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Growth factor receptor-bound protein 2 (Adapter protein GRB2) (Protein Ash) (SH2/SH3 adapter GRB2)

 GRB2_RAT                Reviewed;         217 AA.
P62994; P29354; Q14450; Q5BKA7; Q63057; Q63059;
31-AUG-2004, integrated into UniProtKB/Swiss-Prot.
31-AUG-2004, sequence version 1.
13-FEB-2019, entry version 146.
RecName: Full=Growth factor receptor-bound protein 2;
AltName: Full=Adapter protein GRB2;
AltName: Full=Protein Ash;
AltName: Full=SH2/SH3 adapter GRB2;
Name=Grb2; Synonyms=Ash;
Rattus norvegicus (Rat).
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha;
Muroidea; Muridae; Murinae; Rattus.
STRAIN=Fischer 344; TISSUE=Brain;
PubMed=1384039; DOI=10.1073/pnas.89.19.9015;
Matuoka K., Yamakawa A., Shibata M., Takenawa T.;
"Cloning of ASH, a ubiquitous protein composed of one Src homology
region (SH) 2 and two SH3 domains, from human and rat cDNA
Proc. Natl. Acad. Sci. U.S.A. 89:9015-9019(1992).
STRAIN=Wistar; TISSUE=Brain;
PubMed=7775428; DOI=10.1074/jbc.270.23.13733;
Watanabe K., Fukuchi T., Hosoya H., Shirasawa T., Matsuoka K.,
Miki H., Takenawa T.;
"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.";
J. Biol. Chem. 270:13733-13739(1995).
PubMed=15489334; DOI=10.1101/gr.2596504;
The MGC Project Team;
"The status, quality, and expansion of the NIH full-length cDNA
project: the Mammalian Gene Collection (MGC).";
Genome Res. 14:2121-2127(2004).
PROTEIN SEQUENCE OF 11-21; 77-86; 101-109; 125-136; 143-149 AND
STRAIN=Sprague-Dawley; TISSUE=Hippocampus, and Spinal cord;
Lubec G., Afjehi-Sadat L., Chen W.-Q.;
Submitted (APR-2007) to UniProtKB.
van der Geer P., Hunter T.;
"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.";
EMBO J. 12:5161-5172(1993).
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.;
"Insulin stimulates association of insulin receptor substrate-1 with
the protein abundant Src homology/growth factor receptor-bound protein
J. Biol. Chem. 268:11167-11171(1993).
-!- FUNCTION: Adapter protein that provides a critical link between
cell surface growth factor receptors and the Ras signaling
pathway. {ECO:0000250, ECO:0000269|PubMed:7775428}.
-!- SUBUNIT: Associates (via SH2 domain) with activated EGF and PDGF
receptors (tyrosine phosphorylated). Interacts with PDGFRA
(tyrosine phosphorylated); the interaction may be indirect.
Interacts with IRS4 (when Tyr-phosphorylated). Also associates to
other cellular Tyr-phosphorylated proteins such as SIT1, 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. Interacts with SOS1. Forms a
complex with MUC1 and SOS1, through interaction of the SH3 domains
with SOS1 and the SH2 domain with phosphorylated MUC1. Interacts
with phosphorylated MET. Interacts with phosphorylated TOM1L1.
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 NISCH, PTPNS1 and REPS2.
Interacts with syntrophin SNTA1. Interacts (via SH3 domains) with
REPS1. Interacts (via SH3 domains) with PIK3C2B. Interacts with
CBL and CBLB. Interacts with AJUBA and CLNK. Interacts (via SH2
domain) with TEK/TIE2 (tyrosine phosphorylated). Interacts with
SHB, INPP5D/SHIP1, SKAP1 and SKAP2. Interacts with PTPN11.
Interacts with PRNP. Interacts with RALGPS1. Interacts also with
HCST. Interacts with KDR. Interacts with FLT1 (tyrosine-
phosphorylated). Interacts with GAPT and PTPRE. Interacts (via SH2
domain) with KIF26A. Interacts (via SH3 2) with GAB2. Interacts
with ADAM15. Interacts with THEMIS2. Interacts (via SH2 domain)
with AXL (phosphorylated). Interacts (via SH2 domain) with KIT
(phosphorylated). Interacts with PTPRJ and BCR. Interacts with
PTPN23. Interacts with FLT4 (tyrosine phosphorylated). Interacts
with EPHB1 and SHC1; activates the MAPK/ERK cascade to regulate
cell migration. Part of a complex including TNK2, GRB2 and one
receptor tyrosine kinase (RTK) such as AXL and PDGFRL, in which
GRB2 promotes RTK recruitment by TNK2. Interacts with ERBB4.
Interacts with NTRK1 (phosphorylated upon ligand-binding).
Interacts with PTK2/FAK1 (tyrosine phosphorylated). Interacts with
PTK2B/PYK2 (tyrosine phosphorylated). Interacts with SCIMP.
Interacts (via SH3 domains) with GAREM1 (via proline-rich domain
and tyrosine phosphorylated); the interaction occurs upon EGF
stimulation. Interacts with DAB2. Interacts with TESPA1. Interacts
with THEMIS. Interacts with PLCG1, LAT and THEMIS upon TCR
activation in thymocytes; the association is weaker in the absence
of TESPA1. Interacts with CD28. Interacts with RAB13; may recruit
RAB13 to the leading edge of migrating endothelial cells where it
can activate RHOA. Interacts with ASAP3 (phosphorylated form) (By
similarity). Interacts (via SH2 domain) with CSF1R and IRS1
(tyrosine phosphorylated) (PubMed:8262059, PubMed:8388384).
Interacts (via SH2 domain) with PTPRH (phosphorylated form) (By
similarity). Interacts with PTPRO (phosphorylated form) (By
similarity). Interacts with PTPRB (phosphorylated form) (By
similarity). Interacts (via SH3 domain 2) with PRR14 (via proline-
rich region) (By similarity). Interacts with ST5 (By similarity).
{ECO:0000250|UniProtKB:P62993, ECO:0000250|UniProtKB:Q60631,
ECO:0000269|PubMed:8262059, ECO:0000269|PubMed:8388384}.
P21575:Dnm1; NbExp=3; IntAct=EBI-401775, EBI-80070;
P35739:Ntrk1; NbExp=6; IntAct=EBI-401775, EBI-976667;
P18545:PDE6G (xeno); NbExp=2; IntAct=EBI-401775, EBI-2622029;
P18031:PTPN1 (xeno); NbExp=3; IntAct=EBI-401775, EBI-968788;
-!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250}. Cytoplasm
{ECO:0000250}. Endosome {ECO:0000250}. Golgi apparatus
Event=Alternative splicing; Named isoforms=3;
Comment=Additional isoforms seem to exist.;
Name=1; Synonyms=Ash-L;
IsoId=P62994-1, P29354-1;
Name=2; Synonyms=Ash-M;
IsoId=P62994-2, P29354-3;
Name=3; Synonyms=Ash-S;
IsoId=P62994-3, P29354-4;
-!- TISSUE SPECIFICITY: Wide tissue distribution.
-!- DOMAIN: The SH3 domains mediate interaction with RALGPS1 and SHB.
-!- SIMILARITY: Belongs to the GRB2/sem-5/DRK family. {ECO:0000305}.
Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
Distributed under the Creative Commons Attribution (CC BY 4.0) License
EMBL; X62853; CAA44665.1; -; mRNA.
EMBL; D49846; BAA08645.1; -; mRNA.
EMBL; D49847; BAA08646.1; -; mRNA.
EMBL; BC091144; AAH91144.1; -; mRNA.
PIR; S26050; S26050.
RefSeq; NP_110473.2; NM_030846.2. [P62994-1]
UniGene; Rn.3360; -.
ProteinModelPortal; P62994; -.
SMR; P62994; -.
BioGrid; 249501; 12.
CORUM; P62994; -.
IntAct; P62994; 15.
MINT; P62994; -.
STRING; 10116.ENSRNOP00000005347; -.
iPTMnet; P62994; -.
PhosphoSitePlus; P62994; -.
SwissPalm; P62994; -.
jPOST; P62994; -.
PaxDb; P62994; -.
PRIDE; P62994; -.
Ensembl; ENSRNOT00000005347; ENSRNOP00000005347; ENSRNOG00000003990. [P62994-1]
GeneID; 81504; -.
KEGG; rno:81504; -.
CTD; 2885; -.
RGD; 619758; Grb2.
eggNOG; KOG3601; Eukaryota.
GeneTree; ENSGT00940000155738; -.
HOGENOM; HOG000251625; -.
HOVERGEN; HBG005404; -.
InParanoid; P62994; -.
KO; K04364; -.
OrthoDB; 1091250at2759; -.
PhylomeDB; P62994; -.
TreeFam; TF354288; -.
Reactome; R-RNO-109704; PI3K Cascade.
Reactome; R-RNO-112412; SOS-mediated signalling.
Reactome; R-RNO-1250347; SHC1 events in ERBB4 signaling.
Reactome; R-RNO-1257604; PIP3 activates AKT signaling.
Reactome; R-RNO-1295596; Spry regulation of FGF signaling.
Reactome; R-RNO-1433557; Signaling by SCF-KIT.
Reactome; R-RNO-1433559; Regulation of KIT signaling.
Reactome; R-RNO-167044; Signalling to RAS.
Reactome; R-RNO-179812; GRB2 events in EGFR signaling.
Reactome; R-RNO-180292; GAB1 signalosome.
Reactome; R-RNO-180336; SHC1 events in EGFR signaling.
Reactome; R-RNO-182971; EGFR downregulation.
Reactome; R-RNO-186763; Downstream signal transduction.
Reactome; R-RNO-1963640; GRB2 events in ERBB2 signaling.
Reactome; R-RNO-1963642; PI3K events in ERBB2 signaling.
Reactome; R-RNO-2029482; Regulation of actin dynamics for phagocytic cup formation.
Reactome; R-RNO-210993; Tie2 Signaling.
Reactome; R-RNO-2179392; EGFR Transactivation by Gastrin.
Reactome; R-RNO-2424491; DAP12 signaling.
Reactome; R-RNO-2428933; SHC-related events triggered by IGF1R.
Reactome; R-RNO-2730905; Role of LAT2/NTAL/LAB on calcium mobilization.
Reactome; R-RNO-2871796; FCERI mediated MAPK activation.
Reactome; R-RNO-2871809; FCERI mediated Ca+2 mobilization.
Reactome; R-RNO-354194; GRB2:SOS provides linkage to MAPK signaling for Integrins.
Reactome; R-RNO-375165; NCAM signaling for neurite out-growth.
Reactome; R-RNO-388841; Costimulation by the CD28 family.
Reactome; R-RNO-389359; CD28 dependent Vav1 pathway.
Reactome; R-RNO-391160; Signal regulatory protein family interactions.
Reactome; R-RNO-5654688; SHC-mediated cascade:FGFR1.
Reactome; R-RNO-5654689; PI-3K cascade:FGFR1.
Reactome; R-RNO-5654693; FRS-mediated FGFR1 signaling.
Reactome; R-RNO-5654695; PI-3K cascade:FGFR2.
Reactome; R-RNO-5654699; SHC-mediated cascade:FGFR2.
Reactome; R-RNO-5654700; FRS-mediated FGFR2 signaling.
Reactome; R-RNO-5654704; SHC-mediated cascade:FGFR3.
Reactome; R-RNO-5654706; FRS-mediated FGFR3 signaling.
Reactome; R-RNO-5654710; PI-3K cascade:FGFR3.
Reactome; R-RNO-5654712; FRS-mediated FGFR4 signaling.
Reactome; R-RNO-5654719; SHC-mediated cascade:FGFR4.
Reactome; R-RNO-5654720; PI-3K cascade:FGFR4.
Reactome; R-RNO-5654726; Negative regulation of FGFR1 signaling.
Reactome; R-RNO-5654727; Negative regulation of FGFR2 signaling.
Reactome; R-RNO-5654732; Negative regulation of FGFR3 signaling.
Reactome; R-RNO-5654733; Negative regulation of FGFR4 signaling.
Reactome; R-RNO-5663213; RHO GTPases Activate WASPs and WAVEs.
Reactome; R-RNO-5673001; RAF/MAP kinase cascade.
Reactome; R-RNO-6807004; Negative regulation of MET activity.
Reactome; R-RNO-6811558; PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling.
Reactome; R-RNO-74749; Signal attenuation.
Reactome; R-RNO-74751; Insulin receptor signalling cascade.
Reactome; R-RNO-8851805; MET activates RAS signaling.
Reactome; R-RNO-8851907; MET activates PI3K/AKT signaling.
Reactome; R-RNO-8853659; RET signaling.
Reactome; R-RNO-8856825; Cargo recognition for clathrin-mediated endocytosis.
Reactome; R-RNO-8856828; Clathrin-mediated endocytosis.
Reactome; R-RNO-8865999; MET activates PTPN11.
Reactome; R-RNO-8875555; MET activates RAP1 and RAC1.
Reactome; R-RNO-8875656; MET receptor recycling.
Reactome; R-RNO-8983432; Interleukin-15 signaling.
Reactome; R-RNO-9027284; Erythropoietin activates RAS.
Reactome; R-RNO-9028731; Activated NTRK2 signals through FRS2 and FRS3.
Reactome; R-RNO-912526; Interleukin receptor SHC signaling.
Reactome; R-RNO-912631; Regulation of signaling by CBL.
Reactome; R-RNO-983695; Antigen activates B Cell Receptor (BCR) leading to generation of second messengers.
PRO; PR:P62994; -.
Proteomes; UP000002494; Chromosome 10.
Bgee; ENSRNOG00000003990; Expressed in 10 organ(s), highest expression level in spleen.
Genevisible; P62994; RN.
GO; GO:0005911; C:cell-cell junction; IEA:Ensembl.
GO; GO:0008180; C:COP9 signalosome; ISS:UniProtKB.
GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
GO; GO:0005829; C:cytosol; TAS:Reactome.
GO; GO:0005768; C:endosome; ISS:UniProtKB.
GO; GO:0005794; C:Golgi apparatus; IEA:UniProtKB-SubCell.
GO; GO:0070436; C:Grb2-EGFR complex; IEA:Ensembl.
GO; GO:0005730; C:nucleolus; IEA:Ensembl.
GO; GO:0005654; C:nucleoplasm; IEA:Ensembl.
GO; GO:0005634; C:nucleus; ISS:UniProtKB.
GO; GO:0032991; C:protein-containing complex; IDA:RGD.
GO; GO:0012506; C:vesicle membrane; IEA:Ensembl.
GO; GO:0019899; F:enzyme binding; IPI:RGD.
GO; GO:0046875; F:ephrin receptor binding; IEA:Ensembl.
GO; GO:0005154; F:epidermal growth factor receptor binding; IPI:RGD.
GO; GO:0042802; F:identical protein binding; IEA:Ensembl.
GO; GO:0043560; F:insulin receptor substrate binding; IPI:RGD.
GO; GO:0005168; F:neurotrophin TRKA receptor binding; IEA:Ensembl.
GO; GO:0051219; F:phosphoprotein binding; IPI:RGD.
GO; GO:0001784; F:phosphotyrosine residue binding; IPI:RGD.
GO; GO:0019904; F:protein domain specific binding; IPI:RGD.
GO; GO:0019901; F:protein kinase binding; IEA:Ensembl.
GO; GO:0019903; F:protein phosphatase binding; IEA:Ensembl.
GO; GO:0017124; F:SH3 domain binding; ISS:UniProtKB.
GO; GO:0005070; F:SH3/SH2 adaptor activity; IEA:Ensembl.
GO; GO:0007568; P:aging; IPI:RGD.
GO; GO:0048646; P:anatomical structure formation involved in morphogenesis; IEA:Ensembl.
GO; GO:0060670; P:branching involved in labyrinthine layer morphogenesis; IEA:Ensembl.
GO; GO:0030154; P:cell differentiation; IEA:Ensembl.
GO; GO:0071479; P:cellular response to ionizing radiation; IEA:Ensembl.
GO; GO:0008286; P:insulin receptor signaling pathway; IEA:Ensembl.
GO; GO:0030838; P:positive regulation of actin filament polymerization; IEA:Ensembl.
GO; GO:2000379; P:positive regulation of reactive oxygen species metabolic process; IEA:Ensembl.
GO; GO:0051291; P:protein heterooligomerization; IDA:RGD.
GO; GO:0007265; P:Ras protein signal transduction; TAS:RGD.
GO; GO:0031623; P:receptor internalization; IEA:Ensembl.
GO; GO:0043408; P:regulation of MAPK cascade; IEA:Ensembl.
GO; GO:0042770; P:signal transduction in response to DNA damage; IEA:Ensembl.
CDD; cd11949; SH3_GRB2_C; 1.
CDD; cd11946; SH3_GRB2_N; 1.
Gene3D; 3.30.505.10; -; 1.
InterPro; IPR030219; Grb2.
InterPro; IPR035643; GRB2_C_SH3.
InterPro; IPR035641; GRB2_N_SH3.
InterPro; IPR000980; SH2.
InterPro; IPR036860; SH2_dom_sf.
InterPro; IPR036028; SH3-like_dom_sf.
InterPro; IPR001452; SH3_domain.
PANTHER; PTHR24418:SF290; PTHR24418:SF290; 1.
Pfam; PF00017; SH2; 1.
Pfam; PF00018; SH3_1; 2.
SMART; SM00252; SH2; 1.
SMART; SM00326; SH3; 2.
SUPFAM; SSF50044; SSF50044; 2.
SUPFAM; SSF55550; SSF55550; 1.
PROSITE; PS50001; SH2; 1.
PROSITE; PS50002; SH3; 2.
1: Evidence at protein level;
Acetylation; Alternative splicing; Complete proteome; Cytoplasm;
Direct protein sequencing; Endosome; Golgi apparatus; Nucleus;
Phosphoprotein; Reference proteome; Repeat; SH2 domain; SH3 domain.
CHAIN 1 217 Growth factor receptor-bound protein 2.
DOMAIN 1 58 SH3 1. {ECO:0000255|PROSITE-
DOMAIN 60 152 SH2. {ECO:0000255|PROSITE-
DOMAIN 156 215 SH3 2. {ECO:0000255|PROSITE-
MOD_RES 1 1 N-acetylmethionine.
MOD_RES 6 6 N6-acetyllysine.
MOD_RES 50 50 N6-acetyllysine.
MOD_RES 109 109 N6-acetyllysine.
MOD_RES 211 211 Phosphothreonine.
VAR_SEQ 60 217 Missing (in isoform 3).
VAR_SEQ 157 170 Missing (in isoform 2).
SEQUENCE 217 AA; 25206 MW; 83A4B0BA1B248DC4 CRC64;

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