Atlas of Genetics and Cytogenetics in Oncology and Haematology
ERRFI1 (ERBB receptor feedback inhibitor 1)
| Identity |
| Other names | GENE-33 |
| MIG-6 | |
| MIG6 | |
| RALT | |
| HGNC | ERRFI1 |
| Location | 1p36.23 |
| Local_order | Centromere - ERRFI1 - PAK7 - TNFRSF9 - UTS2 - PER3 - Telomere |
| DNA/RNA |
| Description | The MIG-6 gene is composed of 4 exons, and its coding region spans from exon 2 to within exon 4. |
| Transcription | MIG-6 transcription can be rapidly up-regulated by many stress stimuli such as mechanical forces, injury and hypoxia, and by serum as well as various growth factors including EGF and HGF/SF. It is regulated during cell cycle progression, and peaks at the mid-G1 phase. The transcription results in a 3.1-kb mRNA. |
| Protein |
 | |
| 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. | |
| 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. |
| Mutations |
| Germinal | A heterozygous germline mutation at MIG-6 codon 373 (Ala → Val) has been identified in a primary lung cancer patient with squamous cell carcinoma. |
| Somatic | Two somatic mutations have been identified in non-small cell lung cancer cell lines: a nonsense mutation at codon 83 (Glu → stop codon) in the NCI-H322 adenocarcinoma cell line; and a missense mutation at codon 109 (Asp → Asn) in the NCI-H226 squamous cell carcinoma cell line. |
| Implicated in |
| Entity | Various human cancers |
| Note | The MIG-6 gene is located at chromosome 1p36, a locus that is frequently associated with human cancers. Decreased expression of MIG-6 is reported in breast, ovarian, pancreatic, and skin cancers. Several mutations have been identified in lung cancer, and loss of heterozygosity seems to be associated with smoking, squamous cell carcinoma, and late-stage lung cancer patients. |
| External links |
| Bibliography |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| Mig-6, signal transduction, stress response and cancer. |
| Zhang YW, Vande Woude GF. |
| Cell Cycle 2007; 6:507-13. (REVIEW) |
| PMID 17351343 |
| 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 |
| REVIEW articles | automatic search in PubMed |
| Last year publications | automatic search in PubMed |
| Contributor(s) |
| Written | 04-2008 | Yu-Wen Zhang |
| Van Andel Research Institute, 333 Bostwick Ave. NE, Grand Rapids, MI 49503, USA |
| Citation |
| This paper should be referenced as such : |
| Zhang YW . ERRFI1 (ERBB receptor feedback inhibitor 1). Atlas Genet Cytogenet Oncol Haematol. April 2008 . URL : http://AtlasGeneticsOncology.org/Genes/ERRFI1ID44147ch1p36.html |
| © Atlas of Genetics and Cytogenetics in Oncology and Haematology | indexed on : Mon Aug 11 21:13:38 2008 |
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