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Protein

Growth factor receptor-bound protein 2

Gene

Grb2

Organism
Rattus norvegicus (Rat)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

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

GO - Molecular functioni

  • epidermal growth factor receptor binding Source: UniProtKB
  • insulin receptor substrate binding Source: RGD
  • phosphoprotein binding Source: RGD
  • phosphotyrosine binding Source: RGD
  • poly(A) RNA binding Source: Ensembl
  • protein domain specific binding Source: RGD
  • SH3 domain binding Source: UniProtKB

GO - Biological processi

Complete GO annotation...

Enzyme and pathway databases

ReactomeiREACT_271828. PI3K events in ERBB2 signaling.
REACT_272857. GAB1 signalosome.
REACT_280793. Interleukin-3, 5 and GM-CSF signaling.
REACT_282745. NCAM signaling for neurite out-growth.
REACT_283992. GRB2 events in ERBB2 signaling.
REACT_285615. Regulation of actin dynamics for phagocytic cup formation.
REACT_288944. SOS-mediated signalling.
REACT_289184. Signal attenuation.
REACT_290221. Signal regulatory protein (SIRP) family interactions.
REACT_291658. PI3K Cascade.
REACT_295971. SHC1 events in EGFR signaling.
REACT_297589. GPVI-mediated activation cascade.
REACT_297788. EGFR Transactivation by Gastrin.
REACT_299102. PIP3 activates AKT signaling.
REACT_301200. Downstream signal transduction.
REACT_301547. G beta:gamma signalling through PI3Kgamma.
REACT_302394. Role of LAT2/NTAL/LAB on calcium mobilization.
REACT_302655. Interleukin receptor SHC signaling.
REACT_306713. Costimulation by the CD28 family.
REACT_307156. SHC1 events in ERBB4 signaling.
REACT_307725. Spry regulation of FGF signaling.
REACT_313573. Regulation of KIT signaling.
REACT_316519. CD28 dependent Vav1 pathway.
REACT_316581. Signalling to RAS.
REACT_319562. SHC-mediated signalling.
REACT_320393. GRB2 events in EGFR signaling.
REACT_320606. Regulation of signaling by CBL.
REACT_332169. DAP12 signaling.
REACT_334873. Tie2 Signaling.
REACT_335137. Signaling by SCF-KIT.
REACT_340722. FCERI mediated Ca+2 mobilization.
REACT_341785. Antigen activates B Cell Receptor (BCR) leading to generation of second messengers.
REACT_345055. EGFR downregulation.
REACT_345666. GRB2:SOS provides linkage to MAPK signaling for Integrins.
REACT_345905. SHC1 events in ERBB2 signaling.
REACT_353315. FCERI mediated MAPK activation.
REACT_357361. PI-3K cascade:FGFR4.
REACT_357712. SHC-mediated cascade:FGFR2.
REACT_358345. RHO GTPases Activate WASPs and WAVEs.
REACT_358624. Negative regulation of FGFR4 signaling.
REACT_359240. FRS2-mediated FGFR4 signaling.
REACT_359268. Negative regulation of FGFR2 signaling.
REACT_359276. Negative regulation of FGFR1 signaling.
REACT_359641. PI-3K cascade:FGFR1.
REACT_359767. SHC-mediated cascade:FGFR3.
REACT_360014. FRS-mediated FGFR3 signaling.
REACT_360543. FRS-mediated FGFR2 signaling.
REACT_360800. Negative regulation of FGFR3 signaling.
REACT_360842. PI-3K cascade:FGFR2.
REACT_360887. FRS-mediated FGFR1 signaling.
REACT_361671. SHC-mediated cascade:FGFR1.
REACT_362207. SHC-mediated cascade:FGFR4.
REACT_362510. PI-3K cascade:FGFR3.

Names & Taxonomyi

Protein namesi
Recommended name:
Growth factor receptor-bound protein 2
Alternative name(s):
Adapter protein GRB2
Protein Ash
SH2/SH3 adapter GRB2
Gene namesi
Name:Grb2
Synonyms:Ash
OrganismiRattus norvegicus (Rat)
Taxonomic identifieri10116 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus
ProteomesiUP000002494 Componenti: Chromosome 10

Organism-specific databases

RGDi619758. Grb2.

Subcellular locationi

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Endosome, Golgi apparatus, Nucleus

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 217217Growth factor receptor-bound protein 2PRO_0000088201Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei1 – 11N-acetylmethionineBy similarity
Modified residuei6 – 61N6-acetyllysineBy similarity
Modified residuei50 – 501N6-acetyllysineBy similarity
Modified residuei109 – 1091N6-acetyllysineBy similarity
Modified residuei211 – 2111PhosphothreonineBy similarity

Keywords - PTMi

Acetylation, Phosphoprotein

Proteomic databases

PaxDbiP62994.
PRIDEiP62994.

PTM databases

PhosphoSiteiP62994.

Expressioni

Tissue specificityi

Wide tissue distribution.1 Publication

Gene expression databases

GenevisibleiP62994. RN.

Interactioni

Subunit structurei

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).By similarity2 Publications

Binary interactionsi

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

Protein-protein interaction databases

BioGridi249501. 10 interactions.
IntActiP62994. 14 interactions.
MINTiMINT-93691.
STRINGi10116.ENSRNOP00000005347.

Structurei

3D structure databases

ProteinModelPortaliP62994.
SMRiP62994. Positions 1-217.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini1 – 5858SH3 1PROSITE-ProRule annotationAdd
BLAST
Domaini60 – 15293SH2PROSITE-ProRule annotationAdd
BLAST
Domaini156 – 21560SH3 2PROSITE-ProRule annotationAdd
BLAST

Domaini

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

Sequence similaritiesi

Belongs to the GRB2/sem-5/DRK family.Curated
Contains 1 SH2 domain.PROSITE-ProRule annotation
Contains 2 SH3 domains.PROSITE-ProRule annotation

Keywords - Domaini

Repeat, SH2 domain, SH3 domain

Phylogenomic databases

eggNOGiNOG298780.
GeneTreeiENSGT00550000074482.
HOGENOMiHOG000251625.
HOVERGENiHBG005404.
InParanoidiP62994.
KOiK04364.
OMAiRFQDSVQ.
OrthoDBiEOG75F4F6.
PhylomeDBiP62994.
TreeFamiTF354288.

Family and domain databases

Gene3Di3.30.505.10. 1 hit.
InterProiIPR030219. Grb2.
IPR000980. SH2.
IPR001452. SH3_domain.
[Graphical view]
PANTHERiPTHR22820:SF27. PTHR22820:SF27. 1 hit.
PfamiPF00017. SH2. 1 hit.
PF00018. SH3_1. 2 hits.
[Graphical view]
PRINTSiPR00401. SH2DOMAIN.
PR00452. SH3DOMAIN.
SMARTiSM00252. SH2. 1 hit.
SM00326. SH3. 2 hits.
[Graphical view]
SUPFAMiSSF50044. SSF50044. 2 hits.
SSF55550. SSF55550. 2 hits.
PROSITEiPS50001. SH2. 1 hit.
PS50002. SH3. 2 hits.
[Graphical view]

Sequences (3)i

Sequence statusi: Complete.

This entry describes 3 isoformsi produced by alternative splicing. AlignAdd to basket

Note: Additional isoforms seem to exist.

Isoform 1 (identifier: P62994-1) [UniParc]FASTAAdd to basket

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.

« Hide

        10         20         30         40         50
MEAIAKYDFK ATADDELSFK RGDILKVLNE ECDQNWYKAE LNGKDGFIPK
60 70 80 90 100
NYIEMKPHPW FFGKIPRAKA EEMLSKQRHD GAFLIRESES APGDFSLSVK
110 120 130 140 150
FGNDVQHFKV LRDGAGKYFL WVVKFNSLNE LVDYHRSTSV SRNQQIFLRD
160 170 180 190 200
IEQVPQQPTY VQALFDFDPQ EDGELGFRRG DFIHVMDNSD PNWWKGACHG
210
QTGMFPRNYV TPVNRNV
Length:217
Mass (Da):25,206
Last modified:August 31, 2004 - v1
Checksum:i83A4B0BA1B248DC4
GO
Isoform 2 (identifier: P62994-2) [UniParc] [UniParc]FASTAAdd to basket

Also known as: Ash-M

The sequence of this isoform differs from the canonical sequence as follows:
     157-170: Missing.

Show »
Length:203
Mass (Da):23,556
Checksum:i8FB4869BE35F6CF5
GO
Isoform 3 (identifier: P62994-3) [UniParc] [UniParc]FASTAAdd to basket

Also known as: Ash-S

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

Show »
Length:59
Mass (Da):6,880
Checksum:i61EC429649FEBFF0
GO

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei60 – 217158Missing in isoform 3. 1 PublicationVSP_001838Add
BLAST
Alternative sequencei157 – 17014Missing in isoform 2. 1 PublicationVSP_001840Add
BLAST

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X62853 mRNA. Translation: CAA44665.1.
D49846 mRNA. Translation: BAA08645.1.
D49847 mRNA. Translation: BAA08646.1.
BC091144 mRNA. Translation: AAH91144.1.
PIRiS26050.
RefSeqiNP_110473.2. NM_030846.2. [P62994-1]
UniGeneiRn.3360.

Genome annotation databases

EnsembliENSRNOT00000005347; ENSRNOP00000005347; ENSRNOG00000003990. [P62994-1]
GeneIDi81504.
KEGGirno:81504.

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X62853 mRNA. Translation: CAA44665.1.
D49846 mRNA. Translation: BAA08645.1.
D49847 mRNA. Translation: BAA08646.1.
BC091144 mRNA. Translation: AAH91144.1.
PIRiS26050.
RefSeqiNP_110473.2. NM_030846.2. [P62994-1]
UniGeneiRn.3360.

3D structure databases

ProteinModelPortaliP62994.
SMRiP62994. Positions 1-217.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi249501. 10 interactions.
IntActiP62994. 14 interactions.
MINTiMINT-93691.
STRINGi10116.ENSRNOP00000005347.

Chemistry

BindingDBiP62994.

PTM databases

PhosphoSiteiP62994.

Proteomic databases

PaxDbiP62994.
PRIDEiP62994.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSRNOT00000005347; ENSRNOP00000005347; ENSRNOG00000003990. [P62994-1]
GeneIDi81504.
KEGGirno:81504.

Organism-specific databases

CTDi2885.
RGDi619758. Grb2.

Phylogenomic databases

eggNOGiNOG298780.
GeneTreeiENSGT00550000074482.
HOGENOMiHOG000251625.
HOVERGENiHBG005404.
InParanoidiP62994.
KOiK04364.
OMAiRFQDSVQ.
OrthoDBiEOG75F4F6.
PhylomeDBiP62994.
TreeFamiTF354288.

Enzyme and pathway databases

ReactomeiREACT_271828. PI3K events in ERBB2 signaling.
REACT_272857. GAB1 signalosome.
REACT_280793. Interleukin-3, 5 and GM-CSF signaling.
REACT_282745. NCAM signaling for neurite out-growth.
REACT_283992. GRB2 events in ERBB2 signaling.
REACT_285615. Regulation of actin dynamics for phagocytic cup formation.
REACT_288944. SOS-mediated signalling.
REACT_289184. Signal attenuation.
REACT_290221. Signal regulatory protein (SIRP) family interactions.
REACT_291658. PI3K Cascade.
REACT_295971. SHC1 events in EGFR signaling.
REACT_297589. GPVI-mediated activation cascade.
REACT_297788. EGFR Transactivation by Gastrin.
REACT_299102. PIP3 activates AKT signaling.
REACT_301200. Downstream signal transduction.
REACT_301547. G beta:gamma signalling through PI3Kgamma.
REACT_302394. Role of LAT2/NTAL/LAB on calcium mobilization.
REACT_302655. Interleukin receptor SHC signaling.
REACT_306713. Costimulation by the CD28 family.
REACT_307156. SHC1 events in ERBB4 signaling.
REACT_307725. Spry regulation of FGF signaling.
REACT_313573. Regulation of KIT signaling.
REACT_316519. CD28 dependent Vav1 pathway.
REACT_316581. Signalling to RAS.
REACT_319562. SHC-mediated signalling.
REACT_320393. GRB2 events in EGFR signaling.
REACT_320606. Regulation of signaling by CBL.
REACT_332169. DAP12 signaling.
REACT_334873. Tie2 Signaling.
REACT_335137. Signaling by SCF-KIT.
REACT_340722. FCERI mediated Ca+2 mobilization.
REACT_341785. Antigen activates B Cell Receptor (BCR) leading to generation of second messengers.
REACT_345055. EGFR downregulation.
REACT_345666. GRB2:SOS provides linkage to MAPK signaling for Integrins.
REACT_345905. SHC1 events in ERBB2 signaling.
REACT_353315. FCERI mediated MAPK activation.
REACT_357361. PI-3K cascade:FGFR4.
REACT_357712. SHC-mediated cascade:FGFR2.
REACT_358345. RHO GTPases Activate WASPs and WAVEs.
REACT_358624. Negative regulation of FGFR4 signaling.
REACT_359240. FRS2-mediated FGFR4 signaling.
REACT_359268. Negative regulation of FGFR2 signaling.
REACT_359276. Negative regulation of FGFR1 signaling.
REACT_359641. PI-3K cascade:FGFR1.
REACT_359767. SHC-mediated cascade:FGFR3.
REACT_360014. FRS-mediated FGFR3 signaling.
REACT_360543. FRS-mediated FGFR2 signaling.
REACT_360800. Negative regulation of FGFR3 signaling.
REACT_360842. PI-3K cascade:FGFR2.
REACT_360887. FRS-mediated FGFR1 signaling.
REACT_361671. SHC-mediated cascade:FGFR1.
REACT_362207. SHC-mediated cascade:FGFR4.
REACT_362510. PI-3K cascade:FGFR3.

Miscellaneous databases

NextBioi614959.
PROiP62994.

Gene expression databases

GenevisibleiP62994. RN.

Family and domain databases

Gene3Di3.30.505.10. 1 hit.
InterProiIPR030219. Grb2.
IPR000980. SH2.
IPR001452. SH3_domain.
[Graphical view]
PANTHERiPTHR22820:SF27. PTHR22820:SF27. 1 hit.
PfamiPF00017. SH2. 1 hit.
PF00018. SH3_1. 2 hits.
[Graphical view]
PRINTSiPR00401. SH2DOMAIN.
PR00452. SH3DOMAIN.
SMARTiSM00252. SH2. 1 hit.
SM00326. SH3. 2 hits.
[Graphical view]
SUPFAMiSSF50044. SSF50044. 2 hits.
SSF55550. SSF55550. 2 hits.
PROSITEiPS50001. SH2. 1 hit.
PS50002. SH3. 2 hits.
[Graphical view]
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  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.

Entry informationi

Entry nameiGRB2_RAT
AccessioniPrimary (citable) accession number: P62994
Secondary accession number(s): P29354
, Q14450, Q5BKA7, Q63057, Q63059
Entry historyi
Integrated into UniProtKB/Swiss-Prot: August 31, 2004
Last sequence update: August 31, 2004
Last modified: June 24, 2015
This is version 113 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into Uniref entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.