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| | MIG-6 genomic and protein structures. Exons: E1 to E4; coding regions: blue boxes; non-coding regions: orange boxes; CRIB: Cdc42/Rac-interaction and binding domain; AH region: ACK1 homology region; EBR: EGFR-binding region; 14-3-3 BD: 14-3-3 binding motif; SH3 BD: Src homology-3 domain binding motifs; two PEST sequences are indicated in red boxes. |
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| Description | MIG-6 is a 58-kDa non-kinase scaffolding adaptor protein consisting of 462 amino-acids. Several conserved protein-protein interaction motifs/domains are present in this protein: a CRIB domain is in the N-terminus, and has been shown to interact with CDC42 and IκBα ; multiple proline-rich motifs are present in the middle of the molecule, and can bind to SH3 domain containing proteins like GRB2; and a 14-3-3 protein binding motif and two PEST sequences are also present. A large portion of its C-terminus (AH domain) shares a high homology with ACK1 kinase, and an EGFR-binding domain is mapped within this region. |
| Expression | MIG-6 is highly expressed in the liver and kidney. Moderate to low expression is observed in the brain, lung, placenta, heart, thymus, and some other tissues. |
| Localisation | It is mainly localized in the cytoplasm. |
| Function | MIG-6 is a negative feedback regulator of EGFR and Met receptor tyrosine kinase signaling. MIG-6 inhibits EGFR-mediated cell transformation and cell cycle progression in NIH3T3 cells. It can physically interact with EGFR, causing inhibition of EGFR phosphorylation and downstream activation. This inhibition is likely due to a blockage of EGFR dimer formation by MIG-6, as a crystal structure reveals binding of MIG-6 to the EGFR kinase domain interface. MIG-6 inhibits Met-mediated cell migration, likely through blocking HGF/SF-induced CDC42 activation (although it does not physically interact with Met). Expression of MIG-6 has also been shown to activate NFκB by sequestering IκBα. The involvement of other MIG-6-interacting molecules in regulating the signaling output remains to be determined.
MIG-6 may function as a tumor suppressor gene, and is likely to play an important role in skin morphogenesis, tissue homeostasis and stress response. Disruption of Mig-6 results in hyperproliferation of the cells in the tissues like joint, gallbladder and skin. Mice with Mig-6 deficiency are prone to the formation of lung, gallbladder, bile duct, and skin cancers, and they develop early onset degenerative joint disease in heavily used joints. Reduced expression of MIG-6 has been observed in several human cancers including breast, ovarian, and skin cancers. While rare, mutations in MIG-6 have also been identified in human lung cancer. |
| Loss of RALT/MIG-6 expression in ERBB2-amplified breast carcinomas enhances ErbB-2 oncogenic potency and favors resistance to Herceptin. |
| Anastasi S, Sala G, Huiping C, Caprini E, Russo G, Iacovelli S, Lucini F, Ingvarsson S, Segatto O. |
| Oncogene 2005; 24:4540-8. |
| PMID 15856022 |
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| Targeted expression of RALT in mouse skin inhibits epidermal growth factor receptor signalling and generates a Waved-like phenotype. |
| Ballaro C, Ceccarelli S, Tiveron C, Tatangelo L, Salvatore AM, Segatto O, Alema S. |
| EMBO Rep 2005; 6:755-61. |
| PMID 16007071 |
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| Mig6 is a negative regulator of EGF receptor-mediated skin morphogenesis and tumor formation. |
| Ferby I, Reschke M, Kudlacek O, Knyazev P, Pante G, Amann K, Sommergruber W, Kraut N, Ullrich A, Fassler R, Klein R. |
| Nat Med 2006; 12:568-73. |
| PMID 16648858 |
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| Inhibition of ErbB-2 mitogenic and transforming activity by RALT, a mitogen-induced signal transducer which binds to the ErbB-2 kinase domain. |
| Fiorentino L, Pertica C, Fiorini M, Talora C, Crescenzi M, Castellani L, Alema S, Benedetti P, Segatto O. |
| Mol Cell Biol 2000; 20:7735-50. |
| PMID 11003669 |
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| Mig-6 is a negative regulator of the epidermal growth factor receptor signal. |
| Hackel PO, Gishizky M, Ullrich A. |
| Biol Chem 2001; 382:1649-62. |
| PMID 11843178 |
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| Gene 33/Mig-6, a transcriptionally inducible adapter protein that binds GTP-Cdc42 and activates SAPK/JNK. A potential marker transcript for chronic pathologic conditions, such as diabetic nephropathy. Possible role in the response to persistent stress. |
| Makkinje A, Quinn DA, Chen A, Cadilla CL, Force T, Bonventre JV, Kyriakis JM. |
| J Biol Chem 2000; 275:17838-47. |
| PMID 10749885 |
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| Mitogen-inducible gene 6 is an endogenous inhibitor of HGF/Met-induced cell migration and neurite growth. |
| Pante G, Thompson J, Lamballe F, Iwata T, Ferby I, Barr FA, Davies AM, Maina F, Klein R. |
| J Cell Biol 2005; 171:337-48. |
| PMID 16247031 |
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| Genomewide loss of heterozygosity and its clinical associations in non small cell lung cancer. |
| Tseng RC, Chang JW, Hsien FJ, Chang YH, Hsiao CF, Chen JT, Chen CY, Jou YS, Wang YC. |
| Int J Cancer 2005; 117:241-7. |
| PMID 15900585 |
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| A novel mechanism of nuclear factor κB activation through the binding between inhibitor of nuclear factor-κBα and the processed NH2-terminal region of Mig-6. |
| Tsunoda T, Inokuchi J, Baba I, Okumura K, Naito S, Sasazuki , Shirasawa S. |
| Cancer Res 2002; 62:5668-71. |
| PMID 12384522 |
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| Identification of a novel mitogen-inducible gene (mig-6): regulation during G1 progression and differentiation. |
| Wick M, Burger C, Funk M, Muller R. |
| Exp Cell Res 1995; 219:527-35. |
| PMID 7641805 |
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| Gene 33 is an endogenous inhibitor of epidermal growth factor (EGF) receptor signaling and mediates dexamethasone-induced suppression of EGF function. |
| Xu D, Makkinje A, Kyriakis JM. |
| J Biol Chem 2005; 280:2924-33. |
| PMID 15556944 |
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| Inhibition of the EGF receptor by binding of MIG6 to an activating kinase domain interface. |
| Zhang X, Pickin KA, Bose R, Jura N, Cole PA, Kuriyan J. |
| Nature 2007; 450:741-4. |
| PMID 18046415 |
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| Evidence that MIG-6 is a tumor-suppressor gene. |
| Zhang YW, Staal B, Su Y, Swiatek P, Zhao P, Cao B, Resau J, Sigler R, Bronson R, Vande Woude GF. |
| Oncogene 2007; 26:269-76. |
| PMID 16819504 |
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| Targeted disruption of Mig-6 in the mouse genome leads to early onset degenerative joint disease. |
| Zhang YW, Su Y, Lanning N, Swiatek PJ, Bronson RT, Sigler R, Martin RW, Vande Woude GF. |
| Proc Natl Acad Sci USA 2005; 102:11740-5. |
| PMID 16087873 |
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| Mig-6, signal transduction, stress response and cancer. |
| Zhang YW, Vande Woude GF. |
| Cell Cycle 2007; 6:507-13. (REVIEW) |
| PMID 17351343 |
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