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

Summary

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: mouse all
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Genomic context

Location:: 19q13.2

Exon count:: 18

Annotation release	Status	Assembly	Chr	Location
RS_2023_10	current	GRCh38.p14 (GCF_000001405.40)	19	NC_000019.10 (38409058..38426219, complement)
RS_2023_10	current	T2T-CHM13v2.0 (GCF_009914755.1)	19	NC_060943.1 (41211234..41228392, complement)
105.20220307	previous assembly	GRCh37.p13 (GCF_000001405.25)	19	NC_000019.9 (38899698..38916859, complement)

Chromosome 19 - NC_000019.10 Genomic Context describing neighboring genes

Genomic regions, transcripts, and products

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Genomic Sequence:

Go to nucleotide: Graphics FASTA GenBank

Expression

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See details

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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GeneRIFs: Gene References Into Functions

What's a GeneRIF?

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.
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.
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.
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.
RasGRP4 cooperates with AML1 mutations in T cell leukemogenesis as a class I mutation
Title: Possible involvement of RasGRP4 in leukemogenesis.
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.
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.
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.
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.
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.

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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 EBI GWAS CatalogPubMed

Variation

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See variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

See Variation Viewer (GRCh38)

Interactions

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Products	Interactant	Other Gene	Complex	Source	Pubs	Description

General gene information

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Markers

SHGC-37260 (e-PCR)
- UniSTS:5888

RH65873 (e-PCR)
- UniSTS:63602

G44334 (e-PCR)
- UniSTS:95121

L17877 (e-PCR)
- UniSTS:61334

NoName (e-PCR)
- UniSTS:482466

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
enables GTP-dependent protein binding	NAS Non-traceable Author Statement more info	PubMed
enables calcium ion binding	IEA Inferred from Electronic Annotation 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

Process	Evidence Code	Pubs
involved_in Ras protein signal transduction	IBA Inferred from Biological aspect of Ancestor more info
involved_in activation of phospholipase C activity	NAS Non-traceable Author Statement more info	PubMed
involved_in cell population proliferation	IDA Inferred from Direct Assay more info	PubMed
involved_in cell surface receptor protein tyrosine kinase signaling pathway	NAS Non-traceable Author Statement more info	PubMed
involved_in myeloid cell differentiation	TAS Traceable Author Statement more info	PubMed
involved_in positive regulation of Ras protein signal transduction	IDA Inferred from Direct Assay more info	PubMed
involved_in regulation of G protein-coupled receptor signaling pathway	NAS Non-traceable Author Statement more info	PubMed
involved_in response to extracellular stimulus	IDA Inferred from Direct Assay more info	PubMed

Component	Evidence Code	Pubs
located_in cytosol	IDA Inferred from Direct Assay more info
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)

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
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. ...
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. ...
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. ...
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
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. ...
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_2023_10

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

Reference GRCh38.p14 Primary Assembly

Genomic

NC_000019.10 Reference GRCh38.p14 Primary Assembly

Range

38409058..38426219 complement

Download

GenBank, FASTA, Sequence Viewer (Graphics)

RNA

XR_935732.3 RNA Sequence

Related

ENST00000588404.5

Alternate T2T-CHM13v2.0

Genomic

NC_060943.1 Alternate T2T-CHM13v2.0

Range

41211234..41228392 complement

Download

GenBank, FASTA, Sequence Viewer (Graphics)

RNA

XR_008485082.1 RNA Sequence

Suppressed Reference Sequence(s)

The following Reference Sequences have been suppressed. Explain

NM_052949.2: Suppressed sequence

Description

NM_052949.2: This RefSeq was permanently suppressed because it is a nonsense-mediated mRNA decay (NMD) candidate.
NM_170602.1: Suppressed sequence

Description

NM_170602.1: This RefSeq was permanently suppressed because it is a nonsense-mediated mRNA decay (NMD) candidate.
NM_170603.1: Suppressed sequence

Description

NM_170603.1: This RefSeq was permanently suppressed because it is a nonsense-mediated mRNA decay (NMD) candidate.