P62994 (GRB2_RAT) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended 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

Organism

Rattus norvegicus (Rat) [Reference proteome]

Taxonomic identifier

10116 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Rattus

Protein attributes

Sequence length	217 AA.
Sequence status	Complete.
Protein existence	Evidence 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, IRS1, 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 (via SH2 domain) with CSF1R (tyrosine phosphorylated). 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. 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 component	Cytoplasm Endosome Golgi apparatus Nucleus
Coding sequence diversity	Alternative splicing
Domain	Repeat SH2 domain SH3 domain
PTM	Acetylation Phosphoprotein
Technical term	Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	Ras 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: Compara branching involved in labyrinthine layer morphogenesis Inferred from electronic annotation. Source: Compara cell differentiation Inferred from electronic annotation. Source: Compara cellular response to ionizing radiation Inferred from electronic annotation. Source: Compara insulin receptor signaling pathway Inferred from electronic annotation. Source: Compara positive regulation of actin filament polymerization Inferred from electronic annotation. Source: Compara positive regulation of reactive oxygen species metabolic process Inferred from electronic annotation. Source: Compara protein heterooligomerization Inferred from direct assay PubMed 15272025. Source: RGD receptor internalization Inferred from electronic annotation. Source: Compara regulation of MAPK cascade Inferred from electronic annotation. Source: Compara signal transduction in response to DNA damage Inferred from electronic annotation. Source: Compara
Cellular_component	Golgi apparatus Inferred from electronic annotation. Source: UniProtKB-SubCell Grb2-EGFR complex Inferred from electronic annotation. Source: Compara cytosol Traceable author statement. Source: Reactome endosome Inferred from sequence or structural similarity. Source: UniProtKB signalosome Inferred from sequence or structural similarity. Source: UniProtKB vesicle membrane Inferred from electronic annotation. Source: Compara
Molecular_function	SH3 domain binding Inferred from sequence or structural similarity. Source: UniProtKB epidermal growth factor receptor binding Inferred from sequence or structural similarity. Source: UniProtKB
Complete GO annotation...

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 key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 217	217	Growth factor receptor-bound protein 2		PRO_0000088201
Regions
	Domain	1 – 58	58	SH3 1
	Domain	60 – 152	93	SH2
	Domain	156 – 215	60	SH3 2
Amino acid modifications
	Modified residue	1	1	N-acetylmethionine By similarity
	Modified residue	6	1	N6-acetyllysine By similarity
	Modified residue	50	1	N6-acetyllysine By similarity
	Modified residue	109	1	N6-acetyllysine By similarity
	Modified residue	211	1	Phosphothreonine By similarity
Natural variations
	Alternative sequence	60 – 217	158	Missing in isoform 3.		VSP_001838
	Alternative sequence	157 – 170	14	Missing in isoform 2.		VSP_001840

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 (Ash-L) [UniParc]. Last modified August 31, 2004. Version 1. Checksum: 83A4B0BA1B248DC4	FASTA	217	25,206
	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
	Isoform 2 (Ash-M) [UniParc] [UniParc]. Checksum: 8FB4869BE35F6CF5	FASTA	203	23,556
	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 IEQVPQEDGE LGFRRGDFIH VMDNSDPNWW 190 200 KGACHGQTGM FPRNYVTPVN RNV
	Isoform 3 (Ash-S) [UniParc] [UniParc]. Checksum: 61EC429649FEBFF0	FASTA	59	6,880
	10 20 30 40 50 MEAIAKYDFK ATADDELSFK RGDILKVLNE ECDQNWYKAE LNGKDGFIPK NYIEMKPHP

References

	« Hide 'large scale' referencesShow '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, 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.
IPI	IPI00203630. IPI00231574. IPI00382077.
PIR	S26050.
RefSeq	NP_110473.2. NM_030846.2.
UniGene	Rn.3360.
3D structure databases
ProteinModelPortal	P62994.
ModBase	Search...
Protein-protein interaction databases
IntAct	P62994. 1 interaction.
MINT	MINT-93691.
PTM databases
PhosphoSite	P62994.
Proteomic databases
PaxDb	P62994.
PRIDE	P62994.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSRNOT00000005347; ENSRNOP00000005347; ENSRNOG00000003990.
GeneID	81504.
KEGG	rno:81504.
Organism-specific databases
CTD	2885.
RGD	619758. Grb2.
Phylogenomic databases
eggNOG	NOG298780.
GeneTree	ENSGT00550000074482.
HOGENOM	HOG000251625.
HOVERGEN	HBG005404.
InParanoid	P62994.
KO	K04364.
OrthoDB	EOG4XSKQS.
Enzyme and pathway databases
Reactome	REACT_109781. Immune System. REACT_111984. Signal Transduction.
Gene expression databases
ArrayExpress	P62994.
Genevestigator	P62994.
GermOnline	ENSRNOG00000003990. Rattus norvegicus.
Family and domain databases
Gene3D	3.30.505.10. 1 hit.
InterPro	IPR000108. p67phox. IPR000980. SH2. IPR001452. SH3_domain. [Graphical view]
Pfam	PF00017. SH2. 1 hit. PF00018. SH3_1. 2 hits. [Graphical view]
PRINTS	PR00499. P67PHOX. PR00401. SH2DOMAIN. PR00452. SH3DOMAIN.
SMART	SM00252. SH2. 1 hit. SM00326. SH3. 2 hits. [Graphical view]
SUPFAM	SSF50044. SH3. 1 hit.
PROSITE	PS50001. SH2. 1 hit. PS50002. SH3. 2 hits. [Graphical view]
ProtoNet	Search...
Other
BindingDB	P62994.
NextBio	614959.

Entry information

Entry name

GRB2_RAT

Accession

Primary (citable) accession number: P62994
Secondary accession number(s): P29354 , Q14450, Q5BKA7, Q63057, Q63059

Entry history

Integrated into UniProtKB/Swiss-Prot:	August 31, 2004
Last sequence update:	August 31, 2004
Last modified:	May 1, 2013
This is version 92 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program