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GRB10 (growth factor receptor-bound protein 10)

Written2002-08Sébastien Degot
I.G.B.M.C, 1, rue Laurent FRIES, BP 163 67404 ILLKIRH, France

(Note : for Links provided by Atlas : click)

Identity

Alias_namesgrowth factor receptor-bound protein 10
HGNC (Hugo) GRB10
LocusID (NCBI) 2887
Atlas_Id 278
Location 7p12.1  [Link to chromosome band 7p12]
Location_base_pair Starts at 50657760 and ends at 50800050 bp from pter ( according to hg19-Feb_2009)  [Mapping GRB10.png]
Local_order between two potential genes LOC221982 (in telomeric position) and LOC222987 (in centromeric position).
Fusion genes
(updated 2016)
GRB10 (7p12.1) / CSTF3 (11p13)GRB10 (7p12.1) / MAD1L1 (7p22.3)GRB10 (7p12.1) / R3HDM1 (2q21.3)
GRB10 (7p12.1) / SDK1 (7p22.2)GRB10 (7p12.1) / SLC2A13 (12q12)GRB10 (7p12.1) / STEAP1B (7p15.3)
VOPP1 (7p11.2) / GRB10 (7p12.1)

DNA/RNA

Description at least 16 exons spanning approximately 50 kb
Transcription Four splicing variants are known for human Grb10 gene :
hGrb10 beta alias Grb-IR (accession number U34355)
hGrb10 gamma alias Grb10/IR-SV1 or hGrb-IRbeta/hGrb10
hGrb10 epsilon alias KIAA0207 (accession number D86962)
hGrb10 zeta alias hGrb10 gamma
This nomenclature is a new nomenclature for Grb10 splice variants that was agreed by several researchers
Grb10 gene has a broad expression profile with different size of transcripts depending on the isoforms. Moreover, Grb10 is imprinted in a highly isoform- and tissue-specific manner.

Protein

 
Description isoform beta: 548 aa, 62 kDa (aa: amino acids)
isoform gamma: 536 aa, 61 kDa
isoform epsilon: 588 aa, 66 kDa
isoform zeta: 594 aa, 67 kDa
The different splice variants share a similar structure with :
  • a small proline-rich sequence (11 aa) close to the amino-terminus that can interact with SH3 domain of c-Abl in vitro (domain named Pro on the figure above).
  • a Ras-associated-like domain (84 aa) homologous to the C. elegans MIG-10 protein raising the possibility that Grb10 could directly interact with Ras-like GTP-binding protein (domain named RA on the figure above).
  • a central Pleckstrin homology domain of 124 aa except for the isoform alpha which contains only 85 aa (domain named PH on the figure above).This domain was proposed to play an important role in targeting Grb10 to the mitochondria.
  • the BPS (Between PH and SH2) domain is composed of 48 aa and binds to the activated insulin and/or IGF-1 receptors.
  • an SH2 domain (104 aa) which interacts with phosphotyrosine of several proteins.
  • PH domain, BPS domain and SH2 domain compose a region of 300 aa termed GM (Grb/Mig). Grb10 is able to dimerize/oligomerize through interaction between the N-terminal domain of one molecule and the GM region of another one
  • Expression Grb10 protein has been detected in most human cell lines using a highly specific antibody.
    Localisation Most of the endogenous Grb10 is peripherally associated with the mitochondria where it interacts with pools of Raf-1. Treatment with serum or IGF-I is able to induce the relocalization of a small proportion of the endogenous Grb10 to the plasma membrane.
    Function Grb10 is able to interact with a lot of proteins (Insulin receptor, IGF-1 receptor, ELK receptor, PDGFRB, GHR, EGFR, RET, HGFR, FGFR, RAF-1, MEK1, JAK2, BCR-Abl TEC kinase, NEDD4, cABL, AKT, c-KIT).
    Several studies suggest a role for Grb10 in cell proliferation. However, despite the clear involvement of Grb10 in pathways activated by IR and IGF-R, there is still some controversy about whether its effect is inhibitory or stimulatory. One report showed that stable overexpression of mGRB10 alpha inhibits IGF-1 mediated cell proliferation, whereas another report demonstrated that overexpression of the same mGrb10 alpha increased DNA synthesis upon growth factor stimulation (PDGFBB, IG-1, or insulin). These contradictions might be explained by the use of different cell lines or experimental procedures.
    Grb10 seems to have also a role in apoptosis regulation. Grb10 SH2 domain is able to interact with Raf1 and MEK1. Transfection of SH2 domain Grb10 mutants induces apoptosis in HTC-IR and COS-7 cells suggesting that Grb10 may influence the equilibrium between ERK and JNK pathways and determine the choice between proliferation and programmed cell death. As Grb10 is located at the mitochondrial membrane it may be involved in communication between plasma membrane receptors and apoptosis regulators located on the mitochondrial outer membrane.
    Grb10 interacts with Akt and is proposed to be a positive regulator of the Akt pathway downstream of PI3-K. By acting as an adaptator involved in the relocalization of Akt to the cell membrane, Grb10 may contribute to Akt activation and regulation of different biological processes such as proliferation, apoptosis and growth.
    Homology Grb10 is a member of the Grb7 family of adapter molecules which contains three member Grb7, Grb10 and Grb14. Grb10 counterparts are found in mouse, rat, fly and worm.

    Implicated in

    Note
    Disease The mapping of Grb10 gene to 7p made it a candidate gene for Russel-Silver Syndrome (RSS). But recent data suggest that Grb10 is unlikely to be the gene responsible for RSS.
      

    Bibliography

    Cloning, chromosome localization, expression, and characterization of an Src homology 2 and pleckstrin homology domain-containing insulin receptor binding protein hGrb10gamma.
    Dong LQ, Du H, Porter SG, Kolakowski LF Jr, Lee AV, Mandarino LJ, Fan J, Yee D, Liu F
    The Journal of biological chemistry. 1997 ; 272 (46) : 29104-29112.
    PMID 9360986
     
    Inhibition of hGrb10 binding to the insulin receptor by functional domain-mediated oligomerization.
    Dong LQ, Porter S, Hu D, Liu F
    The Journal of biological chemistry. 1998 ; 273 (28) : 17720-17725.
    PMID 9651371
     
    Human GRB-IRbeta/GRB10. Splice variants of an insulin and growth factor receptor-binding protein with PH and SH2 domains.
    Frantz JD, Giorgetti-Peraldi S, Ottinger EA, Shoelson SE
    The Journal of biological chemistry. 1997 ; 272 (5) : 2659-2667.
    PMID 9006901
     
    The Grb7 family proteins: structure, interactions with other signaling molecules and potential cellular functions.
    Han DC, Shen TL, Guan JL
    Oncogene. 2001 ; 20 (44) : 6315-6321.
    PMID 11607834
     
    Role for the adaptor protein Grb10 in the activation of Akt.
    Jahn T, Seipel P, Urschel S, Peschel C, Duyster J
    Molecular and cellular biology. 2002 ; 22 (4) : 979-991.
    PMID 11809791
     
    Assignment of growth factor receptor-bound protein 10 (GRB10) to human chromosome 7p11.2-p12.
    Jerome CA, Scherer SW, Tsui LC, Gietz RD, Triggs-Raine B
    Genomics. 1997 ; 40 (1) : 215-216.
    PMID 9070953
     
    Grb-IR: a SH2-domain-containing protein that binds to the insulin receptor and inhibits its function.
    Liu F, Roth RA
    Proceedings of the National Academy of Sciences of the United States of America. 1995 ; 92 (22) : 10287-10291.
    PMID 7479769
     
    Evidence against GRB10 as the gene responsible for Silver-Russell syndrome.
    McCann JA, Zheng H, Islam A, Goodyer CG, Polychronakos C
    Biochemical and biophysical research communications. 2001 ; 286 (5) : 943-948.
    PMID 11527390
     
    The role of mGrb10alpha in insulin-like growth factor I-mediated growth.
    Morrione A, Valentinis B, Resnicoff M, Xu S, Baserga R
    The Journal of biological chemistry. 1997 ; 272 (42) : 26382-26387.
    PMID 9334212
     
    Localization of endogenous Grb10 to the mitochondria and its interaction with the mitochondrial-associated Raf-1 pool.
    Nantel A, Huber M, Thomas DY
    The Journal of biological chemistry. 1999 ; 274 (50) : 35719-35724.
    PMID 10585452
     
    Interaction of the Grb10 adapter protein with the Raf1 and MEK1 kinases.
    Nantel A, Mohammad-Ali K, Sherk J, Posner BI, Thomas DY
    The Journal of biological chemistry. 1998 ; 273 (17) : 10475-10484.
    PMID 9553107
     
    Interaction of a GRB-IR splice variant (a human GRB10 homolog) with the insulin and insulin-like growth factor I receptors. Evidence for a role in mitogenic signaling.
    O'Neill TJ, Rose DW, Pillay TS, Hotta K, Olefsky JM, Gustafson TA
    The Journal of biological chemistry. 1996 ; 271 (37) : 22506-22513.
    PMID 8798417
     
    Grb10, a positive, stimulatory signaling adapter in platelet-derived growth factor BB-, insulin-like growth factor I-, and insulin-mediated mitogenesis.
    Wang J, Dai H, Yousaf N, Moussaif M, Deng Y, Boufelliga A, Swamy OR, Leone ME, Riedel H
    Molecular and cellular biology. 1999 ; 19 (9) : 6217-6228.
    PMID 10454568
     
    Sequence analysis identifies a ras-associating (RA)-like domain in the N-termini of band 4.1/JEF domains and in the Grb7/10/14 adapter family.
    Wojcik J, Girault JA, Labesse G, Chomilier J, Mornon JP, Callebaut I
    Biochemical and biophysical research communications. 1999 ; 259 (1) : 113-120.
    PMID 10334925
     
    Imprinting of human GRB10 and its mutations in two patients with Russell-Silver syndrome.
    Yoshihashi H, Maeyama K, Kosaki R, Ogata T, Tsukahara M, Goto Y, Hata J, Matsuo N, Smith RJ, Kosaki K
    American journal of human genetics. 2000 ; 67 (2) : 476-482.
    PMID 10856193
     

    Citation

    This paper should be referenced as such :
    Degot, S
    GRB10 (growth factor receptor-bound protein 10)
    Atlas Genet Cytogenet Oncol Haematol. 2003;7(1):1-3.
    Free journal version : [ pdf ]   [ DOI ]
    On line version : http://AtlasGeneticsOncology.org/Genes/GRB10ID278.html


    Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 1 ]
      Lung: Translocations in Squamous Cell Carcinoma


    External links

    Nomenclature
    HGNC (Hugo)GRB10   4564
    LRG (Locus Reference Genomic)LRG_1032
    Cards
    AtlasGRB10ID278
    Entrez_Gene (NCBI)GRB10  2887  growth factor receptor bound protein 10
    AliasesGRB-IR; Grb-10; IRBP; MEG1; 
    RSS
    GeneCards (Weizmann)GRB10
    Ensembl hg19 (Hinxton)ENSG00000106070 [Gene_View]  chr7:50657760-50800050 [Contig_View]  GRB10 [Vega]
    Ensembl hg38 (Hinxton)ENSG00000106070 [Gene_View]  chr7:50657760-50800050 [Contig_View]  GRB10 [Vega]
    ICGC DataPortalENSG00000106070
    TCGA cBioPortalGRB10
    AceView (NCBI)GRB10
    Genatlas (Paris)GRB10
    WikiGenes2887
    SOURCE (Princeton)GRB10
    Genetics Home Reference (NIH)GRB10
    Genomic and cartography
    GoldenPath hg19 (UCSC)GRB10  -     chr7:50657760-50800050 -  7p12.2   [Description]    (hg19-Feb_2009)
    GoldenPath hg38 (UCSC)GRB10  -     7p12.2   [Description]    (hg38-Dec_2013)
    EnsemblGRB10 - 7p12.2 [CytoView hg19]  GRB10 - 7p12.2 [CytoView hg38]
    Mapping of homologs : NCBIGRB10 [Mapview hg19]  GRB10 [Mapview hg38]
    OMIM601523   
    Gene and transcription
    Genbank (Entrez)AB000731 AF000017 AF000018 AF001534 AI360831
    RefSeq transcript (Entrez)NM_001001549 NM_001001550 NM_001001555 NM_005311
    RefSeq genomic (Entrez)NC_000007 NC_018918 NG_012305 NT_007819 NW_004929330
    Consensus coding sequences : CCDS (NCBI)GRB10
    Cluster EST : UnigeneHs.164060 [ NCBI ]
    CGAP (NCI)Hs.164060
    Alternative Splicing GalleryENSG00000106070
    Gene ExpressionGRB10 [ NCBI-GEO ]   GRB10 [ EBI - ARRAY_EXPRESS ]   GRB10 [ SEEK ]   GRB10 [ MEM ]
    Gene Expression Viewer (FireBrowse)GRB10 [ Firebrowse - Broad ]
    SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
    GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
    BioGPS (Tissue expression)2887
    GTEX Portal (Tissue expression)GRB10
    Protein : pattern, domain, 3D structure
    UniProt/SwissProtQ13322   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
    NextProtQ13322  [Sequence]  [Exons]  [Medical]  [Publications]
    With graphics : InterProQ13322
    Splice isoforms : SwissVarQ13322
    PhosPhoSitePlusQ13322
    Domaine pattern : Prosite (Expaxy)PH_DOMAIN (PS50003)    RA (PS50200)    SH2 (PS50001)   
    Domains : Interpro (EBI)BPS-dom    PH_dom-like    PH_domain    RA_dom    SH2    Ubiquitin-rel_dom   
    Domain families : Pfam (Sanger)BPS (PF08947)    PH (PF00169)    RA (PF00788)    SH2 (PF00017)   
    Domain families : Pfam (NCBI)pfam08947    pfam00169    pfam00788    pfam00017   
    Domain families : Smart (EMBL)PH (SM00233)  RA (SM00314)  SH2 (SM00252)  
    Conserved Domain (NCBI)GRB10
    DMDM Disease mutations2887
    Blocks (Seattle)GRB10
    PDB (SRS)1NRV    3HK0   
    PDB (PDBSum)1NRV    3HK0   
    PDB (IMB)1NRV    3HK0   
    PDB (RSDB)1NRV    3HK0   
    Structural Biology KnowledgeBase1NRV    3HK0   
    SCOP (Structural Classification of Proteins)1NRV    3HK0   
    CATH (Classification of proteins structures)1NRV    3HK0   
    SuperfamilyQ13322
    Human Protein AtlasENSG00000106070
    Peptide AtlasQ13322
    HPRD03312
    IPIIPI00012752   IPI00218909   IPI00218910   IPI00790216   IPI00871859   IPI00384887   IPI00879698   IPI00789632   
    Protein Interaction databases
    DIP (DOE-UCLA)Q13322
    IntAct (EBI)Q13322
    FunCoupENSG00000106070
    BioGRIDGRB10
    STRING (EMBL)GRB10
    ZODIACGRB10
    Ontologies - Pathways
    QuickGOQ13322
    Ontology : AmiGOSH3/SH2 adaptor activity  insulin receptor binding  protein binding  cytoplasm  cytosol  plasma membrane  insulin receptor signaling pathway  negative regulation of Wnt signaling pathway  positive regulation of vascular endothelial growth factor receptor signaling pathway  response to insulin  negative regulation of phosphorylation  positive regulation of phosphorylation  negative regulation of glycogen biosynthetic process  negative regulation of glucose import  negative regulation of insulin receptor signaling pathway  insulin-like growth factor receptor signaling pathway  
    Ontology : EGO-EBISH3/SH2 adaptor activity  insulin receptor binding  protein binding  cytoplasm  cytosol  plasma membrane  insulin receptor signaling pathway  negative regulation of Wnt signaling pathway  positive regulation of vascular endothelial growth factor receptor signaling pathway  response to insulin  negative regulation of phosphorylation  positive regulation of phosphorylation  negative regulation of glycogen biosynthetic process  negative regulation of glucose import  negative regulation of insulin receptor signaling pathway  insulin-like growth factor receptor signaling pathway  
    REACTOMEQ13322 [protein]
    REACTOME PathwaysR-HSA-1433557 Signaling by SCF-KIT [pathway]
    REACTOME PathwaysR-HSA-74751 Insulin receptor signalling cascade [pathway]
    REACTOME PathwaysR-HSA-74713 IRS activation [pathway]
    REACTOME PathwaysR-HSA-74749 Signal attenuation [pathway]
    NDEx NetworkGRB10
    Atlas of Cancer Signalling NetworkGRB10
    Wikipedia pathwaysGRB10
    Orthology - Evolution
    OrthoDB2887
    GeneTree (enSembl)ENSG00000106070
    Phylogenetic Trees/Animal Genes : TreeFamGRB10
    HOVERGENQ13322
    HOGENOMQ13322
    Homologs : HomoloGeneGRB10
    Homology/Alignments : Family Browser (UCSC)GRB10
    Gene fusions - Rearrangements
    Fusion : MitelmanGRB10/CSTF3 [7p12.1/11p13]  
    Fusion : MitelmanGRB10/MAD1L1 [7p12.1/7p22.3]  [t(7;7)(p12;p22)]  
    Fusion : MitelmanGRB10/SDK1 [7p12.1/7p22.2]  [t(7;7)(p12;p22)]  
    Fusion : MitelmanGRB10/SLC2A13 [7p12.1/12q12]  [t(7;12)(p12;q12)]  
    Fusion : MitelmanGRB10/STEAP1B [7p12.1/7p15.3]  [t(7;7)(p12;p15)]  
    Fusion : MitelmanVOPP1/GRB10 [7p11.2/7p12.1]  [t(7;7)(p11;p12)]  
    Fusion: TCGAGRB10 7p12.1 CSTF3 11p13 OV
    Fusion: TCGAGRB10 7p12.1 MAD1L1 7p22.3 LUAD
    Fusion: TCGAGRB10 7p12.1 SLC2A13 12q12 BRCA
    Fusion: TCGAGRB10 7p12.1 STEAP1B 7p15.3 BLCA
    Polymorphisms : SNP and Copy number variants
    NCBI Variation ViewerGRB10 [hg38]
    dbSNP Single Nucleotide Polymorphism (NCBI)GRB10
    dbVarGRB10
    ClinVarGRB10
    1000_GenomesGRB10 
    Exome Variant ServerGRB10
    ExAC (Exome Aggregation Consortium)GRB10 (select the gene name)
    Genetic variants : HAPMAP2887
    Genomic Variants (DGV)GRB10 [DGVbeta]
    DECIPHER (Syndromes)7:50657760-50800050  ENSG00000106070
    CONAN: Copy Number AnalysisGRB10 
    Mutations
    ICGC Data PortalGRB10 
    TCGA Data PortalGRB10 
    Broad Tumor PortalGRB10
    OASIS PortalGRB10 [ Somatic mutations - Copy number]
    Somatic Mutations in Cancer : COSMICGRB10  [overview]  [genome browser]  [tissue]  [distribution]  
    Mutations and Diseases : HGMDGRB10
    LOVD (Leiden Open Variation Database)Whole genome datasets
    LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
    LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
    BioMutasearch GRB10
    DgiDB (Drug Gene Interaction Database)GRB10
    DoCM (Curated mutations)GRB10 (select the gene name)
    CIViC (Clinical Interpretations of Variants in Cancer)GRB10 (select a term)
    intoGenGRB10
    NCG5 (London)GRB10
    Cancer3DGRB10(select the gene name)
    Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
    Diseases
    OMIM601523   
    Orphanet
    MedgenGRB10
    Genetic Testing Registry GRB10
    NextProtQ13322 [Medical]
    TSGene2887
    GENETestsGRB10
    Huge Navigator GRB10 [HugePedia]
    snp3D : Map Gene to Disease2887
    BioCentury BCIQGRB10
    ClinGenGRB10 (curated)
    Clinical trials, drugs, therapy
    Chemical/Protein Interactions : CTD2887
    Chemical/Pharm GKB GenePA28960
    Clinical trialGRB10
    Miscellaneous
    canSAR (ICR)GRB10 (select the gene name)
    Other databaseThe Grb7, Grb10 and Grb14 protein family
    Probes
    Litterature
    PubMed88 Pubmed reference(s) in Entrez
    GeneRIFsGene References Into Functions (Entrez)
    CoreMineGRB10
    EVEXGRB10
    GoPubMedGRB10
    iHOPGRB10
    REVIEW articlesautomatic search in PubMed
    Last year publicationsautomatic search in PubMed

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    indexed on : Fri Nov 18 20:09:44 CET 2016

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