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| 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. |
| 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 |
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| 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 |
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| 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 |
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| 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 |
| |
| 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 |
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| 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 |
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| 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 |
| |
| 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 |
| |
| 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 |
| |
| 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 |
| |
| 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 |
| |
| 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 |
| |
| 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 |
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