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ERRFI1 (ERBB receptor feedback inhibitor 1)

Written2008-04Yu-Wen Zhang
Van Andel Research Institute, 333 Bostwick Ave. NE, Grand Rapids, MI 49503, USA

(Note : for Links provided by Atlas : click)

Identity

Alias (NCBI)GENE-33
MIG-6
MIG6
RALT
HGNC (Hugo) ERRFI1
HGNC Alias symbMIG-6
GENE-33
RALT
LocusID (NCBI) 54206
Atlas_Id 44147
Location 1p36.23  [Link to chromosome band 1p36]
Location_base_pair Starts at 8011727 and ends at 8026309 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping ERRFI1.png]
Local_order Centromere - ERRFI1 - PAK7 - TNFRSF9 - UTS2 - PER3 - Telomere
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
CAMTA1 (1p36.31)::ERRFI1 (1p36.23)ERRFI1 (1p36.23)::ERRFI1 (1p36.23)ERRFI1 (1p36.23)::LUZP1 (1p36.12)
ERRFI1 (1p36.23)::MFN2 (1p36.22)SERPINB1 (6p25.2)::ERRFI1 (1p36.23)TMCO4 (1p36.13)::ERRFI1 (1p36.23)

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

Note
  
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.
  

Bibliography

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
 
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
 
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
 
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
 
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
 
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
 
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
 
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
 
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
 
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
 
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
 
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
 
Mig-6, signal transduction, stress response and cancer.
Zhang YW, Vande Woude GF.
Cell Cycle 2007; 6:507-13. (REVIEW)
PMID 17351343
 

Citation

This paper should be referenced as such :
Zhang, YW
ERRFI1 (ERBB receptor feedback inhibitor 1)
Atlas Genet Cytogenet Oncol Haematol. 2009;13(3):198-200.
Free journal version : [ pdf ]   [ DOI ]


External links

 

Nomenclature
HGNC (Hugo)ERRFI1   18185
Cards
AtlasERRFI1ID44147ch1p36
Entrez_Gene (NCBI)ERRFI1    ERBB receptor feedback inhibitor 1
AliasesGENE-33; MIG-6; MIG6; RALT
GeneCards (Weizmann)ERRFI1
Ensembl hg19 (Hinxton)ENSG00000116285 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000116285 [Gene_View]  ENSG00000116285 [Sequence]  chr1:8011727-8026309 [Contig_View]  ERRFI1 [Vega]
ICGC DataPortalENSG00000116285
TCGA cBioPortalERRFI1
AceView (NCBI)ERRFI1
Genatlas (Paris)ERRFI1
SOURCE (Princeton)ERRFI1
Genetics Home Reference (NIH)ERRFI1
Genomic and cartography
GoldenPath hg38 (UCSC)ERRFI1  -     chr1:8011727-8026309 -  1p36.23   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)ERRFI1  -     1p36.23   [Description]    (hg19-Feb_2009)
GoldenPathERRFI1 - 1p36.23 [CytoView hg19]  ERRFI1 - 1p36.23 [CytoView hg38]
ImmunoBaseENSG00000116285
Genome Data Viewer NCBIERRFI1 [Mapview hg19]  
OMIM608069   
Gene and transcription
Genbank (Entrez)AJ276373 AK027830 AK096149 AK315718 AL137274
RefSeq transcript (Entrez)NM_018948
Consensus coding sequences : CCDS (NCBI)ERRFI1
Gene ExpressionERRFI1 [ NCBI-GEO ]   ERRFI1 [ EBI - ARRAY_EXPRESS ]   ERRFI1 [ SEEK ]   ERRFI1 [ MEM ]
Gene Expression Viewer (FireBrowse)ERRFI1 [ Firebrowse - Broad ]
GenevisibleExpression of ERRFI1 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)54206
GTEX Portal (Tissue expression)ERRFI1
Human Protein AtlasENSG00000116285-ERRFI1 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ9UJM3   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ9UJM3  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ9UJM3
PhosPhoSitePlusQ9UJM3
Domains : Interpro (EBI)Cdc42-bd-like    Mig-6   
Domain families : Pfam (Sanger)GTPase_binding (PF09027)    Inhibitor_Mig-6 (PF11555)   
Domain families : Pfam (NCBI)pfam09027    pfam11555   
Conserved Domain (NCBI)ERRFI1
PDB (RSDB)2RF9    2RFD    2RFE    4I21    4R3P    4R3R    4ZJV   
PDB Europe2RF9    2RFD    2RFE    4I21    4R3P    4R3R    4ZJV   
PDB (PDBSum)2RF9    2RFD    2RFE    4I21    4R3P    4R3R    4ZJV   
PDB (IMB)2RF9    2RFD    2RFE    4I21    4R3P    4R3R    4ZJV   
Structural Biology KnowledgeBase2RF9    2RFD    2RFE    4I21    4R3P    4R3R    4ZJV   
SCOP (Structural Classification of Proteins)2RF9    2RFD    2RFE    4I21    4R3P    4R3R    4ZJV   
CATH (Classification of proteins structures)2RF9    2RFD    2RFE    4I21    4R3P    4R3R    4ZJV   
SuperfamilyQ9UJM3
AlphaFold pdb e-kbQ9UJM3   
Human Protein Atlas [tissue]ENSG00000116285-ERRFI1 [tissue]
HPRD09218
Protein Interaction databases
DIP (DOE-UCLA)Q9UJM3
IntAct (EBI)Q9UJM3
BioGRIDERRFI1
STRING (EMBL)ERRFI1
ZODIACERRFI1
Ontologies - Pathways
QuickGOQ9UJM3
Ontology : AmiGOGTPase activator activity  protein binding  nucleus  cytoplasm  cytosol  negative regulation of epidermal growth factor-activated receptor activity  negative regulation of epidermal growth factor-activated receptor activity  SH3 domain binding  protein kinase binding  extrinsic component of cytoplasmic side of plasma membrane  extrinsic component of cytoplasmic side of plasma membrane  small GTPase binding  negative regulation of protein autophosphorylation  negative regulation of interleukin-1 beta production  negative regulation of tumor necrosis factor production  cellular response to insulin stimulus  negative regulation of collagen biosynthetic process  cellular response to platelet-derived growth factor stimulus  negative regulation of epidermal growth factor receptor signaling pathway  skin morphogenesis  regulation of keratinocyte differentiation  regulation of keratinocyte differentiation  lung alveolus development  lung vasculature development  lung epithelium development  regulation of type B pancreatic cell proliferation  negative regulation of ERK1 and ERK2 cascade  cellular response to epidermal growth factor stimulus  cellular hyperosmotic response  cellular response to dexamethasone stimulus  negative regulation of cardiac muscle hypertrophy in response to stress  
Ontology : EGO-EBIGTPase activator activity  protein binding  nucleus  cytoplasm  cytosol  negative regulation of epidermal growth factor-activated receptor activity  negative regulation of epidermal growth factor-activated receptor activity  SH3 domain binding  protein kinase binding  extrinsic component of cytoplasmic side of plasma membrane  extrinsic component of cytoplasmic side of plasma membrane  small GTPase binding  negative regulation of protein autophosphorylation  negative regulation of interleukin-1 beta production  negative regulation of tumor necrosis factor production  cellular response to insulin stimulus  negative regulation of collagen biosynthetic process  cellular response to platelet-derived growth factor stimulus  negative regulation of epidermal growth factor receptor signaling pathway  skin morphogenesis  regulation of keratinocyte differentiation  regulation of keratinocyte differentiation  lung alveolus development  lung vasculature development  lung epithelium development  regulation of type B pancreatic cell proliferation  negative regulation of ERK1 and ERK2 cascade  cellular response to epidermal growth factor stimulus  cellular hyperosmotic response  cellular response to dexamethasone stimulus  negative regulation of cardiac muscle hypertrophy in response to stress  
NDEx NetworkERRFI1
Atlas of Cancer Signalling NetworkERRFI1
Wikipedia pathwaysERRFI1
Orthology - Evolution
OrthoDB54206
GeneTree (enSembl)ENSG00000116285
Phylogenetic Trees/Animal Genes : TreeFamERRFI1
Homologs : HomoloGeneERRFI1
Homology/Alignments : Family Browser (UCSC)ERRFI1
Gene fusions - Rearrangements
Fusion : MitelmanERRFI1::LUZP1 [1p36.23/1p36.12]  
Fusion : MitelmanTMCO4::ERRFI1 [1p36.13/1p36.23]  
Fusion Cancer (Beijing)ERRFI1 [1p36.23]  -  MFN2 [1p36.22]  [FUSC003752]
Fusion : QuiverERRFI1
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerERRFI1 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)ERRFI1
dbVarERRFI1
ClinVarERRFI1
MonarchERRFI1
1000_GenomesERRFI1 
Exome Variant ServerERRFI1
GNOMAD BrowserENSG00000116285
Varsome BrowserERRFI1
ACMGERRFI1 variants
VarityQ9UJM3
Genomic Variants (DGV)ERRFI1 [DGVbeta]
DECIPHERERRFI1 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisERRFI1 
Mutations
ICGC Data PortalERRFI1 
TCGA Data PortalERRFI1 
Broad Tumor PortalERRFI1
OASIS PortalERRFI1 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICERRFI1  [overview]  [genome browser]  [tissue]  [distribution]  
Somatic Mutations in Cancer : COSMIC3DERRFI1
Mutations and Diseases : HGMDERRFI1
LOVD (Leiden Open Variation Database)[gene] [transcripts] [variants]
BioMutaERRFI1
DgiDB (Drug Gene Interaction Database)ERRFI1
DoCM (Curated mutations)ERRFI1
CIViC (Clinical Interpretations of Variants in Cancer)ERRFI1
OncoKBERRFI1
NCG (London)ERRFI1
Cancer3DERRFI1
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM608069   
Orphanet
DisGeNETERRFI1
MedgenERRFI1
Genetic Testing Registry ERRFI1
NextProtQ9UJM3 [Medical]
GENETestsERRFI1
Target ValidationERRFI1
Huge Navigator ERRFI1 [HugePedia]
ClinGenERRFI1
Clinical trials, drugs, therapy
MyCancerGenomeERRFI1
Protein Interactions : CTDERRFI1
Pharm GKB GenePA142671904
PharosQ9UJM3
Clinical trialERRFI1
Miscellaneous
canSAR (ICR)ERRFI1
HarmonizomeERRFI1
DataMed IndexERRFI1
Probes
Litterature
PubMed102 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
EVEXERRFI1
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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