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P62994 (GRB2_RAT) Reviewed, UniProtKB/Swiss-Prot

Last modified June 11, 2014. Version 103. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (1) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Growth factor receptor-bound protein 2
Alternative name(s):
Adapter protein GRB2
Protein Ash
SH2/SH3 adapter GRB2
Gene names
Name:Grb2
Synonyms:Ash
OrganismRattus norvegicus (Rat) [Reference proteome]
Taxonomic identifier10116 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus

Protein attributes

Sequence length217 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Adapter protein that provides a critical link between cell surface growth factor receptors and the Ras signaling pathway By similarity. Ref.2

Subunit structure

Associates with activated Tyr-phosphorylated EGF receptor/EGFR and PDGF receptors via its SH2 domain. Also associates to other cellular Tyr-phosphorylated proteins such as SIT1, IRS4, SHC and LNK; probably via the concerted action of both its SH2 and SH3 domains. It also seems to interact with RAS in the signaling pathway leading to DNA synthesis. Binds to and translocates the guanine nucleotide exchange factors SOS. Interacts with phosphorylated TOM1L1 and MET. Interacts with the phosphorylated C-terminus of SH2B2. Interacts with phosphorylated SIT1, LAX1, LAT, LAT2 and LIME1 upon TCR and/or BCR activation. Interacts with PTPNS1, REPS2 and the syntrophin SNTA1. Interacts with REPS1 and PIK3C2B via its SH3 domains. Interacts with CBL and CBLB. Interacts with AJUBA By similarity. Interacts with SHB, INPP5D/SHIP1, SKAP1, SKAP2 and CLNK By similarity. Forms a complex with MUC1 and SOS1, through interaction of the SH3 domains SH2 domain with phosphorylated MUC1. Interacts with PRNP By similarity. Interacts with NISCH, RALGPS1 and with HCST By similarity. Interacts with GAPT, THEMIS and PTPRE By similarity. Interacts (via SH3 2) with GAB2 By similarity. Interacts with ADAM15. Interacts with PTPRJ and BCR By similarity. Interacts with THEMIS2. Interacts (via SH2 domain) with AXL and KIT (phosphorylated). Interacts with PTK2B/PYK2 (tyrosine phosphorylated) By similarity. Interacts with EPHB1 and SHC1; activates the MAPK/ERK cascade to regulate cell migration. Interacts with PTPN23 By similarity. Interacts with FLT1, KDR and FLT4 (tyrosine phosphorylated). Interacts (via SH2 domain) with TEK/TIE2 (tyrosine phosphorylated) By similarity. Part of a complex including TNK2, GRB2 and one receptor tyrosine kinase (RTK) such as AXL, in which GRB2 promotes RTK recruitment by TNK2 By similarity. Interacts with PDGFRA (tyrosine phosphorylated); the interaction may be indirect By similarity. Interacts with PTPN11. Interacts with NTRK1 (phosphorylated upon ligand-binding) By similarity. Interacts with ERBB4. Interacts with PTK2/FAK1 (tyrosine phosphorylated). Interacts with SCIMP By similarity. Interacts with PLCG1, LAT, THEMIS and TESPA1 upon TCR activation in thymocytes. Interacts with DAB2 By similarity. Interacts (via SH3 domains) with GAREM (via proline-rich domain and tyrosine phosphorylated); the interaction occurs upon EGF stimulation By similarity. Interacts with RAB13; may recruit RAB13 to the leading edge of migrating endothelial cells where it can activate RHOA. Interacts with ASAP3 (phosphorylated form). Interacts with CD28 By similarity. Interacts (via SH2 domain) with CSF1R and IRS1 (tyrosine phosphorylated). Ref.5 Ref.6

Subcellular location

Nucleus By similarity. Cytoplasm By similarity. Endosome By similarity. Golgi apparatus By similarity.

Tissue specificity

Wide tissue distribution. Ref.1

Domain

The SH3 domains mediate interaction with RALGPS1 and SHB By similarity.

Sequence similarities

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

Contains 1 SH2 domain.

Contains 2 SH3 domains.

Ontologies

Keywords
   Cellular componentCytoplasm
Endosome
Golgi apparatus
Nucleus
   Coding sequence diversityAlternative splicing
   DomainRepeat
SH2 domain
SH3 domain
   PTMAcetylation
Phosphoprotein
   Technical termComplete proteome
Direct protein sequencing
Reference proteome
Gene Ontology (GO)
   Biological_processRas protein signal transduction

Traceable author statement Ref.2. Source: RGD

aging

Inferred from physical interaction PubMed 11954667. Source: RGD

anatomical structure formation involved in morphogenesis

Inferred from electronic annotation. Source: Ensembl

branching involved in labyrinthine layer morphogenesis

Inferred from electronic annotation. Source: Ensembl

cell differentiation

Inferred from electronic annotation. Source: Ensembl

cellular response to ionizing radiation

Inferred from electronic annotation. Source: Ensembl

insulin receptor signaling pathway

Inferred from electronic annotation. Source: Ensembl

positive regulation of actin filament polymerization

Inferred from electronic annotation. Source: Ensembl

positive regulation of reactive oxygen species metabolic process

Inferred from electronic annotation. Source: Ensembl

positive regulation of signal transduction

Inferred from electronic annotation. Source: GOC

protein heterooligomerization

Inferred from direct assay PubMed 15272025. Source: RGD

receptor internalization

Inferred from electronic annotation. Source: Ensembl

regulation of MAPK cascade

Inferred from electronic annotation. Source: Ensembl

signal transduction in response to DNA damage

Inferred from electronic annotation. Source: Ensembl

   Cellular_componentCOP9 signalosome

Inferred from sequence or structural similarity. Source: UniProtKB

Golgi apparatus

Inferred from electronic annotation. Source: UniProtKB-SubCell

Grb2-EGFR complex

Inferred from electronic annotation. Source: Ensembl

cytoplasm

Inferred from sequence or structural similarity. Source: UniProtKB

cytosol

Traceable author statement. Source: Reactome

endosome

Inferred from sequence or structural similarity. Source: UniProtKB

nucleus

Inferred from sequence or structural similarity. Source: UniProtKB

protein complex

Inferred from direct assay PubMed 10973965. Source: RGD

vesicle membrane

Inferred from electronic annotation. Source: Ensembl

   Molecular_functionSH3 domain binding

Inferred from sequence or structural similarity. Source: UniProtKB

epidermal growth factor receptor binding

Inferred from sequence or structural similarity. Source: UniProtKB

insulin receptor substrate binding

Inferred from physical interaction PubMed 12891559. Source: RGD

phosphoprotein binding

Inferred from physical interaction PubMed 8910399. Source: RGD

phosphotyrosine binding

Inferred from physical interaction PubMed 9271418. Source: RGD

protein binding

Inferred from physical interaction PubMed 10748052PubMed 12023880PubMed 16357825PubMed 17437541PubMed 8940134. Source: IntAct

protein domain specific binding

Inferred from physical interaction PubMed 10973965. Source: RGD

Complete GO annotation...

Binary interactions

With

Entry

#Exp.

IntAct

Notes

Dnm1P215753EBI-401775,EBI-80070
Ntrk1P357396EBI-401775,EBI-976667
PDE6GP185452EBI-401775,EBI-2622029From a different organism.
PTPN1P180313EBI-401775,EBI-968788From a different organism.

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]

Note: Additional isoforms seem to exist.
Isoform 1 (identifier: P62994-1)

Also known as: Ash-L;

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
Isoform 2 (identifier: P62994-2)

Also known as: Ash-M;

The sequence of this isoform differs from the canonical sequence as follows:
     157-170: Missing.
Isoform 3 (identifier: P62994-3)

Also known as: Ash-S;

The sequence of this isoform differs from the canonical sequence as follows:
     60-217: Missing.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 217217Growth factor receptor-bound protein 2
PRO_0000088201

Regions

Domain1 – 5858SH3 1
Domain60 – 15293SH2
Domain156 – 21560SH3 2

Amino acid modifications

Modified residue11N-acetylmethionine By similarity
Modified residue61N6-acetyllysine By similarity
Modified residue501N6-acetyllysine By similarity
Modified residue1091N6-acetyllysine By similarity
Modified residue2111Phosphothreonine By similarity

Natural variations

Alternative sequence60 – 217158Missing in isoform 3.
VSP_001838
Alternative sequence157 – 17014Missing in isoform 2.
VSP_001840

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 (Ash-L) [UniParc].

Last modified August 31, 2004. Version 1.
Checksum: 83A4B0BA1B248DC4

FASTA21725,206
        10         20         30         40         50         60 
MEAIAKYDFK ATADDELSFK RGDILKVLNE ECDQNWYKAE LNGKDGFIPK NYIEMKPHPW 

        70         80         90        100        110        120 
FFGKIPRAKA EEMLSKQRHD GAFLIRESES APGDFSLSVK FGNDVQHFKV LRDGAGKYFL 

       130        140        150        160        170        180 
WVVKFNSLNE LVDYHRSTSV SRNQQIFLRD IEQVPQQPTY VQALFDFDPQ EDGELGFRRG 

       190        200        210 
DFIHVMDNSD PNWWKGACHG QTGMFPRNYV TPVNRNV 

« Hide

Isoform 2 (Ash-M) [UniParc] [UniParc].

Checksum: 8FB4869BE35F6CF5
Show »

FASTA20323,556
Isoform 3 (Ash-S) [UniParc] [UniParc].

Checksum: 61EC429649FEBFF0
Show »

FASTA596,880

References

« Hide 'large scale' references
[1]"Cloning of ASH, a ubiquitous protein composed of one Src homology region (SH) 2 and two SH3 domains, from human and rat cDNA libraries."
Matuoka K., Yamakawa A., Shibata M., Takenawa T.
Proc. Natl. Acad. Sci. U.S.A. 89:9015-9019(1992) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY.
Strain: Fischer 344.
Tissue: Brain.
[2]"Splicing isoforms of rat Ash/Grb2. Isolation and characterization of the cDNA and genomic DNA clones and implications for the physiological roles of the isoforms."
Watanabe K., Fukuchi T., Hosoya H., Shirasawa T., Matsuoka K., Miki H., Takenawa T.
J. Biol. Chem. 270:13733-13739(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 2 AND 3), FUNCTION.
Strain: Wistar.
Tissue: Brain.
[3]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
Tissue: Thymus.
[4]Lubec G., Afjehi-Sadat L., Chen W.-Q.
Submitted (APR-2007) to UniProtKB
Cited for: PROTEIN SEQUENCE OF 11-21; 77-86; 101-109; 125-136; 143-149 AND 208-215, IDENTIFICATION BY MASS SPECTROMETRY.
Strain: Sprague-Dawley.
Tissue: Hippocampus and Spinal cord.
[5]"Mutation of Tyr697, a GRB2-binding site, and Tyr721, a PI 3-kinase binding site, abrogates signal transduction by the murine CSF-1 receptor expressed in Rat-2 fibroblasts."
van der Geer P., Hunter T.
EMBO J. 12:5161-5172(1993) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH CSF1R.
[6]"Insulin stimulates association of insulin receptor substrate-1 with the protein abundant Src homology/growth factor receptor-bound protein 2."
Tobe K., Matuoka K., Tamemoto H., Ueki K., Kaburagi Y., Asai S., Noguchi T., Matsuda M., Tanaka S., Hattori S., Fukui Y., Akanuma Y., Yazaki Y., Takenawa T., Kadowaki T.
J. Biol. Chem. 268:11167-11171(1993) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH IRS1.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
X62853 mRNA. Translation: CAA44665.1.
D49846 mRNA. Translation: BAA08645.1.
D49847 mRNA. Translation: BAA08646.1.
BC091144 mRNA. Translation: AAH91144.1.
PIRS26050.
RefSeqNP_110473.2. NM_030846.2. [P62994-1]
UniGeneRn.3360.

3D structure databases

ProteinModelPortalP62994.
SMRP62994. Positions 1-217.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid249501. 10 interactions.
IntActP62994. 14 interactions.
MINTMINT-93691.

Chemistry

BindingDBP62994.

PTM databases

PhosphoSiteP62994.

Proteomic databases

PaxDbP62994.
PRIDEP62994.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSRNOT00000005347; ENSRNOP00000005347; ENSRNOG00000003990. [P62994-1]
GeneID81504.
KEGGrno:81504.

Organism-specific databases

CTD2885.
RGD619758. Grb2.

Phylogenomic databases

eggNOGNOG298780.
GeneTreeENSGT00550000074482.
HOGENOMHOG000251625.
HOVERGENHBG005404.
InParanoidP62994.
KOK04364.
OMAVETKFVQ.
OrthoDBEOG75F4F6.
PhylomeDBP62994.
TreeFamTF354288.

Enzyme and pathway databases

ReactomeREACT_212996. Signal Transduction.
REACT_227097. Immune System.

Gene expression databases

GenevestigatorP62994.

Family and domain databases

Gene3D3.30.505.10. 1 hit.
InterProIPR000980. SH2.
IPR001452. SH3_domain.
[Graphical view]
PfamPF00017. SH2. 1 hit.
PF00018. SH3_1. 2 hits.
[Graphical view]
PRINTSPR00401. SH2DOMAIN.
PR00452. SH3DOMAIN.
SMARTSM00252. SH2. 1 hit.
SM00326. SH3. 2 hits.
[Graphical view]
SUPFAMSSF50044. SSF50044. 2 hits.
SSF55550. SSF55550. 2 hits.
PROSITEPS50001. SH2. 1 hit.
PS50002. SH3. 2 hits.
[Graphical view]
ProtoNetSearch...

Other

NextBio614959.

Entry information

Entry nameGRB2_RAT
AccessionPrimary (citable) accession number: P62994
Secondary accession number(s): P29354 expand/collapse secondary AC list , Q14450, Q5BKA7, Q63057, Q63059
Entry history
Integrated into UniProtKB/Swiss-Prot: August 31, 2004
Last sequence update: August 31, 2004
Last modified: June 11, 2014
This is version 103 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families