Affinage

GRB10

Growth factor receptor-bound protein 10 · UniProt Q13322

Length
594 aa
Mass
67.2 kDa
Annotated
2026-06-10
100 papers in source corpus 52 papers cited in narrative 52 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GRB10 is a multi-domain adaptor protein that functions as a context-dependent regulator of receptor tyrosine kinase (RTK) and insulin/IGF signaling, coupling activated receptors to downstream control of growth, metabolism, and receptor turnover (PMID:8621530, PMID:17620412). Through its SH2 domain and an adjacent BPS domain, GRB10 binds activated receptors including the insulin receptor (IR), IGF-1R, RET, ELK, and FLT3 in a kinase-activity- and phosphotyrosine-dependent manner, with the SH2 and BPS domains engaging the receptor activation loop (PMID:7665556, PMID:8621530, PMID:9506989, PMID:23246379); structural work shows the SH2 domain dimerizes and is geometrically tuned to recognize the turn-containing dual phosphotyrosines of IR/IGF-1R activation loops (PMID:12551896). The BPS domain acts as a pseudosubstrate inhibitor, directly suppressing IR and IGF-1R kinase activity without itself binding phosphotyrosine (PMID:11287005), while SH2-domain engagement additionally blocks IRS and Shc access to the receptor and attenuates downstream PI3K/Akt and ERK-MAPK signaling (PMID:12493740, PMID:14615605). GRB10 also serves as an adaptor bridging the NEDD4 (Nedd4) HECT E3 ubiquitin ligase to IGF-1R and IR via a phosphotyrosine-independent SH2–C2 interface, driving receptor multiubiquitination, internalization, and degradation (PMID:12697834, PMID:18286479, PMID:20980250). GRB10 is integrated into a feedback circuit as a direct mTORC1 substrate: phosphorylation stabilizes GRB10 and enforces negative feedback on PI3K and ERK pathways, and at high mTORC1 activity phospho-GRB10 switches its binding from IR to raptor to suppress mTORC1 itself (PMID:21659605, PMID:24746805). Its activity is further tuned by Src/Fyn phosphorylation at Tyr67, which reduces IR binding (PMID:10871840), and by Akt phosphorylation at Ser428, which creates a 14-3-3 binding site (PMID:15722337). In vivo, GRB10 is an imprinted gene whose maternally expressed peripheral allele restrains fetal growth and negatively regulates insulin sensitivity, muscle mass, and adiposity, while the paternally expressed neuronal allele influences social behavior (PMID:17620412, PMID:17562854, PMID:21270893, PMID:22623587); in the hypothalamus GRB10 binds the leptin receptor and enhances leptin signaling in AgRP and POMC neurons through KATP and TRP channels (PMID:36593271). Imprinted, allele-specific expression is controlled by a CTCF-bound intronic insulator that organizes allele-specific chromatin looping (PMID:36108632).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1995 Medium

    Established GRB10 as an SH2-domain adaptor and identified RTKs—rather than the EGF receptor—as its preferred partners, defining its molecular class and pointing to receptor-specific signaling.

    Evidence Expression-library cloning with phospho-EGFR, plus yeast two-hybrid/GST pulldown identifying activation-dependent RET binding

    PMID:7665556 PMID:7731717

    Open questions at the time
    • Functional consequence of receptor binding not established
    • Physiological RTK partner remained ambiguous at cloning
  2. 1996 High

    Defined the insulin and IGF-1 receptors as principal GRB10 targets bound in a ligand- and kinase-activity-dependent manner via the SH2 domain, and linked binding to a functional effect on mitogenesis.

    Evidence Yeast two-hybrid, GST pulldown with purified IR/IGF-IR, phosphopeptide mapping, and SH2-domain microinjection mitogenesis assays in fibroblasts

    PMID:8621530 PMID:8776723 PMID:8798417

    Open questions at the time
    • Direction of regulation (positive vs negative) unresolved
    • IRS-independence of the IR C-terminus interaction not mechanistically explained
  3. 1997 Medium

    Showed insulin-triggered cytosol-to-membrane translocation and receptor preference (IR over IGF-1R), localizing GRB10 action to the activated receptor at the membrane.

    Evidence Cell fractionation, phosphopeptide binding, and receptor-specific co-IP in defined fibroblast lines

    PMID:9006901 PMID:9062339

    Open questions at the time
    • Receptor preference context-dependent across cell types
    • Additional binding regions beyond SH2 not fully mapped
  4. 1998 High

    Identified the BPS domain as a second activation-loop-dependent binding module and broadened the partner set (GHR/JAK2, Tec, BCR-ABL, Raf-1/MEK1), revealing GRB10 as a multivalent adaptor with both receptor and cytoplasmic-kinase contacts.

    Evidence Domain mapping with IR activation-loop mutagenesis, GST pulldown, yeast two-hybrid, and reporter assays across multiple kinases

    PMID:9506989 PMID:9553107 PMID:9632636 PMID:9747873 PMID:9753425

    Open questions at the time
    • Whether BPS directly inhibits kinase activity not yet tested
    • Physiological relevance of cytoplasmic-kinase interactions unclear
  5. 2000 High

    Resolved an upstream regulatory input: Src/Fyn phosphorylation of GRB10 Tyr67 reduces IR binding, showing GRB10–receptor affinity is itself tunable by tyrosine phosphorylation.

    Evidence In vitro Src/Fyn kinase assays, Y67G mutagenesis, and co-IP binding assays

    PMID:10871840

    Open questions at the time
    • In vivo stoichiometry of Tyr67 phosphorylation unknown
    • Physiological trigger for Src/Fyn action on GRB10 not defined
  6. 2001 High

    Established a direct biochemical mechanism—the BPS domain acts as a pseudosubstrate inhibitor of IR/IGF-1R kinase activity—explaining how GRB10 can dampen receptor signaling.

    Evidence Reconstituted in vitro kinase assays with purified BPS and kinase domains plus phosphopeptide competition

    PMID:11287005

    Open questions at the time
    • Quantitative contribution of BPS inhibition in cells not established
    • Interplay with SH2-mediated effects not dissected here
  7. 2002 Medium

    Defined how GRB10 attenuates IR signaling—by blocking IRS access to the receptor—while also showing context-dependent positive coupling to Akt downstream of other RTKs.

    Evidence Yeast tri-hybrid, phosphorylation time-courses in CHO/IR and adipocytes; Akt complex and kinase assays with c-kit

    PMID:11809791 PMID:12493740

    Open questions at the time
    • Reconciliation of positive vs negative roles across receptors incomplete
    • Direct Akt-binding interface not mapped
  8. 2003 High

    Showed GRB10 controls receptor stability by recruiting Nedd4 to ubiquitinate IGF-1R, and bridged its adaptor functions to MAPK suppression, PI3K coupling, and GIGYF partner recruitment.

    Evidence Reciprocal co-IP, ubiquitination assays with catalytic-mutant Nedd4 and inhibitors, PI3K activity assays, and yeast two-hybrid for GIGYF1/2

    PMID:12697834 PMID:12771153 PMID:12783867 PMID:14615605

    Open questions at the time
    • Whether degradation versus signaling inhibition predominates in vivo unresolved
    • GIGYF functional role not fully defined
  9. 2003 High

    Provided the structural basis for IR/IGF-1R selectivity by showing the GRB10 SH2 domain dimerizes and is shaped to recognize dual-phosphotyrosine activation-loop turns.

    Evidence 1.65 Å crystal structure plus analytical ultracentrifugation

    PMID:12551896

    Open questions at the time
    • Functional role of SH2 dimerization in cells not tested
    • Full-length protein architecture not captured
  10. 2005 Medium

    Linked Akt-dependent phosphorylation of GRB10 (Ser428) to 14-3-3 recruitment and showed endogenous GRB10 loss enhances IGF signaling partly by limiting phosphatase access to the receptor.

    Evidence Akt in vitro kinase assay with S428 mutagenesis and 14-3-3 co-IP; siRNA knockdown with pervanadate rescue

    PMID:15722337 PMID:16037382

    Open questions at the time
    • Downstream consequence of 14-3-3 binding on GRB10 function unclear
    • Identity of the relevant phosphatase not established
  11. 2007 High

    Demonstrated in vivo that the maternally expressed peripheral Grb10 allele is a physiological negative regulator of growth and insulin sensitivity, validating cell-based inhibitory models.

    Evidence Maternal-allele Grb10 knockout mice with hyperinsulinemic-euglycemic clamps and tissue phosphorylation analysis

    PMID:17562854 PMID:17620412

    Open questions at the time
    • Tissue-autonomous contributions not yet separated
    • Molecular basis of overgrowth distinct from insulin sensitivity unresolved
  12. 2010 High

    Provided atomic-level mechanism for GRB10 as a degradation adaptor: its SH2 domain binds NEDD4 C2 at non-canonical sites independent of phosphotyrosine and can simultaneously engage IGF1R, explaining bridging.

    Evidence 2.0 Å crystal structure of the NEDD4 C2–GRB10 SH2 complex

    PMID:20980250

    Open questions at the time
    • Ternary GRB10–NEDD4–receptor complex not structurally resolved
    • Regulation of complex assembly in cells not addressed
  13. 2011 High

    Placed GRB10 in a defining feedback circuit by identifying it as a direct mTORC1 substrate whose phosphorylation stabilizes the protein and inhibits PI3K and ERK-MAPK signaling.

    Evidence Large-scale quantitative phosphoproteomics, mTORC1 kinase assays, rapamycin treatment, and pathway readouts; allele-specific brain expression and behavior via conditional KO

    PMID:21270893 PMID:21659605

    Open questions at the time
    • Precise phosphosites integrating signals not yet harmonized across studies
    • Mechanism linking phosphorylation to stabilization unresolved
  14. 2014 High

    Defined a phospho-switch in which mTOR phosphorylation at Ser501/503 redirects GRB10 binding from IR to raptor, suppressing mTORC1 and controlling adipose lipolysis and thermogenesis.

    Evidence Phospho-specific mutagenesis, raptor co-IP, fat-specific Grb10 KO with lipolysis/thermogenesis assays and rapamycin rescue

    PMID:24746805

    Open questions at the time
    • Quantitative balance between IR and raptor binding in vivo unclear
    • Generality of the switch across tissues not established
  15. 2018 Medium

    Established tissue-autonomous and inducible roles—muscle-specific GRB10 loss drives hypertrophy and insulin sensitivity, and hepatic GRB10 reactivation by ATF4 under ER stress promotes steatosis.

    Evidence Muscle-specific conditional KO with clamps; liver-specific KO with tunicamycin/HFD and ATF4 promoter analysis

    PMID:29370381 PMID:29555819

    Open questions at the time
    • Signals dictating tissue-specific reactivation incompletely defined
    • Crosstalk between metabolic and growth phenotypes unresolved
  16. 2022 High

    Resolved the epigenetic basis of GRB10 imprinting by showing a paternal CTCF-bound intronic insulator (CBR2.3) governs allele-specific chromatin looping and Grb10-Ddc expression.

    Evidence Polymorphic mice, 4C-seq looping, allele-specific CTCF ChIP, and conditional paternal CBR2.3 deletion with phenotyping

    PMID:36108632

    Open questions at the time
    • Connection between looping changes and GRB10 protein-level functions not traced
    • Conservation of the insulator in humans not addressed
  17. 2023 High

    Extended GRB10 function to central energy balance by showing it binds the leptin receptor in hypothalamic neurons and enhances leptin signaling via KATP and TRP channels to promote weight loss.

    Evidence AgRP/POMC-specific conditional KO and overexpression, LepR co-IP, and patch-clamp electrophysiology

    PMID:36593271

    Open questions at the time
    • Molecular mechanism by which GRB10 modulates channel activity unclear
    • Relationship to GRB10's RTK/mTORC1 functions in neurons not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How GRB10's opposing positive and negative signaling roles, its degradation-adaptor function, and its mTORC1 feedback are integrated and dynamically prioritized within a single cell remains unresolved.
  • No unified model reconciling pseudosubstrate inhibition, IRS blockade, and Nedd4-mediated degradation
  • Full-length GRB10 structure and its conformational regulation by phosphorylation unknown
  • Determinants of context-dependent positive versus negative output not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0098772 molecular function regulator activity 3 GO:0140096 catalytic activity, acting on a protein 3
Localization
GO:0005886 plasma membrane 2 GO:0005739 mitochondrion 1 GO:0005768 endosome 1 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1430728 Metabolism 3 R-HSA-392499 Metabolism of proteins 3
Partners
AKT1FLT3GIGYF1IGF1RINSRLEPRNEDD4RAF1

Evidence

Reading pass · 52 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 GRB10 was cloned as a new SH2 domain protein by screening expression libraries with the tyrosine-phosphorylated EGF receptor C-terminus. It contains an SH2 domain and a central domain with similarity to a C. elegans gene. At least three forms exist in fibroblasts from alternate translational start sites. GRB10 undergoes serine but not tyrosine phosphorylation after EGF treatment. GRB10 binds poorly to the EGF receptor, suggesting a different binding partner. Expression library screening, co-immunoprecipitation, phosphorylation assays Oncogene Medium 7731717
1995 GRB10 SH2 domain interacts with the RET receptor tyrosine kinase in a phosphorylation/activation-dependent manner, as demonstrated by yeast two-hybrid screen and GST pulldown. GRB10 is the first identified signaling intermediate for RET. Yeast two-hybrid screen, GST fusion protein pulldown, in vivo co-immunoprecipitation using EGFR/Ret chimera The Journal of biological chemistry Medium 7665556
1996 GRB10 SH2 domain binds the insulin receptor (IR) in an insulin-dependent, kinase-activity-dependent manner. The interaction requires the IR C-terminus, with highest affinity for phosphopeptide containing pTyr-1322. GRB10 does not associate with IRS-1, suggesting an IRS-1-independent function of the IR C-terminus. Yeast two-hybrid, GST fusion protein pulldown with purified IR, co-precipitation from cell extracts, phosphopeptide binding assays The Journal of biological chemistry High 8621530
1996 GRB10 SH2 domain interacts with the IGF-I receptor (IGF-IR) in a tyrosine kinase-active, receptor-dependent manner, not requiring juxtamembrane Tyr950. GRB10 co-precipitates with IGF-IR in cell lysates. Microinjection of GRB10 SH2 domain fusion protein inhibited insulin- and IGF-I-stimulated mitogenesis but not EGF-stimulated mitogenesis in fibroblasts. Yeast two-hybrid (interaction trap), Western blotting of yeast extracts, microinjection of GST-SH2 fusion protein, DNA synthesis assay Molecular endocrinology Medium 8776723
1996 Ligand-activated ELK receptor tyrosine kinase (Eph family) associates with GRB10 via SH2 domain interaction at ELK phospho-Tyr-929 in vascular endothelial cells. This association is phosphorylation-dependent and occurs in vivo upon LERK-2/Fc stimulation. Yeast two-hybrid screen, site-directed mutagenesis, GST pulldown with phosphorylated recombinant ELK, co-immunoprecipitation from endothelial cells The Journal of biological chemistry Medium 8798570
1996 GRB10/IR-SV1 SH2 domain interacts specifically in vitro with insulin receptor derived from mammalian cells and with IGF-I receptor. Microinjection of the SH2 domain fusion protein inhibited insulin- and IGF-I-stimulated mitogenesis but not EGF-stimulated mitogenesis in fibroblasts. Yeast two-hybrid, GST fusion protein in vitro binding, microinjection into fibroblasts, DNA synthesis assay The Journal of biological chemistry Medium 8798417
1997 GRB10 protein translocates from cytosol to membrane upon insulin stimulation, mediated by direct interactions with the insulin receptor via SH2 domain and additional regions. The SH2 domain binds at least two sites in the IR: the kinase activation loop and the juxtamembrane site. GRB10 also binds c-Abl SH3 domain via a conserved site, as well as PDGF and EGF receptors. Cell fractionation, co-immunoprecipitation, synthetic phosphopeptide binding assays, mutated receptor studies The Journal of biological chemistry Medium 9006901
1997 GRB10 interacts preferentially with insulin receptor over IGF-I receptor in intact mouse fibroblasts. Hormone-activated IR co-precipitated with three GRB10 isoforms, whereas GRB10 was essentially undetectable in IGF-IR immunoprecipitates under the same conditions. Co-immunoprecipitation from R-IR and R+ cell lines with hormone stimulation The Journal of clinical investigation Medium 9062339
1998 GRB10 contains a second novel kinase-activity-dependent binding domain, the BPS domain (between PH and SH2), located in ~50 amino acids. The BPS domain interacts with IR and IGF-IR in a kinase-dependent manner requiring the activation loop phosphotyrosines (Y1150/Y1151). The IR interacts with both BPS and SH2 domains; IGF-IR preferentially with BPS; EGFR preferentially with SH2. Domain mapping, site-directed mutagenesis of IR activation loop (Y1150F/Y1151F), GST pulldown, yeast two-hybrid The Journal of biological chemistry High 9506989
1998 GRB10 SH2 domain interacts with Raf-1 and MEK1 kinases in a phosphotyrosine-independent manner. Interaction with Raf-1 is constitutive; interaction with MEK1 requires insulin treatment and follows MAPK activation. Mutation of MEK1 Thr-386 reduces binding. SH2 domain residues Arg-βB5 and Asp-EF2 are required for binding both receptors and kinases. Overexpression of SH2 domain mutants induces apoptosis reversible by wild-type co-expression. Yeast two-hybrid, random mutagenesis of SH2 domain, site-directed mutagenesis of MEK1, transfection/apoptosis assays The Journal of biological chemistry Medium 9553107
1998 GRB10 interacts with GHR (growth hormone receptor) and JAK2 upon GH stimulation in Huh-7 hepatoma cells. GRB10 inhibits transcription of SRE of c-fos and GH response element 2 of Spi2.1 reporter genes but has no effect on STAT5-dependent reporter genes, placing GRB10 as a downstream inhibitor of GH signaling via JAK2 but independent of STAT5. Phage library screening with phosphorylated GHR cytoplasmic domain, co-immunoprecipitation from Huh-7 cells, co-transfection reporter assays The Journal of biological chemistry Medium 9632636
1998 GRB10/GrbIR is an in vivo substrate of Tec tyrosine kinase. In HEK293 cells, GRB10 becomes profoundly tyrosine-phosphorylated by Tec but not by Syk, JAK2, or insulin receptor. GRB10 expression suppresses Tec-driven and cytokine-driven activation of the c-fos promoter. Yeast two-hybrid screen, transient expression tyrosine phosphorylation assay in HEK293 cells, reporter gene assay Genes to cells Medium 9753425
1998 GRB10 interacts with BCR-ABL in a phosphotyrosine-dependent manner at Bcr sites (aa242-446), distinct from the Grb2 binding site. This interaction is kinase-activation-dependent in vivo. A BCR-ABL mutant lacking GRB10 interaction (Bcr/1-242-Abl) partially reduced IL-3 independence and focus formation, indicating GRB10 interaction is important for BCR-ABL transforming function. Yeast two-hybrid with LexA-BCR-ABL bait, in vitro binding, co-immunoprecipitation from CML cells, functional IL-3 independence and focus formation assays Oncogene Medium 9747873
1999 Endogenous GRB10 localizes predominantly to mitochondria (peripherally associated), as shown by immunofluorescence and subcellular fractionation. Small pools translocate to plasma membrane and actin-rich ruffles after IGF-I or serum treatment. GRB10 co-immunoprecipitates with Raf-1 from mitochondrial fractions, and this interaction is enhanced by UV-induced Raf-1 activation. The GRB10-binding site on Raf-1 co-localizes with the Ras-binding domain. Immunofluorescence microscopy, subcellular fractionation, co-immunoprecipitation from mitochondrial fraction, yeast two-hybrid The Journal of biological chemistry Medium 10585452
1999 GRB10 acts as a positive stimulatory signaling adapter in PDGF-BB-, IGF-I-, and insulin-mediated mitogenesis in normal fibroblasts. PDGF receptor β Y771 is required for GRB10 SH2 domain association. Multiple independent strategies (cDNA overexpression, SH2 domain microinjection, cell-permeable peptides) consistently support a positive mitogenic role distinct from EGF. Ecdysone-regulated overexpression, microinjection, cell-permeable Drosophila antennapedia homeodomain fusion peptides, cell proliferation/DNA synthesis assays, co-immunoprecipitation Molecular and cellular biology Medium 10454568
2000 GRB10 is phosphorylated on tyrosine (Tyr67) by Src and Fyn kinases but not by the insulin receptor kinase directly. Src/Fyn-mediated phosphorylation negatively regulates GRB10 binding to the IR; a Y67G GRB10 mutant shows higher affinity for IR. In vitro kinase assays with purified Src/Fyn, herbimycin A inhibitor, dominant-negative/constitutively-active Src/Fyn transfection, site-directed mutagenesis (Y67G), co-immunoprecipitation Oncogene High 10871840
2001 GRB10 BPS domain directly inhibits substrate phosphorylation by activated tyrosine kinase domains of IR and IGF-1R in vitro. Inhibition is dependent on activation-loop phosphorylation but peptide competition shows the BPS domain does not bind phosphotyrosine directly, providing a pseudosubstrate-like inhibition mechanism. In vitro kinase assay with purified recombinant BPS domain and tyrosine kinase domains, phosphopeptide competition experiments FEBS letters High 11287005
2001 GRB10 associates with VEGF receptor KDR (VEGFR-2) in response to VEGF stimulation and positively regulates KDR levels and tyrosine phosphorylation. GRB10 tyrosine phosphorylation in response to VEGF requires an intact SH2 domain and is partially mediated by Src. The positive effect on KDR is independent of GRB10 SH2 domain. Co-immunoprecipitation from HUVEC and 293/KDR cells, GRB10 mutant overexpression, qRT-PCR, MAPK signaling readout Oncogene Medium 11494124
2002 GRB10 inhibits IRS-1/IRS-2 PI3K/Akt signaling by physically blocking IRS access to the IR via its SH2 domain. Overexpression reduced insulin-stimulated IRS-1/2 tyrosine phosphorylation and delayed/reduced Akt phosphorylation. Yeast tri-hybrid assays showed GRB10 blocks IR-IRS association. GRB10 does not affect IR catalytic activity toward Tyr972 or Tyr1158/1162/1163. Overexpression in CHO/IR cells and adipocytes, yeast tri-hybrid assay, phosphorylation time-course, co-immunoprecipitation The Journal of biological chemistry Medium 12493740
2002 GRB10 forms a constitutive complex with Akt, and GRB10 co-expression with c-kit synergistically activates Akt in a wortmannin-sensitive, PI3K-independent manner downstream of PI3K. GRB10 is recruited to c-kit via SH2 domain in a phosphotyrosine-dependent manner. Both SH2 and PH domains of GRB10 are required for Akt activation. Yeast two-hybrid screen with c-kit cytoplasmic domain, co-immunoprecipitation, Akt kinase assay, dominant-negative/deletion mutants, wortmannin inhibition, Ba/F3 IL-3 independence assay Molecular and cellular biology Medium 11809791
2003 GRB10 forms a complex with Nedd4 E3 ubiquitin ligase and IGF-IR. GRB10 promotes ligand-dependent ubiquitination and accelerated internalization and degradation of IGF-IR via both proteasomal and lysosomal pathways. Catalytically inactive Nedd4-CS mutant or GRB10 mutant lacking SH2 domain both impair IGF-IR ubiquitination. GRB10 acts as an adapter bridging Nedd4 to IGF-IR. Co-immunoprecipitation, overexpression in mouse embryo fibroblasts, ubiquitination assay, receptor half-life measurement, inhibitors MG132 and chloroquine, dansylcadaverine treatment, Nedd4-CS catalytic mutant Molecular and cellular biology High 12697834
2003 GRB10 N-terminus interacts with two novel proteins, GIGYF1 and GIGYF2, via GYF domain binding to tandem proline-rich regions. In IGF-I-stimulated cells, GIGYF1 binding to GRB10 increases, and both transiently associate with IGF-IR, with GIGYF1 later dissociating while GRB10 remains. Overexpression of GRB10-binding GIGYF1 fragment increases IGF-I-stimulated receptor tyrosine phosphorylation. Yeast two-hybrid screen with GRB10 N-terminus bait, mutation analysis, co-immunoprecipitation from R+ fibroblasts, overexpression assays The Journal of biological chemistry Medium 12771153
2003 GRB10 negatively regulates insulin-stimulated MAPK signaling by inhibiting Shc tyrosine phosphorylation in an SH2 domain-dependent manner. Overexpression reduced insulin-stimulated MAPK/Elk1 phosphorylation; RNAi knockdown enhanced MAPK, Shc, and Akt phosphorylation. Overexpression in CHO/IR cells and adipocytes, RNA interference in HeLa/IR cells, phosphorylation assays, SH2-deletion mutant Molecular endocrinology Medium 14615605
2003 GRB10 functions as a critical component of the IR signaling complex linking IR to p85 PI3K, regulating PI3K activity and metabolic insulin responses (glycogen synthesis, glucose and amino acid transport, lipogenesis). Direct association between GRB10 and p85 was demonstrated; no association between GRB10 and IRS proteins was detected. Dominant-negative GRB10 SH2 domain and Pro-rich region abolished metabolic insulin response in 3T3-L1 adipocytes. Co-immunoprecipitation, PI3K activity assay, dominant-negative domain expression, metabolic assays in 3T3-L1 adipocytes and L6 cells The Journal of biological chemistry Medium 12783867
2003 The GRB10 SH2 domain forms a non-covalent dimer in solution under physiologic conditions. Crystal structure at 1.65 Å resolution reveals a dimer interface involving residues in/flanking the C-terminal alpha helix conserved in Grb7/10/14. Val-522 (BG loop) and Asp-500 (EF loop) position interferes with P+3 phosphopeptide binding, favoring dimeric turn-containing phosphotyrosine sequences such as IR/IGF-1R activation loops. X-ray crystallography (1.65 Å), analytical ultracentrifugation for dimerization in solution The Journal of biological chemistry High 12551896
2004 GRB10 prevents Nedd4-mediated degradation of VEGF-R2. GRB10 constitutively associates with Nedd4. Co-expression of GRB10 and Nedd4 restores VEGF-R2 expression that is otherwise reduced by Nedd4. Nedd4 itself does not directly ubiquitinate VEGF-R2 (Nedd4C854S ligase-dead mutant retains VEGF-R2 ubiquitination). Thus GRB10 acts as a positive regulator protecting VEGF-R2 from Nedd4-mediated degradation. Co-immunoprecipitation, overexpression of Nedd4 and GRB10 in cells, Nedd4-CS catalytic mutant, MG132 proteasome inhibitor, ubiquitination assay The Journal of biological chemistry Medium 15060076
2005 Endogenous GRB10 knockdown by siRNA enhances IGF-I-mediated phosphorylation of IRS proteins, Akt, and ERK1/2 and increases DNA synthesis. Knockdown also decreases IGF-I-stimulated receptor autophosphorylation, partially reversed by pervanadate (phosphatase inhibitor), indicating GRB10 blocks phosphatase access to the activated IGF-IR. GIGYF proteins interact specifically with GRB10 but not Grb7 or Grb14. siRNA knockdown, phosphorylation assays, DNA synthesis assay, pervanadate treatment, yeast two-hybrid specificity assays Endocrinology Medium 16037382
2005 GRB10 N-terminal domains (absent in BPS-SH2 fragment) are required for effects on IR autophosphorylation and glucose uptake in 3T3-L1 adipocytes. Full-length GRB10 inhibits IR autophosphorylation and glucose uptake, while BPS-SH2 fragment inhibits post-receptor signaling (IRS1, IRS2, Akt, Shc, ERK, APS, c-Cbl) but not receptor phosphorylation or glucose uptake despite more sustained IR binding. Overexpression of full-length vs. truncated GRB10, glucose uptake assay, phosphorylation assays, co-precipitation Molecular and cellular endocrinology Medium 15664450
2006 GRB10 mediates insulin-stimulated ubiquitination and proteasomal degradation of the insulin receptor. Suppression of endogenous GRB10 increased IR protein levels without affecting IR mRNA, and blocked insulin-induced IR ubiquitination and reduction. Overexpression of GRB10 reduced IR protein levels. MG132 (proteasomal inhibitor) but not chloroquine (lysosomal inhibitor) reversed IR reduction. Stable overexpression and RNAi knockdown cell lines, mRNA/protein level analysis, ubiquitination assay, MG132 and chloroquine treatment American journal of physiology. Endocrinology and metabolism Medium 16434550
2007 Peripheral disruption of Grb10 (maternal allele) in mice leads to overgrowth and enhanced insulin-stimulated Akt and MAPK phosphorylation in skeletal muscle and fat. Hyperinsulinemic-euglycemic clamp studies revealed increased insulin sensitivity in peripheral tissues, establishing GRB10 as a negative regulator of insulin signaling and action in vivo. Gene trap knockout mice (maternal allele), hyperinsulinemic-euglycemic clamp, phosphorylation assays in tissues Molecular and cellular biology High 17620412
2007 Adult Grb10Δ2-4 knockout mice show improved glucose tolerance, insulin sensitivity, increased muscle mass, and reduced adiposity. Tissue-specific IR tyrosine phosphorylation changes are consistent with GRB10 preventing phosphatases from accessing IR activation-loop phosphotyrosines. Insulin-induced IRS-1 phosphorylation is enhanced, supporting GRB10 attenuation of IR-to-IRS-1 signal transmission. Grb10 gene disruption mouse model, glucose tolerance and insulin tolerance tests, IR/IRS-1 phosphorylation assays, body composition analysis Molecular and cellular biology High 17562854
2005 Phosphorylation of GRB10 serine 428 by Akt creates a binding site for 14-3-3 proteins. Mutation of Ser428 diminishes 14-3-3 binding. Akt directly binds GRB10 constitutively and phosphorylates GRB10 on Ser428 in an in vitro kinase assay. Yeast two-hybrid screen for 14-3-3 interaction, site-directed mutagenesis (S428), co-immunoprecipitation, in vitro Akt kinase assay The Journal of biological chemistry Medium 15722337
2007 GRB10 and active Raf-1 promote Bad-dependent cell survival. Both GRB10-deficient and Raf-1-deficient MEFs show enhanced apoptosis upon Bad expression. GRB10 SH2, PH, and proline-rich domains plus Akt phosphorylation site and 14-3-3 binding are required for anti-apoptotic function. Raf-1 kinase activity, Src phosphorylation (Tyr340/341), and Ras-binding domain interaction with GRB10 SH2 are required. GRB10 and Raf-1 are required for PI3K/Akt and MAPK pathways to phosphorylate and inactivate Bad. KO MEFs from Grb10 and Raf-1 knockout mice, Bad overexpression apoptosis assay, structure-function analysis with domain mutants, siRNA, signaling inhibitor studies, mutagenesis of Bad phosphorylation sites The Journal of biological chemistry Medium 17535812
2008 The GRB10/Nedd4 complex mediates multiubiquitination (not polyubiquitination) of IGF-IR upon ligand stimulation, which is required for receptor internalization via both clathrin-dependent and -independent pathways. GRB10 and Nedd4 remain associated with IGF-IR in early endosomes and caveosomes and are not degraded themselves, potentially being directed to recycling endosomes. Ubiquitination assays with K48R/K63R ubiquitin mutants, internalization assays, subcellular fractionation, co-immunoprecipitation from endosomes Journal of cellular physiology Medium 18286479
2009 Crystal structure of GRB10 RA and PH domains at 2.6 Å reveals these domains and the intervening linker form an integrated, dimeric structural unit. Biochemical studies showed Grb14 binds activated Ras, suggesting Ras binding may serve as a timing mechanism for downregulation of insulin signaling. Results illuminate membrane-recruitment mechanisms of GRB7/10/14 family and related actin-cytoskeleton proteins. X-ray crystallography (2.6 Å resolution), biochemical Ras binding assays Nature structural & molecular biology High 19648926
2009 GRB10 knockdown in human pancreatic islets reduces insulin and glucagon secretion, suggesting GRB10 plays a role in islet function beyond its known role in insulin signaling. siRNA knockdown in human pancreatic islets, insulin and glucagon secretion assays PLoS genetics Medium 24699409
2010 Crystal structure of NEDD4 C2 domain – GRB10 SH2 complex at 2.0 Å reveals three interaction interfaces. Main interface is an antiparallel β-sheet between GRB10 SH2 F-strand and NEDD4 C2 C-strand. NEDD4 C2 binds at non-classical sites far from the phosphotyrosine-binding pocket, making the interaction phosphotyrosine-independent. GRB10 SH2 can simultaneously bind NEDD4 C2 and IGF1R kinase domain. X-ray crystallography (2.0 Å), structural analysis The Journal of biological chemistry High 20980250
2011 GRB10 is a direct substrate of mTORC1. mTORC1-mediated phosphorylation stabilizes GRB10 protein. Phosphorylated GRB10 acts as a feedback inhibitor of the PI3K and ERK-MAPK pathways. Identified by large-scale quantitative phosphoproteomics. Quantitative phosphoproteomics (large-scale), mTORC1 kinase assay, rapamycin treatment, GRB10 stability assays, pathway readouts Science High 21659605
2011 Within the brain, Grb10 is expressed from the paternal allele (not maternal as in peripheral tissues), and ablation of paternal Grb10 increases social dominance and allogrooming behavior. Loss of the peripherally-expressed maternal allele causes fetal and placental overgrowth. Thus the two parental alleles function in different tissues to influence distinct physiological processes. Conditional knockout mice (paternal vs maternal allele ablation), behavioral testing, body weight/placental weight measurement Nature High 21270893
2012 GRB10 deletion in mice increases myofiber number (not myofiber size) by 142% in skeletal muscle, with increased muscle mass maintained through 12 months. The hypermuscularity arises during embryonic development. Neonatal Grb10-deficient hindlimbs show increased functional gene signatures for myogenic signaling and proliferation. Grb10 knockout mice, histomorphometry (fiber number/size), gene expression profiling, neonatal tissue analysis FASEB journal Medium 22623587
2012 GRB10 physically associates with FLT3 via FLT3 phospho-Tyr572 and Tyr793 in response to FLT3-ligand stimulation, and constitutively with oncogenic FLT3-ITD. GRB10 enhances FL-induced Akt phosphorylation by direct interaction with p85 PI3K subunit downstream of FLT3. GRB10 expression increases STAT5 activation in FLT3-ITD cells and promotes S-phase progression and survival. Co-immunoprecipitation (endogenous and overexpressed), phospho-mutant FLT3 constructs, Akt/ERK/p38 phosphorylation assays, siRNA knockdown, p85 interaction studies, cell cycle analysis Molecular oncology Medium 23246379
2014 mTOR-mediated phosphorylation of GRB10 at Ser501/503 switches its binding preference from the insulin receptor to raptor (mTORC1 component), leading to dissociation of raptor from mTOR and downregulation of mTORC1 signaling as a feedback mechanism. Fat-specific disruption of GRB10 increased mTORC1 signaling in adipose tissue, suppressed lipolysis, and reduced thermogenic function, effects reversed by rapamycin. mTOR phosphorylation assays, phospho-specific mutagenesis (S501/503), raptor co-immunoprecipitation, fat-specific Grb10 KO mice, lipolysis assay, thermogenesis measurement, rapamycin rescue Cell metabolism High 24746805
2007 GRB10 binds to the intracellular portion of LRP6, the Wnt co-receptor, and negatively regulates Wnt signaling. GRB10 overexpression suppressed Wnt3a- and LRP6-induced TCF-dependent reporter activity upstream of β-catenin. RNAi knockdown of GRB10 enhanced Wnt3a-induced reporter activity. GRB10 interferes with Axin binding to LRP6 as the proposed mechanism. Co-immunoprecipitation, TCF reporter assays, RNAi knockdown, β-catenin accumulation assay, Axin binding competition Biochemical and biophysical research communications Medium 17376403
2008 In mouse embryonic fibroblasts, GRB10 and Raf-1 form a complex that co-immunoprecipitates from mitochondrial fractions. GRB10 interacts with MEK1 in an insulin-dependent manner following MAPK activation. Direct GRB10-Gab1 association occurs in a peptide hormone-dependent manner via GRB10 SH2 domain binding to the Crk-binding region of Gab1, and elevated GRB10 potentiates MAPK-dependent mitogenesis in a Gab1-dependent manner. Peptide hormone-dependent co-immunoprecipitation, GRB10 SH2 domain peptide mimetic competition, Gab1 gene disruption cell lines, MAPK inhibitor studies, cell proliferation assays Journal of cellular biochemistry Medium 18985678
2009 GRB10 adapter protein decreases total Kv1.3 potassium channel expression, particularly at the membrane surface, and eliminates BDNF-induced phosphorylation of Kv1.3 via interaction with basally phosphorylated Tyr111-113 and Tyr449 residues on the channel. Negative regulation by GRB10 prevents BDNF-induced current suppression of Kv1.3. GRB10 does not directly complex with Kv1.3 in HEK293 cells but co-immunoprecipitates with Kv1.3 in native olfactory bulb. Immunocytochemistry, co-immunoprecipitation from HEK293 and native olfactory bulb, Kv1.3 point mutations (tyrosine to phenylalanine), patch-clamp electrophysiology, Western blot for expression levels BMC neuroscience Medium 19166614
2016 GRB10 is activated downstream of TORC1 upon IL-4 stimulation in macrophages, associates with IRS-2, NEDD4.2, IL-4Rα and γC, and its knockdown enhances tyrosine phosphorylation of IRS-2 and M2 gene expression. IL-4Rα and γC are ubiquitinated after IL-4 stimulation, suggesting GRB10 regulates IL-4 receptor-signaling complex degradation through interactions with NEDD4.2. siRNA knockdown, co-immunoprecipitation, phosphorylation assays, M2 gene expression assays, ubiquitination assay The Journal of biological chemistry Medium 27742835
2016 GRB10 deletion (maternal allele) substantially increases HSC long-term repopulating capacity and accelerates HSC regeneration after total body irradiation. GRB10-deficient HSCs show increased proliferation with upregulation of CDK4 and Cyclin E. Enhanced HSC regeneration is dependent on activation of the Akt/mTORC1 pathway. Grb10 maternal allele KO mice, competitive transplantation assay, total body irradiation reconstitution, CDK4/Cyclin E expression analysis, rapamycin treatment to test mTORC1 dependence Cell reports Medium 27806297
2018 Ablation of GRB10 specifically in muscle (using α-skeletal actin-Cre) is sufficient to cause muscle enlargement (increased fiber cross-sectional area) and increased insulin-stimulated glucose uptake with enhanced phospho-Akt in muscle. This confirms a muscle-autonomous role for GRB10 in growth and proximal insulin receptor signaling. Muscle-specific Cre-lox conditional KO (Grb10-mKO), hyperinsulinemic-euglycemic clamp, phospho-Akt assay in muscle Endocrinology Medium 29370381
2018 The Grb10 gene is silenced in adult mouse liver but can be reactivated by acute ER stress (tunicamycin or short-term high-fat diet) via ATF4-mediated transcriptional upregulation. Reactivated GRB10 promotes hepatic lipid dysregulation and steatosis; liver-specific GRB10 KO suppresses lipogenic gene expression and acute ER stress-induced hepatosteatosis. Liver-specific KO mice, tunicamycin/HFD challenge, ATF4 identification by luciferase reporter and ChIP/promoter analysis, hepatic lipid/gene expression assays Journal of molecular endocrinology Medium 29555819
2019 GRB10 knockdown in human primary skeletal muscle myotubes enhances insulin-induced PI3K/Akt signaling and glucose uptake associated with increased insulin receptor abundance. mTORC1-mediated phosphorylation of GRB10 at Ser476 is stimulated by both insulin and amino acids independently and additively; rapamycin blocks this phosphorylation and disrupts negative feedback on PI3K/Akt, suggesting mTORC1 controls insulin receptor abundance via GRB10. siRNA knockdown in human primary myotubes, Ser476 phosphorylation assay, rapamycin treatment, glucose uptake assay, insulin receptor abundance measurement American journal of physiology. Endocrinology and metabolism Medium 31794259
2022 An intronic secondary differentially methylated region (CBR2.3) within Grb10 on the paternal chromosome has tissue-specific paternal CTCF binding that functions as an insulator controlling allele-specific chromatin looping contacts with the neighboring Ddc gene. Deletion of paternal CBR2.3 removes this insulator, shifts chromatin looping, creates ectopic enhancer-promoter contacts, and destabilizes normal Grb10-Ddc allele-specific expression with developmental consequences in heart and muscle. Polymorphic mice, 4C-seq chromatin looping, allele-specific CTCF ChIP, conditional paternal CBR2.3 deletion, expression analysis, cardiac/muscle phenotyping Molecular cell High 36108632
2023 GRB10 in hypothalamic AgRP and POMC neurons enhances leptin signaling and promotes weight loss. GRB10 interacts with the leptin receptor (LepR) in hypothalamic neurons. Ablation of GRB10 in AgRP neurons promotes weight gain; overexpression reduces body weight. GRB10 exaggerates inhibitory effects of leptin on AgRP neurons via ATP-sensitive potassium channel (KATP) currents and facilitates leptin's excitatory drive on POMC neurons via TRP channels. Neuron-specific conditional KO and overexpression (AgRP-Cre, POMC-Cre), co-immunoprecipitation for LepR interaction, patch-clamp electrophysiology, body weight measurement, dietary obesity model Nature metabolism High 36593271

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Phosphoproteomic analysis identifies Grb10 as an mTORC1 substrate that negatively regulates insulin signaling. Science (New York, N.Y.) 709 21659605
2003 Disruption of the imprinted Grb10 gene leads to disproportionate overgrowth by an Igf2-independent mechanism. Proceedings of the National Academy of Sciences of the United States of America 219 12829789
2003 The Grb10/Nedd4 complex regulates ligand-induced ubiquitination and stability of the insulin-like growth factor I receptor. Molecular and cellular biology 204 12697834
2011 Distinct physiological and behavioural functions for parental alleles of imprinted Grb10. Nature 157 21270893
2000 Human GRB10 is imprinted and expressed from the paternal and maternal allele in a highly tissue- and isoform-specific fashion. Human molecular genetics 142 10861285
2014 A central role for GRB10 in regulation of islet function in man. PLoS genetics 141 24699409
2005 Grb10 and Grb14: enigmatic regulators of insulin action--and more? The Biochemical journal 138 15901248
1995 The cloning of Grb10 reveals a new family of SH2 domain proteins. Oncogene 138 7731717
1996 Ligand activation of ELK receptor tyrosine kinase promotes its association with Grb10 and Grb2 in vascular endothelial cells. The Journal of biological chemistry 137 8798570
1998 Identification of the Meg1/Grb10 imprinted gene on mouse proximal chromosome 11, a candidate for the Silver-Russell syndrome gene. Proceedings of the National Academy of Sciences of the United States of America 134 9448292
1996 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. The Journal of biological chemistry 128 8798417
1995 The Ret receptor protein tyrosine kinase associates with the SH2-containing adapter protein Grb10. The Journal of biological chemistry 122 7665556
1998 Grb10 interacts differentially with the insulin receptor, insulin-like growth factor I receptor, and epidermal growth factor receptor via the Grb10 Src homology 2 (SH2) domain and a second novel domain located between the pleckstrin homology and SH2 domains. The Journal of biological chemistry 121 9506989
2003 Conserved methylation imprints in the human and mouse GRB10 genes with divergent allelic expression suggests differential reading of the same mark. Human molecular genetics 120 12700169
2000 Duplication of 7p11.2-p13, including GRB10, in Silver-Russell syndrome. American journal of human genetics 117 10631135
2004 Grb10 prevents Nedd4-mediated vascular endothelial growth factor receptor-2 degradation. The Journal of biological chemistry 115 15060076
2007 Peripheral disruption of the Grb10 gene enhances insulin signaling and sensitivity in vivo. Molecular and cellular biology 112 17620412
2007 Mice with a disruption of the imprinted Grb10 gene exhibit altered body composition, glucose homeostasis, and insulin signaling during postnatal life. Molecular and cellular biology 109 17562854
1997 Human GRB-IRbeta/GRB10. Splice variants of an insulin and growth factor receptor-binding protein with PH and SH2 domains. The Journal of biological chemistry 105 9006901
1996 Evidence for the direct interaction of the insulin-like growth factor I receptor with IRS-1, Shc, and Grb10. Molecular endocrinology (Baltimore, Md.) 105 8776723
2014 Grb10 promotes lipolysis and thermogenesis by phosphorylation-dependent feedback inhibition of mTORC1. Cell metabolism 103 24746805
2002 Grb10 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. The Journal of biological chemistry 98 12493740
1998 Interaction of the Grb10 adapter protein with the Raf1 and MEK1 kinases. The Journal of biological chemistry 98 9553107
2003 Two novel proteins that are linked to insulin-like growth factor (IGF-I) receptors by the Grb10 adapter and modulate IGF-I signaling. The Journal of biological chemistry 97 12771153
2003 Imprinting regulation of the murine Meg1/Grb10 and human GRB10 genes; roles of brain-specific promoters and mouse-specific CTCF-binding sites. Nucleic acids research 95 12595547
1999 Grb10, a positive, stimulatory signaling adapter in platelet-derived growth factor BB-, insulin-like growth factor I-, and insulin-mediated mitogenesis. Molecular and cellular biology 95 10454568
1996 Interaction between the Grb10 SH2 domain and the insulin receptor carboxyl terminus. The Journal of biological chemistry 90 8621530
2008 Grb10/Nedd4-mediated multiubiquitination of the insulin-like growth factor receptor regulates receptor internalization. Journal of cellular physiology 87 18286479
1999 Duplication of 7p12.1-p13, including GRB10 and IGFBP1, in a mother and daughter with features of Silver-Russell syndrome. Human genetics 87 10987657
1997 The adapter protein Grb10 associates preferentially with the insulin receptor as compared with the IGF-I receptor in mouse fibroblasts. The Journal of clinical investigation 87 9062339
2002 Role for the adaptor protein Grb10 in the activation of Akt. Molecular and cellular biology 82 11809791
1999 Localization of endogenous Grb10 to the mitochondria and its interaction with the mitochondrial-associated Raf-1 pool. The Journal of biological chemistry 77 10585452
2009 Maternally-inherited Grb10 reduces placental size and efficiency. Developmental biology 75 19833122
2001 The BPS domain of Grb10 inhibits the catalytic activity of the insulin and IGF1 receptors. FEBS letters 75 11287005
1996 Grb10: A new substrate of the insulin-like growth factor I receptor. Cancer research 74 8764099
2000 Imprinting of human GRB10 and its mutations in two patients with Russell-Silver syndrome. American journal of human genetics 73 10856193
2005 Meg1/Grb10 overexpression causes postnatal growth retardation and insulin resistance via negative modulation of the IGF1R and IR cascades. Biochemical and biophysical research communications 67 15752742
2008 A mono-allelic bivalent chromatin domain controls tissue-specific imprinting at Grb10. The EMBO journal 66 18650936
2009 Structural and functional studies of the Ras-associating and pleckstrin-homology domains of Grb10 and Grb14. Nature structural & molecular biology 64 19648926
2013 Regulation of insulin and type 1 insulin-like growth factor signaling and action by the Grb10/14 and SH2B1/B2 adaptor proteins. The FEBS journal 63 23190452
2009 Paternal deletion of Meg1/Grb10 DMR causes maternalization of the Meg1/Grb10 cluster in mouse proximal Chromosome 11 leading to severe pre- and postnatal growth retardation. Human molecular genetics 63 19174477
2005 The adapter protein GRB10 is an endogenous negative regulator of insulin-like growth factor signaling. Endocrinology 62 16037382
1998 Grb10 identified as a potential regulator of growth hormone (GH) signaling by cloning of GH receptor target proteins. The Journal of biological chemistry 62 9632636
2009 Reciprocal imprinting of human GRB10 in placental trophoblast and brain: evolutionary conservation of reversed allelic expression. Human molecular genetics 61 19487367
2018 Circular RNA GRB10 as a competitive endogenous RNA regulating nucleus pulposus cells death in degenerative intervertebral disk. Cell death & disease 57 29476072
2004 Grb10: more than a simple adaptor protein. Frontiers in bioscience : a journal and virtual library 55 14766376
2003 Negative regulation of insulin-stimulated mitogen-activated protein kinase signaling by Grb10. Molecular endocrinology (Baltimore, Md.) 54 14615605
2001 Maternal repression of the human GRB10 gene in the developing central nervous system; evaluation of the role for GRB10 in Silver-Russell syndrome. European journal of human genetics : EJHG 54 11313740
2021 Circ_0009910 shuttled by exosomes regulates proliferation, cell cycle and apoptosis of acute myeloid leukemia cells by regulating miR-5195-3p/GRB10 axis. Hematological oncology 52 33969901
2003 Structural basis for dimerization of the Grb10 Src homology 2 domain. Implications for ligand specificity. The Journal of biological chemistry 51 12551896
2014 Tissue-specific regulation and function of Grb10 during growth and neuronal commitment. Proceedings of the National Academy of Sciences of the United States of America 50 25368187
2006 Role of DNA methylation and histone H3 lysine 27 methylation in tissue-specific imprinting of mouse Grb10. Molecular and cellular biology 46 17101788
1998 The SH2-containing adapter protein GRB10 interacts with BCR-ABL. Oncogene 46 9747873
2009 Dual ablation of Grb10 and Grb14 in mice reveals their combined role in regulation of insulin signaling and glucose homeostasis. Molecular endocrinology (Baltimore, Md.) 45 19541746
2006 Grb10 mediates insulin-stimulated degradation of the insulin receptor: a mechanism of negative regulation. American journal of physiology. Endocrinology and metabolism 45 16434550
2014 Developmental programming mediated by complementary roles of imprinted Grb10 in mother and pup. PLoS biology 42 24586114
2012 FLT3 signals via the adapter protein Grb10 and overexpression of Grb10 leads to aberrant cell proliferation in acute myeloid leukemia. Molecular oncology 42 23246379
2004 Grb10 exceeding the boundaries of a common signaling adapter. Frontiers in bioscience : a journal and virtual library 42 14766395
2003 Growth factor receptor-binding protein 10 (Grb10) as a partner of phosphatidylinositol 3-kinase in metabolic insulin action. The Journal of biological chemistry 41 12783867
2015 Carrageenan Inhibits Insulin Signaling through GRB10-mediated Decrease in Tyr(P)-IRS1 and through Inflammation-induced Increase in Ser(P)307-IRS1. The Journal of biological chemistry 38 25784556
2000 Identification of Grb10 as a direct substrate for members of the Src tyrosine kinase family. Oncogene 38 10871840
2015 Drosophila Gyf/GRB10 interacting GYF protein is an autophagy regulator that controls neuron and muscle homeostasis. Autophagy 37 26086452
1998 Grb10/GrbIR as an in vivo substrate of Tec tyrosine kinase. Genes to cells : devoted to molecular & cellular mechanisms 36 9753425
2007 Genomic imprinting of Dopa decarboxylase in heart and reciprocal allelic expression with neighboring Grb10. Molecular and cellular biology 35 17967881
2000 Grb10 proteins in insulin-like growth factor and insulin receptor signaling (review). International journal of molecular medicine 35 10639593
2016 The TORC1-activated Proteins, p70S6K and GRB10, Regulate IL-4 Signaling and M2 Macrophage Polarization by Modulating Phosphorylation of Insulin Receptor Substrate-2. The Journal of biological chemistry 34 27742835
2001 The adapter protein, Grb10, is a positive regulator of vascular endothelial growth factor signaling. Oncogene 34 11494124
2001 Evidence against GRB10 as the gene responsible for Silver-Russell syndrome. Biochemical and biophysical research communications 34 11527390
2012 Grb10 regulates the development of fiber number in skeletal muscle. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 33 22623587
2020 The circular RNA circ-GRB10 participates in the molecular circuitry inhibiting human intervertebral disc degeneration. Cell death & disease 32 32792505
2023 Hypothalamic Grb10 enhances leptin signalling and promotes weight loss. Nature metabolism 31 36593271
2016 Amelioration of Diabetic Mouse Nephropathy by Catalpol Correlates with Down-Regulation of Grb10 Expression and Activation of Insulin-Like Growth Factor 1 / Insulin-Like Growth Factor 1 Receptor Signaling. PloS one 30 26986757
2003 Grb10 adapter protein as regulator of insulin-like growth factor receptor signaling. Journal of cellular physiology 30 14566960
2009 Brain-derived neurotrophic factor modulation of Kv1.3 channel is disregulated by adaptor proteins Grb10 and nShc. BMC neuroscience 29 19166614
2007 Grb10 and active Raf-1 kinase promote Bad-dependent cell survival. The Journal of biological chemistry 29 17535812
2022 Tissue-specific Grb10/Ddc insulator drives allelic architecture for cardiac development. Molecular cell 25 36108632
2017 Effect of vitrification on in vitro development and imprinted gene Grb10 in mouse embryos. Reproduction (Cambridge, England) 25 28696244
2005 Distinct Grb10 domain requirements for effects on glucose uptake and insulin signaling. Molecular and cellular endocrinology 24 15664450
2014 Grb10 is a dual regulator of receptor tyrosine kinase signaling. Molecular biology reports 23 24420853
2014 Grb10 deletion enhances muscle cell proliferation, differentiation and GLUT4 plasma membrane translocation. Journal of cellular physiology 23 24664951
2023 RILP inhibits tumor progression in osteosarcoma via Grb10-mediated inhibition of the PI3K/AKT/mTOR pathway. Molecular medicine (Cambridge, Mass.) 22 37789274
2016 Deletion of the Imprinted Gene Grb10 Promotes Hematopoietic Stem Cell Self-Renewal and Regeneration. Cell reports 22 27806297
2018 Ablation of Grb10 Specifically in Muscle Impacts Muscle Size and Glucose Metabolism in Mice. Endocrinology 21 29370381
2015 Placental expression of the insulin receptor binding protein GRB10: Relation to human fetoplacental growth and fetal gender. Placenta 21 26390806
2014 Antagonistic roles in fetal development and adult physiology for the oppositely imprinted Grb10 and Dlk1 genes. BMC biology 21 25551289
2010 Structural basis for the interaction between the growth factor-binding protein GRB10 and the E3 ubiquitin ligase NEDD4. The Journal of biological chemistry 21 20980250
2018 De-silencing Grb10 contributes to acute ER stress-induced steatosis in mouse liver. Journal of molecular endocrinology 20 29555819
2014 Negative regulation of Grb10 Interacting GYF Protein 2 on insulin-like growth factor-1 receptor signaling pathway caused diabetic mice cognitive impairment. PloS one 20 25268761
2012 Lentivirus shRNA Grb10 targeting the pancreas induces apoptosis and improved glucose tolerance due to decreased plasma glucagon levels. Diabetologia 20 22222503
2012 Lmx1a is an activator of Rgs4 and Grb10 and is responsible for the correct specification of rostral and medial mdDA neurons. The European journal of neuroscience 20 23106268
2007 GRB10 binds to LRP6, the Wnt co-receptor and inhibits canonical Wnt signaling pathway. Biochemical and biophysical research communications 19 17376403
2003 Inhibition of FGF receptor signalling in Xenopus oocytes: differential effect of Grb7, Grb10 and Grb14. FEBS letters 19 12885405
2002 DDC and COBL, flanking the imprinted GRB10 gene on 7p12, are biallelically expressed. Mammalian genome : official journal of the International Mammalian Genome Society 19 12514746
2008 Mitogenic roles of Gab1 and Grb10 as direct cellular partners in the regulation of MAP kinase signaling. Journal of cellular biochemistry 18 18985678
2008 Type 2 diabetes mellitus in a non-obese mouse model induced by Meg1/Grb10 overexpression. Experimental animals 17 18633161
2005 Phosphorylation of grb10 regulates its interaction with 14-3-3. The Journal of biological chemistry 17 15722337
1998 Genomic structure of the gene for the SH2 and pleckstrin homology domain-containing protein GRB10 and evaluation of its role in Hirschsprung disease. Oncogene 17 9881709
2022 circHtra1/miR-3960/GRB10 Axis Promotes Neuronal Loss and Immune Deficiency in Traumatic Brain Injury. Oxidative medicine and cellular longevity 16 35571247
2019 Role of Grb10 in mTORC1-dependent regulation of insulin signaling and action in human skeletal muscle cells. American journal of physiology. Endocrinology and metabolism 16 31794259
2013 Brain-expressed imprinted genes and adult behaviour: the example of Nesp and Grb10. Mammalian genome : official journal of the International Mammalian Genome Society 16 23974804

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