ERRFI1 (ERBB receptor feedback inhibitor 1)

2008-04-01   Yu-Wen Zhang 

Van Andel Research Institute, 333 Bostwick Ave. NE, Grand Rapids, MI 49503, USA





The MIG-6 gene is composed of 4 exons, and its coding region spans from exon 2 to within exon 4.


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.


Atlas Image
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.


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.


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.


It is mainly localized in the cytoplasm.


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.



A heterozygous germline mutation at MIG-6 codon 373 (Ala → Val) has been identified in a primary lung cancer patient with squamous cell carcinoma.


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 name
Various human cancers
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.


Pubmed IDLast YearTitleAuthors
158560222005Loss of RALT/MIG-6 expression in ERBB2-amplified breast carcinomas enhances ErbB-2 oncogenic potency and favors resistance to Herceptin.Anastasi S et al
160070712005Targeted expression of RALT in mouse skin inhibits epidermal growth factor receptor signalling and generates a Waved-like phenotype.Ballarò C et al
166488582006Mig6 is a negative regulator of EGF receptor-mediated skin morphogenesis and tumor formation.Ferby I et al
110036692000Inhibition of ErbB-2 mitogenic and transforming activity by RALT, a mitogen-induced signal transducer which binds to the ErbB-2 kinase domain.Fiorentino L et al
118431782001Mig-6 is a negative regulator of the epidermal growth factor receptor signal.Hackel PO et al
107498852000Gene 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 et al
162470312005Mitogen-inducible gene 6 is an endogenous inhibitor of HGF/Met-induced cell migration and neurite growth.Pante G et al
159005852005Genomewide loss of heterozygosity and its clinical associations in non small cell lung cancer.Tseng RC et al
123845222002A novel mechanism of nuclear factor kappaB activation through the binding between inhibitor of nuclear factor-kappaBalpha and the processed NH(2)-terminal region of Mig-6.Tsunoda T et al
76418051995Identification of a novel mitogen-inducible gene (mig-6): regulation during G1 progression and differentiation.Wick M et al
155569442005Gene 33 is an endogenous inhibitor of epidermal growth factor (EGF) receptor signaling and mediates dexamethasone-induced suppression of EGF function.Xu D et al
180464152007Inhibition of the EGF receptor by binding of MIG6 to an activating kinase domain interface.Zhang X et al
168195042007Evidence that MIG-6 is a tumor-suppressor gene.Zhang YW et al
160878732005Targeted disruption of Mig-6 in the mouse genome leads to early onset degenerative joint disease.Zhang YW et al
173513432007Mig-6, signal transduction, stress response and cancer.Zhang YW et al

Other Information

Locus ID:

NCBI: 54206
MIM: 608069
HGNC: 18185
Ensembl: ENSG00000116285


dbSNP: 54206
ClinVar: 54206
TCGA: ENSG00000116285


Gene IDTranscript IDUniprot

Expression (GTEx)



Pubmed IDYearTitleCitations
180464152007Inhibition of the EGF receptor by binding of MIG6 to an activating kinase domain interface.138
110036692000Inhibition of ErbB-2 mitogenic and transforming activity by RALT, a mitogen-induced signal transducer which binds to the ErbB-2 kinase domain.58
168195042007Evidence that MIG-6 is a tumor-suppressor gene.54
128331452003Feedback inhibition by RALT controls signal output by the ErbB network.49
204214272010A two-tiered mechanism of EGFR inhibition by RALT/MIG6 via kinase suppression and receptor degradation.49
155569442005Gene 33 is an endogenous inhibitor of epidermal growth factor (EGF) receptor signaling and mediates dexamethasone-induced suppression of EGF function.47
203512672010Mig-6 controls EGFR trafficking and suppresses gliomagenesis.45
248307242014The TGFβ-miR200-MIG6 pathway orchestrates the EMT-associated kinase switch that induces resistance to EGFR inhibitors.45
244250482014microRNA-148a is a prognostic oncomiR that targets MIG6 and BIM to regulate EGFR and apoptosis in glioblastoma.44
194396672009Mig-6 modulates uterine steroid hormone responsiveness and exhibits altered expression in endometrial disease.42


Yu-Wen Zhang

ERRFI1 (ERBB receptor feedback inhibitor 1)

Atlas Genet Cytogenet Oncol Haematol. 2008-04-01

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