable Author Statement
more info
  
located_in membrane IDA
Inferred from Direct Assay
more info
 PubMed 
located_in nucleoplasm IDA
Inferred from Direct Assay
more info
  
is_active_in plasma membrane IBA
Inferred from Biological aspect of Ancestor
more info
  
located_in plasma membrane IDA
Inferred from Direct Assay
more info
  
located_in plasma membrane TAS
Traceable Author Statement
more info
 PubMed 

General protein information

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Preferred Names
RAS guanyl-releasing protein 4
Names
guanyl nucleotide releasing protein 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_001146202.2 → NP_001139674.1  RAS guanyl-releasing protein 4 isoform b

    Status: REVIEWED

    Description
    Transcript Variant: This variant (b) uses an alternate in-frame splice junction compared to variant a. The resulting isoform (b) has the same N- and C-termini but is shorter compared to isoform a.
    Source sequence(s)
    BC146669, FJ768677
    Consensus CDS
    CCDS59382.1
    UniProtKB/TrEMBL
    C0LTP6, C9JC58
    Related
    ENSP00000467604.1, ENST00000586305.5
    Conserved Domains (3) summary
    cd06224
    Location:57 → 170
    REM; Guanine nucleotide exchange factor for Ras-like GTPases; N-terminal domain (RasGef_N), also called REM domain (Ras exchanger motif). This domain is common in nucleotide exchange factors for Ras-like small GTPases and is typically found immediately ...
    smart00109
    Location:527 → 576
    C1; Protein kinase C conserved region 1 (C1) domains (Cysteine-rich domains)
    smart00147
    Location:183 → 418
    RasGEF; Guanine nucleotide exchange factor for Ras-like small GTPases

  2. NM_001146203.2 → NP_001139675.1  RAS guanyl-releasing protein 4 isoform c

    See identical proteins and their annotated locations for NP_001139675.1

    Status: REVIEWED

    Description
    Transcript Variant: This variant (c) lacks an alternate in-frame exon compared to variant a. The resulting isoform (c) has the same N- and C-termini but is shorter compared to isoform a.
    Source sequence(s)
    BQ028385, FJ768677
    Consensus CDS
    CCDS54264.1
    UniProtKB/Swiss-Prot
    Q8TDF6
    Related
    ENSP00000479078.1, ENST00000614135.4
    Conserved Domains (3) summary
    cd06224
    Location:57 → 164
    REM; Guanine nucleotide exchange factor for Ras-like GTPases; N-terminal domain (RasGef_N), also called REM domain (Ras exchanger motif). This domain is common in nucleotide exchange factors for Ras-like small GTPases and is typically found immediately ...
    cd20863
    Location:446 → 502
    C1_RASGRP4; protein kinase C conserved region 1 (C1 domain) found in RAS guanyl-releasing protein 4 (RASGRP4) and similar proteins
    cl02485
    Location:197 → 319
    RasGEF; Guanine nucleotide exchange factor for Ras-like small GTPases. Small GTP-binding proteins of the Ras superfamily function as molecular switches in fundamental events such as signal transduction, cytoskeleton dynamics and intracellular trafficking. ...

  3. NM_001146204.2 → NP_001139676.1  RAS guanyl-releasing protein 4 isoform d

    See identical proteins and their annotated locations for NP_001139676.1

    Status: REVIEWED

    Description
    Transcript Variant: This variant (d) uses an alternate in-frame splice junction compared to variant a. The resulting isoform (d) has the same N- and C-termini but is shorter compared to isoform a.
    Source sequence(s)
    BQ028385, FJ768678
    Consensus CDS
    CCDS59384.1
    UniProtKB/TrEMBL
    C0LTP6, C9JC58
    Related
    ENSP00000468483.1, ENST00000587753.5
    Conserved Domains (3) summary
    cd06224
    Location:57 → 164
    REM; Guanine nucleotide exchange factor for Ras-like GTPases; N-terminal domain (RasGef_N), also called REM domain (Ras exchanger motif). This domain is common in nucleotide exchange factors for Ras-like small GTPases and is typically found immediately ...
    cd20863
    Location:469 → 525
    C1_RASGRP4; protein kinase C conserved region 1 (C1 domain) found in RAS guanyl-releasing protein 4 (RASGRP4) and similar proteins
    cl02485
    Location:197 → 320
    RasGEF; Guanine nucleotide exchange factor for Ras-like small GTPases. Small GTP-binding proteins of the Ras superfamily function as molecular switches in fundamental events such as signal transduction, cytoskeleton dynamics and intracellular trafficking. ...

  4. NM_001146205.2 → NP_001139677.1  RAS guanyl-releasing protein 4 isoform e

    See identical proteins and their annotated locations for NP_001139677.1

    Status: REVIEWED

    Description
    Transcript Variant: This variant (e) uses an alternate in-frame splice junction compared to variant a. The resulting isoform (e) has the same N- and C-termini but is shorter compared to isoform a.
    Source sequence(s)
    BQ028385, FJ768679
    Consensus CDS
    CCDS59383.1
    UniProtKB/TrEMBL
    C0LTP6, C9JC58
    Related
    ENSP00000416463.2, ENST00000454404.6
    Conserved Domains (3) summary
    cd06224
    Location:57 → 164
    REM; Guanine nucleotide exchange factor for Ras-like GTPases; N-terminal domain (RasGef_N), also called REM domain (Ras exchanger motif). This domain is common in nucleotide exchange factors for Ras-like small GTPases and is typically found immediately ...
    cd20863
    Location:504 → 560
    C1_RASGRP4; protein kinase C conserved region 1 (C1 domain) found in RAS guanyl-releasing protein 4 (RASGRP4) and similar proteins
    cl02485
    Location:197 → 398
    RasGEF; Guanine nucleotide exchange factor for Ras-like small GTPases. Small GTP-binding proteins of the Ras superfamily function as molecular switches in fundamental events such as signal transduction, cytoskeleton dynamics and intracellular trafficking. ...

  5. NM_001146206.2 → NP_001139678.1  RAS guanyl-releasing protein 4 isoform f

    See identical proteins and their annotated locations for NP_001139678.1

    Status: REVIEWED

    Description
    Transcript Variant: This variant (f) lacks an alternate in-frame segment compared to variant a. The resulting isoform (f) has the same N- and C-termini but is shorter compared to isoform a.
    Source sequence(s)
    BQ028385, FJ768680
    Consensus CDS
    CCDS54262.1
    UniProtKB/Swiss-Prot
    Q8TDF6
    Related
    ENSP00000484345.1, ENST00000622174.4
    Conserved Domains (2) summary
    cd06224
    Location:57 → 164
    REM; Guanine nucleotide exchange factor for Ras-like GTPases; N-terminal domain (RasGef_N), also called REM domain (Ras exchanger motif). This domain is common in nucleotide exchange factors for Ras-like small GTPases and is typically found immediately ...
    cd20863
    Location:349 → 405
    C1_RASGRP4; protein kinase C conserved region 1 (C1 domain) found in RAS guanyl-releasing protein 4 (RASGRP4) and similar proteins

  6. NM_001146207.2 → NP_001139679.1  RAS guanyl-releasing protein 4 isoform g

    See identical proteins and their annotated locations for NP_001139679.1

    Status: REVIEWED

    Description
    Transcript Variant: This variant (g) lacks an alternate in-frame segment compared to variant a. The resulting isoform (g) has the same N- and C-termini but is shorter compared to isoform a.
    Source sequence(s)
    BQ028385, FJ768682
    Consensus CDS
    CCDS54263.1
    UniProtKB/Swiss-Prot
    Q8TDF6
    Related
    ENSP00000479888.1, ENST00000617966.4
    Conserved Domains (3) summary
    cd06224
    Location:57 → 164
    REM; Guanine nucleotide exchange factor for Ras-like GTPases; N-terminal domain (RasGef_N), also called REM domain (Ras exchanger motif). This domain is common in nucleotide exchange factors for Ras-like small GTPases and is typically found immediately ...
    cd20863
    Location:441 → 497
    C1_RASGRP4; protein kinase C conserved region 1 (C1 domain) found in RAS guanyl-releasing protein 4 (RASGRP4) and similar proteins
    cl02485
    Location:232 → 335
    RasGEF; Guanine nucleotide exchange factor for Ras-like small GTPases. Small GTP-binding proteins of the Ras superfamily function as molecular switches in fundamental events such as signal transduction, cytoskeleton dynamics and intracellular trafficking. ...

  7. NM_170604.3 → NP_733749.1  RAS guanyl-releasing protein 4 isoform a

    See identical proteins and their annotated locations for NP_733749.1

    Status: REVIEWED

    Description
    Transcript Variant: This variant (a) represents the longest transcript and encodes the longest isoform (a).
    Source sequence(s)
    AC005789, AC011469, AF448437, AY048119, BQ028385
    Consensus CDS
    CCDS46068.1
    UniProtKB/Swiss-Prot
    A6H8M4, C0LTP2, C0LTP3, C0LTP4, C0LTP5, C0LTP7, C9J416, C9JHZ1, Q8N858, Q8TDF6, Q96QN5, Q96QN6, Q96QN7
    UniProtKB/TrEMBL
    C0LTP6, C9JC58
    Related
    ENSP00000479844.1, ENST00000615439.5
    Conserved Domains (3) summary
    cd06224
    Location:57 → 164
    REM; Guanine nucleotide exchange factor for Ras-like GTPases; N-terminal domain (RasGef_N), also called REM domain (Ras exchanger motif). This domain is common in nucleotide exchange factors for Ras-like small GTPases and is typically found immediately ...
    smart00109
    Location:541 → 590
    C1; Protein kinase C conserved region 1 (C1) domains (Cysteine-rich domains)
    smart00147
    Location:197 → 432
    RasGEF; Guanine nucleotide exchange factor for Ras-like small GTPases

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_000019.10 Reference GRCh38.p14 Primary Assembly

    Range
    38409058..38426219 complement
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)

RNA

  1. XR_935732.3 RNA Sequence

    Related
    ENST00000588404.5

Alternate T2T-CHM13v2.0

Genomic

  1. NC_060943.1 Alternate T2T-CHM13v2.0

    Range
    41211234..41228392 complement
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)

RNA

  1. XR_008485082.1 RNA Sequence

Suppressed Reference Sequence(s)

The following Reference Sequences have been suppressed. Explain

  1. NM_052949.2: Suppressed sequence

    Description
    NM_052949.2: This RefSeq was permanently suppressed because it is a nonsense-mediated mRNA decay (NMD) candidate.

  2. NM_170602.1: Suppressed sequence

    Description
    NM_170602.1: This RefSeq was permanently suppressed because it is a nonsense-mediated mRNA decay (NMD) candidate.

  3. NM_170603.1: Suppressed sequence

    Description
    NM_170603.1: This RefSeq was permanently suppressed because it is a nonsense-mediated mRNA decay (NMD) candidate.
Nucleotide Protein
Heading Accession and Version
Protein Accession Links
GenPept Link UniProtKB Link
Q8TDF6.2 GenPept UniProtKB/Swiss-Prot:Q8TDF6

Gene LinkOut

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