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FLASH GENE
Symbol GRB2 contributors: mct - updated : 23-02-2017
HGNC name growth factor receptor-bound protein 2
HGNC id 4566
Location 17q25.1      Physical location : 73.314.157 - 73.401.790
Synonym name
  • abundant SRC homology
  • epidermal growth factor receptor-binding protein GRB2
  • growth factor receptor-bound protein 3
  • adapter protein GRB2
    • Synonym symbol(s) ASH, EGFRBP-GRB2, Grb3-3, MST084, MSTP084, HT027
    DNA
    TYPE functioning gene
    STRUCTURE 87.63 kb     5 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked N status confirmed
    RNA
    TRANSCRIPTS type messenger
    text several transcripts resulting from alternative splicing
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    6 splicing 3303 - 217 - 2008 18789888
    deletion in the SH2 domain
    5 - 3181 - 176 - 2008 18789888
    dominant negative over GRB2 triggering apoptosis
    EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart   highly
    Lymphoid/Immunelymph node   highly
     spleen   highly
    Nervousbrain   highly
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • one SH2 binding PGDFRs, EGFR, IRS1, SHC1 (one central SH2 domain flanked by two SH3 domains), SH2 domain having the potential to be used as a binding component of a probe to detect activated-RTK and to evaluate the effect of kinase inhibitors on RTK activation
  • two SH3 domains binding SOS (signal transduction), C-SH3 domain binds to a proline-rich sequence at the very C terminus of FGFR2 prior to growth factor stimulation
  • one K homology (KH) motif bound to a QUA2 motif (RNA binding), lacking a catalytic domain
    • HOMOLOGY
    interspecies homolog to C.elegans Sem5 gene
    homolog to Drosophila Drk
    Homologene
    FAMILY
  • GRB2/sem-5/DRK family
    • CATEGORY regulatory , signaling growth factor
    SUBCELLULAR LOCALIZATION     plasma membrane
        intracellular
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,organelle,Golgi
    intracellular,cytoplasm,organelle,endosome
    basic FUNCTION
  • linking the insulin receptor to Ras signaling pathway through the formation of a complex with SOS1
  • mitogenic RAS signaling through interaction with SHC1
  • may act as an adaptor protein to simultaneously regulate both cell surface localization and reverse signaling of FASLG in Schwann cells
  • major mediator in Ras-MAPK activation induced by numerous receptors because of its association with son of sevenless, a GDP-GTP exchange factor for Ras
  • adaptor molecule that mediates Ras-MAPK activation induced by various receptors
  • plays a pivotal role in both thymic positive and negative selection and amplifies TCR signaling at the top end of the tyrosine phosphorylation cascade via a scaffolding function
  • nonredundant regulator that controls lymphoid follicle organization and germinal center reaction (executes this function by connecting the CXCR5 signaling pathway to lymphotoxin expression but not to chemotaxis)
  • involved in the regulation of CD22 tyrosine phosphorylation, suggesting that it may control BCR signaling by integrating the CD22-SHP-1 negative-feedback loop in B cells
  • GRB2-mediated signaling is critical for lymphotoxin expression in naive B cells
  • plays an important role in B cells via integrating various signaling transduction pathways of the BCR and CXCR5
  • RASGRP1 and GRB2/SOS1 are insulators of signals that lead to RAS activation induced by different stimuli, rather than cooperating downstream of the TCRA
  • GRB2 is strongly implicated in controlling FGFR2 kinase activity prior to growth factor stimulation
  • exerts constitutive control over the mutually dependent activities of FGFR2 and PTPN11
  • SOS1 and its adaptor GRB2 are multidomain proteins that couple fibroblast growth factor (FGF) signaling to activation of the Ras-Erk pathway during development and drive embryonic stem cells toward the primitive endoderm (PrE) lineage
  • GRB2 is a negative regulator of myogenesis and reduces myogenic differentiation by inhibiting actin polymerization/remodeling through its C-terminal SH3 domain
  • GRB2 and GRAP connect the B cell antigen receptor to Erk MAP kinase activation in human B cells
    • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling signal transduction
    a component
  • major component of CBL associated protein
  • GRB2/GAB2/SHC1/LRRK1 signal integrator complex is functionally involved in the balance of cellular stress responses
  • DOK3/GRB2 modulates the balance between activatory and inhibitory LYN functions with the aim to adjust BCR signaling efficiency
    • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • GRB2/SOS1 binding to activated tyrosine-phosphorylated
  • EGFR and PDGFR and other cellular tyrosine phosphorylated proteins receptors to signaling for mitogenesis and cytoskeletal reorganization
  • IRS1 and SHC1 in the INSR to RAS signaling pathway
  • binding to GRF2
  • DISC1-interacting molecule
  • binds to the proline-rich domain of FASLG and regulates its cell surface expression (acting as an adaptor for FASLG to interact with adaptin beta, a molecule known to regulate trafficking)
  • interacting with CLEC17A
  • phosphorylating PRKAB1 at Thr172
  • interaction with both LY6G6F and GRB7 is mediated through its Src homology 2 domains and is dependent on the phosphorylation of LY6G6F
  • interaction of PTPN23 with two adapters of the GRB2 family, essential for numerous signaling pathways, suggesting that PTPN23 might be important for signaling through a plethora of receptors
  • interaction with LRRK1
  • interacting with CXCR5 (specifically controls a branch of CXCR5 signaling in B cells that induces lymphotoxin beta transcription but not chemotaxis)
  • interaction with RHOU (GRB2 couples RHOU to epidermal growth factor receptor signaling and cell migration)
  • ASAP3 regulates ITGB1 dynamics during EGF-stimulated cell migration by interaction with GRB2
  • GRB2 mediates the interaction of TNK2 with EGFR through binding to the EBD and activates TNK2 by releasing the auto-inhibition
  • role for GRB2 as an active regulator of RTK signaling
  • ATXN2 modulates the levels of GRB2 and SRC but not ras signaling
  • controls FGFR2 signaling by regulating receptor kinase and PTPN11 phosphatase activity in the absence of extracellular stimulation
  • scaffold function of SOS1 depended on its ability to bind to the adaptor protein GRB2
  • GRB2 is a new PTK2 activator awith an essential role in coordinating PTPRA tyrosine phosphorylation to enable downstream integrin signaling and migration
  • upon T cell activation, LAT is phosphorylated and associates with GRB2, GRAP2, and PLCG1 through its four distal tyrosine residues
  • GRB2 N-terminal and C-terminal SH3 domains bind to proline rich proteins such as WASL
  • interactions of PIK3AP1 with Src homology 2 (SH2) and SH3 domain-containing adaptor proteins, notably growth factor receptor-bound protein 2 (GRB2) and CRKL
    • cell & other
    REGULATION
    Phosphorylated by FGFR2 (upon stimulation, FGFR2 phosphorylates tyrosine residues on GRB2, promoting dissociation from the receptor and allowing full activation of downstream signaling)
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral     --over  
    in gastric cancer
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    ANIMAL & CELL MODELS