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GRAP

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Summary

GRAP (GRB2 related adaptor protein, HGNC:4562) is a protein-coding gene on chromosome 17p11.2, encoding GRB2-related adapter protein (Q13588). Couples signals from receptor and cytoplasmic tyrosine kinases to the Ras signaling pathway. It is a selective cancer dependency (DepMap: 49.4% of cell lines).

This gene encodes a member of the GRB2/Sem5/Drk family and functions as a cytoplasmic signaling protein which contains an SH2 domain flanked by two SH3 domains. The SH2 domain interacts with ligand-activated receptors for stem cell factor and erythropoietin, and facilitates the formation of a stable complex with the BCR-ABL oncoprotein. This protein also associates with the Ras guanine nucleotide exchange factor SOS1 (son of sevenless homolog 1) through its N-terminal SH3 domain. In general, it couples signals from receptor and cytoplasmic tyrosine kinases to the Ras signaling pathway.

Source: NCBI Gene 10750 — RefSeq curated summary.

At a glance

  • Gene–disease (curated): hearing loss, autosomal recessive (Supportive, GenCC) — +2 more curated relationships
  • GWAS associations: 1
  • Clinical variants (ClinVar): 26 total — 1 likely-pathogenic
  • Phenotypes (HPO): 2
  • Cancer dependency (DepMap): dependent in 49.4% of screened cell lines
  • MANE Select transcript: NM_006613

Identifiers

Gene identifiers

FieldValue
HGNC IDHGNC:4562
Approved symbolGRAP
NameGRB2 related adaptor protein
Location17p11.2
Locus typegene with protein product
StatusApproved
Ensembl geneENSG00000154016
Ensembl biotypeprotein_coding
OMIM604330
Entrez10750

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 5 protein_coding, 1 retained_intron, 1 nonsense_mediated_decay

ENST00000284154, ENST00000395635, ENST00000571380, ENST00000573099, ENST00000583020, ENST00000880613, ENST00000957342

RefSeq mRNA: 2 — MANE Select: NM_006613 NM_001330148, NM_006613

CCDS: CCDS11202, CCDS82085

Canonical transcript exons

ENST00000284154 — 5 exons

ExonStartEnd
ENSE000012946401902065619022144
ENSE000023566401903595819036080
ENSE000026638221904684919046957
ENSE000034691571904180719041904
ENSE000035947001902421519024383

Expression profiles

Bgee: expression breadth ubiquitous, 164 present calls, max score 90.53.

Top tissues by expression

255 total, by Bgee expression score (0-100, higher = more expressed):

TissueAnatomy IDExpression scoreQuality
spleenUBERON:000210690.53gold quality
granulocyteCL:000009489.55gold quality
lymph nodeUBERON:000002988.93gold quality
bloodUBERON:000017882.44gold quality
right lungUBERON:000216779.41gold quality
small intestine Peyer’s patchUBERON:000345478.91gold quality
upper lobe of left lungUBERON:000895278.53gold quality
gall bladderUBERON:000211077.48gold quality
apex of heartUBERON:000209877.30gold quality
upper lobe of lungUBERON:000894877.26gold quality
vermiform appendixUBERON:000115476.97gold quality
right lobe of thyroid glandUBERON:000111976.47gold quality
leukocyteCL:000073876.46gold quality
small intestineUBERON:000210876.32gold quality
omental fat padUBERON:001041475.59gold quality
peritoneumUBERON:000235875.54gold quality
monocyteCL:000057675.32gold quality
adipose tissue of abdominal regionUBERON:000780875.16gold quality
subcutaneous adipose tissueUBERON:000219075.13gold quality
medial globus pallidusUBERON:000247774.51silver quality
right adrenal glandUBERON:000123374.20gold quality
caecumUBERON:000115374.04gold quality
left lobe of thyroid glandUBERON:000112074.02gold quality
smooth muscle tissueUBERON:000113573.98gold quality
myocardiumUBERON:000234973.98gold quality
adipose tissueUBERON:000101373.91gold quality
metanephros cortexUBERON:001053373.71gold quality
thyroid glandUBERON:000204673.58gold quality
right lobe of liverUBERON:000111473.53gold quality
right adrenal gland cortexUBERON:003582773.44gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

ExperimentMarker?Max mean expression
E-CURD-122yes19.05
E-ANND-3yes5.91

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F1

miRNA regulators (miRDB)

25 targeting GRAP, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNAMax scoreAvg scoremiRNA target_count
HSA-MIR-150-5P99.9966.691976
HSA-MIR-185-3P99.9567.011743
HSA-MIR-6768-5P99.9267.361942
HSA-MIR-4731-5P99.8967.232537
HSA-MIR-6861-3P99.6068.46444
HSA-MIR-4758-3P99.1263.96869
HSA-MIR-330-5P98.7367.631788
HSA-MIR-1227-5P98.6565.321549
HSA-MIR-6852-3P98.5467.601468
HSA-MIR-518C-5P98.5369.201640
HSA-MIR-1199-5P98.4466.51829
HSA-MIR-6751-3P98.4466.35835
HSA-MIR-5589-5P98.3464.821148
HSA-MIR-32698.2566.441565
HSA-MIR-6748-3P97.2065.66836
HSA-MIR-6773-5P97.0464.30595
HSA-MIR-468996.9765.791209
HSA-MIR-4793-5P96.8865.90872
HSA-MIR-6508-3P96.7365.48576
HSA-MIR-118296.4164.89336
HSA-MIR-6724-5P96.4163.11507
HSA-MIR-6823-5P96.2665.69919
HSA-MIR-6858-5P96.0564.591020
HSA-MIR-443595.9065.471201
HSA-MIR-452295.7666.23742

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 49.4% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 6)

  • Results suggest that the GRAP gene might have a role in the pathogenesis of Sjogren’s syndrome. (PMID:15174222)
  • Our findings define a pathway involving CD28 binding to Grb-2 and its co-operativity with Vav1 in the regulation of T-cell co-stimulation. (PMID:18295596)
  • Grb2-related adaptor protein (GRAP) was up-regulated in kidney tubules from fibrotic kidneys from diabetic patients, and subsequently confirmed as a novel component of TGF-beta signaling in cultured human renal tubule cells. (PMID:19836472)
  • Findings suggest that the miR-654-5p/GRAP/Ras/Erk signaling pathway in OSCC cells might contribute to the underlying mechanism through which miR-654-5p participates in the regulation of OSCC progression. (PMID:29364705)
  • The function of the growth factor receptor-bound protein 2 (GRB2)-related adaptor protein (GRAP) in the auditory system is not known. (PMID:30610177)
  • m(6)A Modification-mediated GRAP Regulates Vascular Remodeling in Hypoxic Pulmonary Hypertension. (PMID:35972996)

Cross-species orthologs

6 orthologs

OrganismSymbolGene ID
danio_reriograpaENSDARG00000005414
danio_reriograpbENSDARG00000022668
mus_musculusGrapENSMUSG00000004837
rattus_norvegicusGrapENSRNOG00000002599
drosophila_melanogasterdockFBGN0010583
caenorhabditis_elegansWBGENE00006410

Paralogs (9): DAPP1 (ENSG00000070190), NCK2 (ENSG00000071051), GRAP2 (ENSG00000100351), SLA2 (ENSG00000101082), SLA (ENSG00000155926), NCK1 (ENSG00000158092), GRB2 (ENSG00000177885), GRAPL (ENSG00000189152), SH2D5 (ENSG00000189410)

Protein

Protein identifiers

GRB2-related adapter protein — Q13588 (reviewed: Q13588)

All UniProt accessions (4): Q13588, A8MW78, I3L2P9, J3QRP9

UniProt curated annotations — full annotation on UniProt →

Function. Couples signals from receptor and cytoplasmic tyrosine kinases to the Ras signaling pathway. Plays a role in the inner ear and in hearing.

Subunit / interactions. Associates through its SH2 domain with ligand-activated receptors for stem cell factor (KIT) and erythropoietin (EPOR). Also forms a stable complex with the Bcr-Abl oncoprotein. GRAP is associated with the Ras guanine nucleotide exchange factor SOS1, primarily through its N-terminal SH3 domain. Interacts with phosphorylated LAT upon TCR activation. Interacts with SHB.

Subcellular location. Membrane. Synapse.

Disease relevance. Deafness, autosomal recessive, 114 (DFNB114) [MIM:618456] A form of non-syndromic deafness characterized by congenital profound sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the GRB2/sem-5/DRK family.

RefSeq proteins (2): NP_001317077, NP_006604* (*=MANE)

Domains & families (InterPro)

IDNameType
IPR000980SH2Domain
IPR001452SH3_domainDomain
IPR035645GRAP_N_SH3Domain
IPR036028SH3-like_dom_sfHomologous_superfamily
IPR036860SH2_dom_sfHomologous_superfamily
IPR043539Grb2-likeFamily

Pfam: PF00017, PF00018

UniProt features (5 total): domain 3, chain 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

ModelpLDDTFraction very-high
AF-Q13588-F186.280.45

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

IDPathway
R-HSA-1433557Signaling by SCF-KIT

MSigDB gene sets: 108 (showing top): GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS, GOBP_CELL_CELL_SIGNALING, GOBP_RAS_PROTEIN_SIGNAL_TRANSDUCTION, PETROVA_ENDOTHELIUM_LYMPHATIC_VS_BLOOD_UP, RYTTCCTG_ETS2_B, GOBP_SENSORY_PERCEPTION, GOMF_SIGNALING_RECEPTOR_BINDING, GOBP_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, GOCC_SYNAPSE, MARSON_BOUND_BY_FOXP3_STIMULATED, GOCC_COP9_SIGNALOSOME, GOCC_PRESYNAPSE, GOMF_PHOSPHOPROTEIN_BINDING, GOMF_EPIDERMAL_GROWTH_FACTOR_RECEPTOR_BINDING, GOMF_PROTEIN_PHOSPHORYLATED_AMINO_ACID_BINDING

GO Biological Process (5): signal transduction (GO:0007165), Ras protein signal transduction (GO:0007265), cell-cell signaling (GO:0007267), sensory perception of sound (GO:0007605), regulation of MAPK cascade (GO:0043408)

GO Molecular Function (3): phosphotyrosine residue binding (GO:0001784), epidermal growth factor receptor binding (GO:0005154), protein binding (GO:0005515)

GO Cellular Component (8): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), COP9 signalosome (GO:0008180), presynapse (GO:0098793), membrane (GO:0016020), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-1 pathways:

CategoryPathways
Signaling by Receptor Tyrosine Kinases1

GO top-level categories

Rollup of top GO terms by namespace:

CategoryTerms
cellular anatomical structure5
cell communication2
signaling2
cellular process1
regulation of cellular process1
cellular response to stimulus1
small GTPase-mediated signal transduction1
sensory perception of mechanical stimulus1
MAPK cascade1
regulation of intracellular signal transduction1
protein phosphorylated amino acid binding1
growth factor receptor binding1
binding1
nuclear lumen1
intracellular anatomical structure1
cytoplasm1
membrane1
cell periphery1
nuclear protein-containing complex1
synapse1
cell junction1

Protein interactions and networks

STRING

1536 interactions, top by confidence (×1000):

Protein AProtein BPartner UniProtScore
GRAPLCP2Q13094961
GRAPSOS1Q07889898
GRAPGRB2P29354880
GRAPSHC1P29353778
GRAPPLCG1P19174760
GRAPLIME1Q9H400756
GRAPLATO43561734
GRAPSOS2Q07890725
GRAPFYB1O15117711
GRAPMAP4K1Q92918621
GRAPUBASH3AP57075591
GRAPSKAP1Q86WV1585
GRAPPRLHP81277582
GRAPITKQ08881579
GRAPRABIFP47224567

IntAct

45 interactions, top by confidence:

ABTypeScore
GRAPTRIM21psi-mi:“MI:0915”(physical association)0.720
TRIM21GRAPpsi-mi:“MI:0915”(physical association)0.720
GRAPRBPMSpsi-mi:“MI:0915”(physical association)0.560
RBPMSGRAPpsi-mi:“MI:0915”(physical association)0.560
RELGRAPpsi-mi:“MI:0915”(physical association)0.560
GRAPDPPA4psi-mi:“MI:0915”(physical association)0.560
TOXGRAPpsi-mi:“MI:0915”(physical association)0.560
GRAPDNM2psi-mi:“MI:0915”(physical association)0.560
GRAPpsi-mi:“MI:0915”(physical association)0.560
HTTGRAPpsi-mi:“MI:0915”(physical association)0.560
PRRG4GRAPpsi-mi:“MI:0407”(direct interaction)0.440
ADAM10GRAPpsi-mi:“MI:0915”(physical association)0.400

BioGRID (15): GRAP (Two-hybrid), RBPMS (Two-hybrid), GRAP (Two-hybrid), GRAP (Two-hybrid), REL (Two-hybrid), TOX (Two-hybrid), GRAP (Reconstituted Complex), KIT (Reconstituted Complex), EPOR (Reconstituted Complex), SOS1 (Co-fractionation), FASLG (Reconstituted Complex), GRAP (Affinity Capture-Western), GRAP (Reconstituted Complex), GAB2 (Reconstituted Complex), GRB2 (Negative Genetic)

ESM2 similar proteins: A6QLK6, O14508, O35717, O70277, O75382, O88582, O95057, P09851, P20936, P49138, P50904, P57790, P62993, P62994, P87379, Q05B84, Q07883, Q08012, Q13588, Q14145, Q16644, Q2T9Z7, Q3SYZ2, Q5PR73, Q5R4J7, Q5R6S2, Q5R774, Q5RKN4, Q5ZLD3, Q60631, Q66H84, Q66II3, Q684M4, Q6GPJ9, Q6TDP3, Q6YKA8, Q6ZPT1, Q7YRV6, Q861R0, Q8TC17

Diamond homologs: A0A8I3NFE2, A0FI79, A0JNB0, A1Y2K1, A6QLK6, B2RZ59, B5KFD7, D3ZGS3, D7PF45, F1RDG9, G5ECJ6, O14306, O14796, O15357, O35324, O60880, O88890, O88900, P00519, P00520, P00521, P00522, P03949, P06239, P06241, P09851, P0CE43, P10447, P17713, P20936, P29350, P29351, P32019, P34370, P39688, P42684, P42685, P42686, P50904, P53356

SIGNOR signaling

5 interactions.

AEffectBMechanism
ABL1up-regulatesGRAPbinding
VAV1up-regulatesGRAPbinding
METup-regulatesGRAPbinding
SHC1up-regulatesGRAPbinding
FRS2up-regulatesGRAPbinding

Disease & clinical

Clinical variants and AI predictions

ClinVar

26 variants total. Per-class counts are floors (≥ shown; pagination cap):

ClassificationCount (floor)
Pathogenic0
Likely pathogenic1
Uncertain significance17
Likely benign5
Benign1

Top pathogenic / likely-pathogenic (1)

Variant IDHGVSClassification
633599NM_006613.4(GRAP):c.311A>T (p.Gln104Leu)Likely pathogenic

SpliceAI

797 predictions. Top by Δscore:

VariantEffectΔscore
17:19022140:GGTGA:Gacceptor_gain1.0000
17:19022145:C:CCacceptor_gain1.0000
17:19024209:CCCTA:Cdonor_loss1.0000
17:19024210:CCTAC:Cdonor_loss1.0000
17:19024211:CTAC:Cdonor_loss1.0000
17:19024212:TACC:Tdonor_loss1.0000
17:19024213:A:Cdonor_loss1.0000
17:19024214:C:CAdonor_loss1.0000
17:19024381:TAG:Tacceptor_gain1.0000
17:19024382:AG:Aacceptor_gain1.0000
17:19024384:C:CCacceptor_gain1.0000
17:19035956:A:ACdonor_gain1.0000
17:19035957:C:CAdonor_gain1.0000
17:19035957:CTT:Cdonor_gain1.0000
17:19035957:CTTCA:Cdonor_gain1.0000
17:19035959:T:TAdonor_gain1.0000
17:19035977:C:CAdonor_gain1.0000
17:19035993:A:ACdonor_gain1.0000
17:19035994:C:CCdonor_gain1.0000
17:19035994:CT:Cdonor_gain1.0000
17:19035997:T:Adonor_gain1.0000
17:19041805:A:ACdonor_gain1.0000
17:19041806:C:CCdonor_gain1.0000
17:19041901:GGAT:Gacceptor_gain1.0000
17:19041903:AT:Aacceptor_gain1.0000
17:19041904:TC:Tacceptor_loss1.0000
17:19041905:C:CCacceptor_gain1.0000
17:19041905:CTGT:Cacceptor_loss1.0000
17:19041906:T:Gacceptor_loss1.0000
17:19046843:CCCTA:Cdonor_loss1.0000

AlphaMissense

1422 scored. Top likely-pathogenic:

VariantProtein changeam_pathogenicity
17:19041877:A:GW36R1.000
17:19041877:A:TW36R1.000
17:19024291:A:GL131P0.999
17:19024308:G:CF125L0.999
17:19024308:G:TF125L0.999
17:19024310:A:GF125L0.999
17:19035964:G:AS98F0.999
17:19036008:G:CF83L0.999
17:19036008:G:TF83L0.999
17:19036010:A:GF83L0.999
17:19036079:A:GW60R0.999
17:19036079:A:TW60R0.999
17:19041837:G:TP49H0.999
17:19041838:G:AP49S0.999
17:19041838:G:TP49T0.999
17:19041846:C:TG46E0.999
17:19041875:C:AW36C0.999
17:19041875:C:GW36C0.999
17:19046900:A:CF9L0.999
17:19046900:A:TF9L0.999
17:19046902:A:GF9L0.999
17:19024280:A:CY135D0.998
17:19024288:A:TV132D0.998
17:19024360:A:GF108S0.998
17:19024362:G:CH107Q0.998
17:19024362:G:TH107Q0.998
17:19035964:G:TS98Y0.998
17:19036000:C:GR86P0.998
17:19036048:G:TA70D0.998
17:19041847:C:GG46R0.998

dbSNP variants (sampled 300 via entrez): RS1000132617 (17:19032348 C>T), RS1000235019 (17:19020856 G>C), RS1000247685 (17:19031600 A>G), RS1001192834 (17:19021044 C>T), RS1001581627 (17:19027891 T>C,G), RS1001952847 (17:19020790 A>G), RS1002539730 (17:19029945 C>T), RS1002991491 (17:19024895 A>G), RS1003583184 (17:19023489 G>A), RS1003596901 (17:19050730 G>A), RS1004305910 (17:19024730 C>A,T), RS1005893009 (17:19049133 G>A), RS1006341342 (17:19041097 A>C), RS1006422817 (17:19021648 C>A,T), RS1006482955 (17:19041356 G>A)

Disease associations

OMIM: gene MIM:604330 | disease phenotypes: MIM:618456

GenCC curated gene-disease

DiseaseClassificationInheritance
hearing loss, autosomal recessiveSupportiveAutosomal recessive
nonsyndromic genetic hearing lossLimitedAutosomal recessive
hearing loss, autosomal recessive 114LimitedUnknown

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

DiseaseClassificationInheritance
nonsyndromic genetic hearing lossLimitedAR

Mondo (3): hearing loss, autosomal recessive 114 (MONDO:0032761), nonsyndromic genetic hearing loss (MONDO:0019497), hearing loss, autosomal recessive (MONDO:0019588)

Orphanet (0):

HPO phenotypes

2 total (2 of 2 shown, HPO-id order):

HPOTerm
HP:0000007Autosomal recessive inheritance
HP:0000407Sensorineural hearing impairment

GWAS associations

1 associations (top):

StudyTraitp-value
GCST002938_16Copper levels2.000000e-06

MeSH disease descriptors (2)

DescriptorNameTree numbers
C564609Deafness, Autosomal Recessive (supp.)
C580334Nonsyndromic Deafness (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

21 total (human), top 21 by PubMed support.

ChemicalActions (top 5)PubMed papers
(+)-JQ1 compounddecreases expression2
OTX015decreases expression1
mivebresibdecreases expression1
methyleugenoldecreases expression1
ethyl-p-hydroxybenzoateincreases expression1
sodium arsenitedecreases expression1
cobaltous chloridedecreases expression1
pentanaldecreases expression1
di-n-butylphosphoric acidaffects expression1
MT19c compounddecreases expression1
Acetaminophenincreases expression1
Benzo(a)pyrenedecreases expression1
Citrullinedecreases expression1
Estradioldecreases expression1
Hydralazineaffects cotreatment, increases expression1
N-Nitrosopyrrolidinedecreases expression1
Urethanedecreases expression1
Valproic Acidaffects cotreatment, increases expression1
Asbestos, Crocidoliteaffects expression1
Okadaic Aciddecreases expression1
Copper Sulfateincreases expression1

Clinical trials (associated diseases)

1 trials via MONDO — disease-level, not drug-specific.

TrialPhaseStatusTitle
NCT01802190Not specifiedTERMINATEDPrevalence of POU4F3 and SLC17A8 Mutations

About this page

Generated deterministically by Sugi Atlas from primary biomedical databases via BioBTree. Every record on this page traces to a primary source.

Generated
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Sources 75

This page pulls from 75 datasets indexed by BioBTree:

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