Q60760 (GRB10_MOUSE) Reviewed, UniProtKB/Swiss-Prot
Last modified April 16, 2014. Version 126. History...
Names and origin
|Protein names||Recommended name:|
Growth factor receptor-bound protein 10
GRB10 adapter protein
Maternally expressed gene 1 protein
|Organism||Mus musculus (Mouse) [Reference proteome]|
|Taxonomic identifier||10090 [NCBI]|
|Taxonomic lineage||Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus|
|Sequence length||621 AA.|
|Protein existence||Evidence at protein level|
General annotation (Comments)
Adapter protein which modulates coupling of a number of cell surface receptor kinases with specific signaling pathways. Binds to, and suppress signals from, activated receptors tyrosine kinases, including the insulin (INSR) and insulin-like growth factor (IGF1R) receptors. The inhibitory effect can be achieved by 2 mechanisms: interference with the signaling pathway and increased receptor degradation. Delays and reduces AKT1 phosphorylation in response to insulin stimulation. Blocks association between INSR and IRS1 and IRS2 and prevents insulin-stimulated IRS1 and IRS2 tyrosine phosphorylation. Recruits NEDD4 to IGF1R, leading to IGF1R ubiquitination, increased internalization and degradation by both the proteasomal and lysosomal pathways. A similar role in the mediation of ubiquitination has also been suggested with INSR. Negatively regulates Wnt signaling by interacting with LRP6 intracellular portion and interfering with the binding of AXIN1 to LRP6. Positive regulator of the KDR/VEGFR-2 signaling pathway. May inhibit NEDD4-mediated degradation of KDR/VEGFR-2. Ref.10 Ref.11 Ref.14 Ref.15 Ref.17
Phosphorylation by mTORC1 stabilizes and activates GRB10 constituting a feedback pathway by which mTORC1 inhibits INSR-dependent signaling By similarity.
Interacts with ligand-activated tyrosine kinase receptors, including FGFR1, INSR, IGF1R, MET and PDGFRB in a phosphotyrosine-dependent manner through the SH2 domain. Poorly binds to the EGFR. Directly interacts with MAP3K14/NIK and is recruited to the EGFR-ERBB2 complex By similarity. Interacts with GIGYF1/PERQ1 and GIGYF2/TNRC15. When unphosphorylated, interacts with AKT1 and when phosphorylated with YWHAE/14-3-3 epsilon. Interacts with NEDD4. Interacts with LRP6, thus interfering with the binding of AXIN1 to LRP6. Binds to activated NRAS By similarity. Ref.1 Ref.2 Ref.7 Ref.9 Ref.10 Ref.13 Ref.14 Ref.15
Cytoplasm. Note: When complexed with NEDD4 and IGF1R, follows IGF1R internalization, remaining associated with early endosomes. Uncouples from IGF1R before the sorting of the receptor to the lysosomal compartment. Ref.17
At 13.5 dpc, expressed in most embryonic tissues and in placenta. At 14.5 dpc, expressed at high levels in a variety of muscle tissues, including that of the face and trunk, the intercostal muscles, the diaphragm and cardiac muscle, the tongue and limbs (at protein level). In the brain, most abundant expression in the subependymal layers, in the meninges and in the choroid plexus (both epithelium and mesenchyme) (at protein level). High levels in the liver, bronchioles and the cartilage of the atlas, ribs and long bones (at protein level). In the kidney, expression limited to the developing tubules and mesenchyme (at protein level). Also detected in the adrenal gland and pancreatic bud (at protein level). At 12.5 dpc, paternal allele expression detected in the cartilage of the limbs, ribs and face and in the meninges. At 14.5 dpc, paternal allele expressed in the cartilage of the axis, ribs, head, and long bones, in the heart, lungs, gut, umbilicus and tongue, as well as in the meninges of the fourth ventricle. Not detected in the skeletal muscle. In most tissues, paternal expression is lower than maternal. Ref.6 Ref.11
The PH domain binds relatively non-specifically to several phosphoinositides, including PI5P, PI(4,5)P2, PI(3,4)P2 and PI(3,4,5)P3, with modest affinities By similarity.
Disruption of the maternal allele results in overgrowth of both the embryo and placenta such that mutant mice are at birth about 30% larger than normal. This effect occurs during embryogenesis and results in addition in disproportionate overgrowth of the liver with relative sparing of the brain. The major part of the growth phenotype seems to be IGF2-independent. Ref.11
The GRB10 locus is imprinted. The maternal allele is expressed in most tissues, except the brain where it is expressed from the paternal allele. Expression from the maternal allele in fetal and adult brain was however described in Ref.8.
Belongs to the GRB7/10/14 family.
Contains 1 PH domain.
Contains 1 Ras-associating domain.
Contains 1 SH2 domain.
The sequence AAH53842.1 differs from that shown. Reason: Erroneous initiation.
The sequence BAE37514.1 differs from that shown. Reason: Erroneous initiation.
|Coding sequence diversity||Alternative splicing|
|Gene Ontology (GO)|
|Biological_process||insulin receptor signaling pathway|
Inferred from electronic annotation. Source: Ensemblinsulin-like growth factor receptor signaling pathwaynegative regulation of Wnt signaling pathwaynegative regulation of glucose importnegative regulation of glycogen biosynthetic processnegative regulation of insulin receptor signaling pathwaynegative regulation of phosphorylationpositive regulation of phosphorylation
Inferred from electronic annotation. Source: Ensemblpositive regulation of vascular endothelial growth factor receptor signaling pathway
Inferred from sequence or structural similarity. Source: UniProtKBsignal transduction
|Molecular_function||SH3/SH2 adaptor activityinsulin receptor bindingphosphotyrosine binding|
|Complete GO annotation...|
|This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]|
|Isoform 1 (identifier: Q60760-1) |
Also known as: Alpha;
This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
|Isoform 2 (identifier: Q60760-2) |
Also known as: Delta;
The sequence of this isoform differs from the canonical sequence as follows:
|Note: Predominant isoform in most tissues.|
|Isoform 3 (identifier: Q60760-3) |
The sequence of this isoform differs from the canonical sequence as follows:
Sequence annotation (Features)
|Feature key||Position(s)||Length||Description||Graphical view||Feature identifier|
|Chain||1 – 621||621||Growth factor receptor-bound protein 10||PRO_0000150347|
|Domain||194 – 278||85||Ras-associating|
|Domain||318 – 427||110||PH|
|Domain||520 – 601||82||SH2|
Amino acid modifications
|Modified residue||50||1||Phosphoserine By similarity|
|Modified residue||96||1||Phosphoserine; alternate Ref.12|
|Modified residue||96||1||Phosphoserine; by MTOR, MAPK1 and MAPK3; alternate By similarity|
|Modified residue||455||1||Phosphoserine; by MTOR and PKB/AKT1 By similarity|
|Modified residue||458||1||Phosphoserine Ref.16|
|Modified residue||503||1||Phosphoserine; by MTOR, MAPK1 and MAPK3 By similarity|
|Alternative sequence||117 – 196||80||Missing in isoform 3.||VSP_012379|
|Alternative sequence||117 – 141||25||Missing in isoform 2.||VSP_001844|
|Sequence conflict||491 – 492||2||KR → NG in AAB53687. Ref.1|
|Sequence conflict||555||1||A → T in BAC28088. Ref.3|
Helix Strand Turn
|Helix||515 – 517||3|
|Helix||527 – 536||10|
|Beta strand||543 – 548||6|
|Beta strand||556 – 562||7|
|Beta strand||565 – 576||12|
|Beta strand||579 – 585||7|
|Beta strand||588 – 593||6|
|Helix||594 – 601||8|
|Beta strand||608 – 610||3|
|||"The cloning of Grb10 reveals a new family of SH2 domain proteins."|
Ooi J., Yajnik V., Immanuel D., Gordon M., Moskow J.J., Buchberg A., Margolis B.
Oncogene 10:1621-1630(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), INTERACTION WITH EGFR, TISSUE SPECIFICITY, PHOSPHORYLATION.
|||"The adapter protein Grb10 associates preferentially with the insulin receptor as compared with the IGF-I receptor in mouse fibroblasts."|
Laviola L., Giorgino F., Chow J.C., Baquero J.A., Hansen H., Ooi J., Zhu J., Riedel H., Smith R.J.
J. Clin. Invest. 99:830-837(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), INTERACTION WITH INSR AND IGF1R, TISSUE SPECIFICITY.
|||"The transcriptional landscape of the mammalian genome."|
Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J. Hayashizaki Y.
Science 309:1559-1563(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
Tissue: Embryo and Embryonic head.
|||Griffiths C., Sycamore N.|
Submitted (NOV-2004) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
|||"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."|
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2 AND 3).
Tissue: Eye and Olfactory epithelium.
|||"Identification of the Meg1/Grb10 imprinted gene on mouse proximal chromosome 11, a candidate for the Silver-Russell syndrome gene."|
Miyoshi N., Kuroiwa Y., Kohda T., Shitara H., Yonekawa H., Kawabe T., Hasegawa H., Barton S.C., Surani M.A., Kaneko-Ishino T., Ishino F.
Proc. Natl. Acad. Sci. U.S.A. 95:1102-1107(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: IMPRINTING, DEVELOPMENTAL STAGE.
|||"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 O.R., Leone M.E., Riedel H.
Mol. Cell. Biol. 19:6217-6228(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH FGFR1; INSR; IGF1R; MET AND PDGFRB.
|||"Human GRB10 is imprinted and expressed from the paternal and maternal allele in a highly tissue- and isoform-specific fashion."|
Blagitko N., Mergenthaler S., Schulz U., Wollmann H.A., Craigen W., Eggermann T., Ropers H.-H., Kalscheuer V.M.
Hum. Mol. Genet. 9:1587-1595(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: IMPRINTING.
|||"Two novel proteins that are linked to insulin-like growth factor (IGF-I) receptors by the Grb10 adapter and modulate IGF-I signaling."|
Giovannone B., Lee E., Laviola L., Giorgino F., Cleveland K.A., Smith R.J.
J. Biol. Chem. 278:31564-31573(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH GIGYF1 AND GIGYF2.
|||"The Grb10/Nedd4 complex regulates ligand-induced ubiquitination and stability of the insulin-like growth factor I receptor."|
Vecchione A., Marchese A., Henry P., Rotin D., Morrione A.
Mol. Cell. Biol. 23:3363-3372(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH IGF1R AND NEDD4.
|||"Disruption of the imprinted Grb10 gene leads to disproportionate overgrowth by an Igf2-independent mechanism."|
Charalambous M., Smith F.M., Bennett W.R., Crew T.E., Mackenzie F., Ward A.
Proc. Natl. Acad. Sci. U.S.A. 100:8292-8297(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, DISRUPTION PHENOTYPE, IMPRINTING, DEVELOPMENTAL STAGE.
|||"Phosphoproteomic analysis of the developing mouse brain."|
Ballif B.A., Villen J., Beausoleil S.A., Schwartz D., Gygi S.P.
Mol. Cell. Proteomics 3:1093-1101(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-96, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Embryonic brain.
|||"Phosphorylation of grb10 regulates its interaction with 14-3-3."|
Urschel S., Bassermann F., Bai R.Y., Munch S., Peschel C., Duyster J.
J. Biol. Chem. 280:16987-16993(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH AKT1 AND YWHAE, PHOSPHORYLATION.
|||"Distinct Grb10 domain requirements for effects on glucose uptake and insulin signaling."|
Mori K., Giovannone B., Smith R.J.
Mol. Cell. Endocrinol. 230:39-50(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH INSR.
|||"GRB10 binds to LRP6, the Wnt co-receptor and inhibits canonical Wnt signaling pathway."|
Tezuka N., Brown A.M., Yanagawa S.
Biochem. Biophys. Res. Commun. 356:648-654(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH LRP6.
|||"Large-scale phosphorylation analysis of mouse liver."|
Villen J., Beausoleil S.A., Gerber S.A., Gygi S.P.
Proc. Natl. Acad. Sci. U.S.A. 104:1488-1493(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-458, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
|||"Grb10/Nedd4-mediated multiubiquitination of the insulin-like growth factor receptor regulates receptor internalization."|
Monami G., Emiliozzi V., Morrione A.
J. Cell. Physiol. 216:426-437(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, SUBCELLULAR LOCATION.
|+||Additional computationally mapped references.|
|U18996 mRNA. Translation: AAB53687.1.|
AF022072 mRNA. Translation: AAB72103.1.
AK030727 mRNA. Translation: BAC27100.1.
AK032927 mRNA. Translation: BAC28088.1.
AK163841 mRNA. Translation: BAE37514.1. Different initiation.
AL645803, AL663087 Genomic DNA. Translation: CAI23990.1.
AL645803, AL663087 Genomic DNA. Translation: CAI23991.1.
AL663087, AL645803 Genomic DNA. Translation: CAI25685.1.
AL663087, AL645803 Genomic DNA. Translation: CAI25687.1.
BC016111 mRNA. Translation: AAH16111.1.
BC053842 mRNA. Translation: AAH53842.1. Different initiation.
|RefSeq||NP_001171100.1. NM_001177629.1. |
3D structure databases
|SMR||Q60760. Positions 195-437, 456-620. |
Protein-protein interaction databases
|BioGrid||200045. 6 interactions.|
|IntAct||Q60760. 8 interactions.|
Protocols and materials databases
Genome annotation databases
|Ensembl||ENSMUST00000093321; ENSMUSP00000091011; ENSMUSG00000020176. [Q60760-2]|
ENSMUST00000109654; ENSMUSP00000105281; ENSMUSG00000020176. [Q60760-3]
|UCSC||uc007iaz.2. mouse. [Q60760-3]|
uc007iba.2. mouse. [Q60760-2]
|MGI||MGI:103232. Grb10. |
Gene expression databases
Family and domain databases
|Gene3D||22.214.171.124. 1 hit. |
3.30.505.10. 1 hit.
|InterPro||IPR015042. BPS-dom. |
|Pfam||PF08947. BPS. 1 hit. |
PF00169. PH. 1 hit.
PF00788. RA. 1 hit.
PF00017. SH2. 1 hit.
|PRINTS||PR00401. SH2DOMAIN. |
|SMART||SM00233. PH. 1 hit. |
SM00314. RA. 1 hit.
SM00252. SH2. 1 hit.
|SUPFAM||SSF55550. SSF55550. 1 hit. |
|PROSITE||PS50003. PH_DOMAIN. 1 hit. |
PS50200. RA. 1 hit.
PS50001. SH2. 1 hit.
|ChiTaRS||GRB10. mouse. |
|Accession||Primary (citable) accession number: Q60760|
Secondary accession number(s): O35352 Q91WC5
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Chordata Protein Annotation Program|