GRB10 (growth factor receptor-bound protein 10)

2002-08-01   Sébastien Degot 

I.G.B.M.C, 1, rue Laurent FRIES, BP 163 67404 ILLKIRH, France

Identity

HGNC
LOCATION
7p12.1
LOCUSID
ALIAS
GRB-IR,Grb-10,IRBP,MEG1,RSS
FUSION GENES

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.

Proteins

Atlas Image

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

    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

    Pubmed IDLast YearTitleAuthors
    93609861997Cloning, chromosome localization, expression, and characterization of an Src homology 2 and pleckstrin homology domain-containing insulin receptor binding protein hGrb10gamma.Dong LQ et al
    96513711998Inhibition of hGrb10 binding to the insulin receptor by functional domain-mediated oligomerization.Dong LQ et al
    90069011997Human GRB-IRbeta/GRB10. Splice variants of an insulin and growth factor receptor-binding protein with PH and SH2 domains.Frantz JD et al
    116078342001The Grb7 family proteins: structure, interactions with other signaling molecules and potential cellular functions.Han DC et al
    118097912002Role for the adaptor protein Grb10 in the activation of Akt.Jahn T et al
    90709531997Assignment of growth factor receptor-bound protein 10 (GRB10) to human chromosome 7p11.2-p12.Jerome CA et al
    74797691995Grb-IR: a SH2-domain-containing protein that binds to the insulin receptor and inhibits its function.Liu F et al
    115273902001Evidence against GRB10 as the gene responsible for Silver-Russell syndrome.McCann JA et al
    93342121997The role of mGrb10alpha in insulin-like growth factor I-mediated growth.Morrione A et al
    105854521999Localization of endogenous Grb10 to the mitochondria and its interaction with the mitochondrial-associated Raf-1 pool.Nantel A et al
    95531071998Interaction of the Grb10 adapter protein with the Raf1 and MEK1 kinases.Nantel A et al
    87984171996Interaction 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 et al
    104545681999Grb10, a positive, stimulatory signaling adapter in platelet-derived growth factor BB-, insulin-like growth factor I-, and insulin-mediated mitogenesis.Wang J et al
    103349251999Sequence 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 et al
    108561932000Imprinting of human GRB10 and its mutations in two patients with Russell-Silver syndrome.Yoshihashi H et al

    Other Information

    Locus ID:

    NCBI: 2887
    MIM: 601523
    HGNC: 4564
    Ensembl: ENSG00000106070

    Variants:

    dbSNP: 2887
    ClinVar: 2887
    TCGA: ENSG00000106070
    COSMIC: GRB10

    RNA/Proteins

    Gene IDTranscript IDUniprot
    ENSG00000106070ENST00000335866Q13322
    ENSG00000106070ENST00000357271Q13322
    ENSG00000106070ENST00000398810Q13322
    ENSG00000106070ENST00000398812Q13322
    ENSG00000106070ENST00000401949Q13322
    ENSG00000106070ENST00000402497Q13322
    ENSG00000106070ENST00000402578Q13322
    ENSG00000106070ENST00000403097Q13322
    ENSG00000106070ENST00000406641Q13322
    ENSG00000106070ENST00000407526Q13322
    ENSG00000106070ENST00000428711H7C3B9
    ENSG00000106070ENST00000439044C9JTW6
    ENSG00000106070ENST00000643299Q13322
    ENSG00000106070ENST00000644769A0A2R8Y6Q4
    ENSG00000106070ENST00000644879A0A2R8YCL1
    ENSG00000106070ENST00000645075Q13322

    Expression (GTEx)

    0
    5
    10
    15
    20
    25
    30
    35
    40
    45

    Pathways

    PathwaySourceExternal ID
    mTOR signaling pathwayKEGGko04150
    mTOR signaling pathwayKEGGhsa04150
    Signal TransductionREACTOMER-HSA-162582
    Signaling by Insulin receptorREACTOMER-HSA-74752
    Insulin receptor signalling cascadeREACTOMER-HSA-74751
    IRS activationREACTOMER-HSA-74713
    Signal attenuationREACTOMER-HSA-74749
    Signaling by SCF-KITREACTOMER-HSA-1433557
    Developmental BiologyREACTOMER-HSA-1266738
    Axon guidanceREACTOMER-HSA-422475
    RET signalingREACTOMER-HSA-8853659

    Protein levels (Protein atlas)

    Not detected
    Low
    Medium
    High

    References

    Pubmed IDYearTitleCitations
    216596042011The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling.436
    178461262007Identification of novel candidate genes for type 2 diabetes from a genome-wide association scan in the Old Order Amish: evidence for replication from diabetes-related quantitative traits and from independent populations.68
    246994092014A central role for GRB10 in regulation of islet function in man.63
    150600762004Grb10 prevents Nedd4-mediated vascular endothelial growth factor receptor-2 degradation.43
    196489262009Structural and functional studies of the Ras-associating and pleckstrin-homology domains of Grb10 and Grb14.32
    124937402003Grb10 inhibits insulin-stimulated insulin receptor substrate (IRS)-phosphatidylinositol 3-kinase/Akt signaling pathway by disrupting the association of IRS-1/IRS-2 with the insulin receptor.31
    194873672009Reciprocal imprinting of human GRB10 in placental trophoblast and brain: evolutionary conservation of reversed allelic expression.25
    125518962003Structural basis for dimerization of the Grb10 Src homology 2 domain. Implications for ligand specificity.24
    231904522013Regulation of insulin and type 1 insulin-like growth factor signaling and action by the Grb10/14 and SH2B1/B2 adaptor proteins.24
    104545681999Grb10, a positive, stimulatory signaling adapter in platelet-derived growth factor BB-, insulin-like growth factor I-, and insulin-mediated mitogenesis.21

    Citation

    Sébastien Degot

    GRB10 (growth factor receptor-bound protein 10)

    Atlas Genet Cytogenet Oncol Haematol. 2002-08-01

    Online version: http://atlasgeneticsoncology.org/gene/278/grb10-(growth-factor-receptor-bound-protein-10)