| Structural highlights
3m7f is a 2 chain structure with sequence from Lk3 transgenic mice. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Gene: | Grb10, Kiaa0093, Meg1, Nedd-4, Nedd4, Nedd4a (LK3 transgenic mice) |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[GRB10_MOUSE] 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.[1] [2] [3] [4] [5] [NEDD4_MOUSE] E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Monoubiquitinates IGF1R at multiple sites, thus leading to receptor internalization and degradation in lysosomes. Ubiquitinates FGFR1, leading to receptor internalization and degradation in lysosomes. Involved in ubiquitination of ERBB4 intracellular domain E4ICD1 (PubMed:19193720). Predominantly involved in ubiquitination of membrane bound forms of ERBB4 rather than processed precursors and intermediate membrane-anchored 80 kDa fragments (m80HER4), with a lesser role in ubiquitination of ERBB4 intracellular domain E4ICD1 (PubMed:19047365). Promotes ubiquitination of RAPGEF2. Involved in the pathway leading to the degradation of VEGFR-2/KDFR, independently of its ubiquitin-ligase activity. Part of a signaling complex composed of NEDD4, RAP2A and TNIK which regulates neuronal dendrite extension and arborization during development. Ubiquitinates TNK2 and regulates EGF-induced degradation of EGFR and TNF2 (By similarity). Involved in the ubiquitination of ebola virus VP40 protein and this ubiquitination plays a role in facilitating viral budding (By similarity).[6] [7]
Publication Abstract from PubMed
In addition to inhibiting insulin receptor and IGF1R kinase activity by directly binding to the receptors, GRB10 can also negatively regulate insulin and IGF1 signaling by mediating insulin receptor and IGF1R degradation through ubiquitination. It has been shown that GRB10 can interact with the C2 domain of the E3 ubiquitin ligase NEDD4 through its Src homology 2 (SH2) domain. Therefore, GRB10 might act as a connector, bringing NEDD4 close to IGF1R to facilitate the ubiquitination of IGF1R by NEDD4. This is the first case in which it has been found that an SH2 domain could colocalize a ubiquitin ligase and its substrate. Here we report the crystal structure of the NEDD4 C2-GRB10 SH2 complex at 2.0 A. The structure shows that there are three interaction interfaces between NEDD4 C2 and GRB10 SH2. The main interface centers on an antiparallel beta-sheet composed of the F beta-strand of GRB10 SH2 and the C beta-strand of NEDD4 C2. NEDD4 C2 binds at nonclassical sites on the SH2 domain surface, far from the classical phosphotyrosine-binding pocket. Hence, this interaction is phosphotyrosine-independent, and GRB10 SH2 can bind the C2 domain of NEDD4 and the kinase domain of IGF1R simultaneously. Based on these results, a model of how NEDD4 interacts with IGF1R through GRB10 has been proposed. This report provides further evidence that SH2 domains can participate in important signaling interactions beyond the classical recognition of phosphotyrosine.
Structural basis for the interaction between the growth factor-binding protein GRB10 and the E3 ubiquitin ligase NEDD4.,Huang Q, Szebenyi DM J Biol Chem. 2010 Dec 31;285(53):42130-9. Epub 2010 Oct 26. PMID:20980250[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Vecchione A, Marchese A, Henry P, Rotin D, Morrione A. The Grb10/Nedd4 complex regulates ligand-induced ubiquitination and stability of the insulin-like growth factor I receptor. Mol Cell Biol. 2003 May;23(9):3363-72. PMID:12697834
- ↑ Charalambous M, Smith FM, Bennett WR, Crew TE, Mackenzie F, Ward A. Disruption of the imprinted Grb10 gene leads to disproportionate overgrowth by an Igf2-independent mechanism. Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8292-7. Epub 2003 Jun 26. PMID:12829789 doi:http://dx.doi.org/10.1073/pnas.1532175100
- ↑ Mori K, Giovannone B, Smith RJ. Distinct Grb10 domain requirements for effects on glucose uptake and insulin signaling. Mol Cell Endocrinol. 2005 Jan 31;230(1-2):39-50. PMID:15664450 doi:http://dx.doi.org/10.1016/j.mce.2004.11.004
- ↑ Tezuka N, Brown AM, Yanagawa S. GRB10 binds to LRP6, the Wnt co-receptor and inhibits canonical Wnt signaling pathway. Biochem Biophys Res Commun. 2007 May 11;356(3):648-54. Epub 2007 Mar 12. PMID:17376403 doi:http://dx.doi.org/10.1016/j.bbrc.2007.03.019
- ↑ Monami G, Emiliozzi V, Morrione A. Grb10/Nedd4-mediated multiubiquitination of the insulin-like growth factor receptor regulates receptor internalization. J Cell Physiol. 2008 Aug;216(2):426-37. doi: 10.1002/jcp.21405. PMID:18286479 doi:http://dx.doi.org/10.1002/jcp.21405
- ↑ Feng SM, Muraoka-Cook RS, Hunter D, Sandahl MA, Caskey LS, Miyazawa K, Atfi A, Earp HS 3rd. The E3 ubiquitin ligase WWP1 selectively targets HER4 and its proteolytically derived signaling isoforms for degradation. Mol Cell Biol. 2009 Feb;29(3):892-906. doi: 10.1128/MCB.00595-08. Epub 2008 Dec, 1. PMID:19047365 doi:http://dx.doi.org/10.1128/MCB.00595-08
- ↑ Zeng F, Xu J, Harris RC. Nedd4 mediates ErbB4 JM-a/CYT-1 ICD ubiquitination and degradation in MDCK II cells. FASEB J. 2009 Jun;23(6):1935-45. doi: 10.1096/fj.08-121947. Epub 2009 Feb 4. PMID:19193720 doi:http://dx.doi.org/10.1096/fj.08-121947
- ↑ Huang Q, Szebenyi DM. Structural basis for the interaction between the growth factor-binding protein GRB10 and the E3 ubiquitin ligase NEDD4. J Biol Chem. 2010 Dec 31;285(53):42130-9. Epub 2010 Oct 26. PMID:20980250 doi:10.1074/jbc.M110.143412
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