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ITGA6 (integrin, alpha 6)

Identity

Other namesCD49f
ITGA6B
VLA-6
HGNC (Hugo) ITGA6
LocusID (NCBI) 3655
Location 2q31.1
Location_base_pair Starts at 173292314 and ends at 173371181 bp from pter ( according to hg19-Feb_2009)  [Mapping]
 
  Figure 1. Schematic diagram of ITGA6 location on chromosome 2. Chromosome 2 is represented with banding pattern. ITGA6 is located at 31.1 and ranges from 173292314 to 173371181 on reverse strand. The region surrounding ITGA6 is enlarged. Genes are represented by arrows in the direction of transcription.

DNA/RNA

Description ITGA6 (Gene ID: 3655) is located on chromosome 2 at 2q31.1. Gene ranges from 173292314 to 173371181 on the plus strand with a total length of 78870 bp.
Transcription The ITGA6 gene has 2 transcript variants encoding two different isoforms. Transcript variant 1 (NCBI Accession NM_001079818) encodes the longer isoform a (NP_001073286) comprised of 25 exons. Transcript variant 2 (NCBI Accession NM_000210.2) encodes the shorter isoform b (NP_000201) comprised of 26 exons which has a distinct C-terminus with an alterative coding exon compared to isoform a.
Pseudogene There are no known pseudogenes.

Protein

Note The integrin alpha6 gene encodes for a protein of 10733 amino acid residues (NP_000201), with a molecular mass of 119,467 kDa (P23229 ; UniProKB). It contains a signal peptide, extracellular domain, transmembrane domain and a cytoplasmic domain.
 
Description The integrin alpha 6subunit consists of a heavy and a light chain linked by a disulfide bond. It forms heterodimers with beta-1 or beta-4 integrin subunits to make α6β1 integrin or α6β4 integrin.
Expression α6β4 integrin is widely expressed in epithelia and in a few other cell types such as thymocytes, fibloblasts, and Schwann cells. α6β1 integrin is expressed in platelets, leukocytes and many epithelial cells.
Localisation Cell surface and hemidesmosome (Sonnenberg et al., 1991; Alt et al.,2001; Geuijen and Sonnenberg, 2002).
Function Both α6β1 integrin and α6β4 integrin are receptors for the laminin family of extracellular matrix proteins. α6β4 integrin in epithelial cells plays an essential role in strengthening and stabilizing the skin tissue through the formation of hemidesmosome (Dowling et al., 1996; Nievers et al., 1999; Sterk et al., 2000). α6β1 integrin contributes to the formation of organs and tissues before birth (Georges-Labouesse et al., 1996; Niculescu et al., 2011). In malignant carcinoma cells, both of these integrins serve as signaling receptors that triggers signaling cascades that enhance survival, invasion and metastasis (reviewed in Mercurio et al., 2001).
Homology Mouse, rat and human homologs of ITGA6 share greater than 90% amino acid identity.

Mutations

Note A homozyous 1-bp deletion mutation (791delC) have been identified in an infant with epidermolysis bullosa with pyloric atresia and esophageal stenosis (Ruzzi et al., 1997).

Implicated in

Entity Glioblastoma multiforme
Note Lathia et al identified integrin α6 as a hallmark of glioblastoma stem cells (GSCs) (Lathia et al., 2010). In this study, authors find that integrin α6 is co-expressed with conventional GSC markers such as CD15 and CD133, and localized to the perivascular compartment. However, integrin α6 expression enriches for GSCs lacking CD133 expression. Combining expression of both CD133 and integrin α6 led to higher enrichment of GSCs than CD133 alone did. shRNA mediated knockdown of integrin α6 expression results in a reduction of GSC phenotype such as GSC self renewal and tumor formation. The results suggest that integrin α6 is a promising target for antiglioblastoma therapy.
Disease Glioblastoma Multiforme (GBM) is the most common and malignant primary brain tumor with poor prognosis (Singh et al., 2004). Upon diagonosis, 5 year survival rate is less the 3%. GBM is almost incurable because it is cellular heterogeneous and GBM mass invade functional brain area, which makes impossible for the surgeons to totally remove the cancer tissues. Also, it is resistant to the radiation and other treatments (Stupp et al., 2005). Recently, Integrin α6 garnered a lot of attention as potential candidate for effective glioblastoma therapeutic target due to its high expression in neural stem cells and ability to interact with laminin (Lathia et al., 2010).
  
Entity Breast cancer
Note Both α6β1 integrin and α6β4 integrin contribute to survival of breast carcinoma cells under stress conditions (Chung et al., 2002; Chung et al., 2004a) through upregulation of VEGF expression, either at the level of transcription or translation. The α6β4 integrin dependent translation of VEGF derives from the ability of this integrin to stimulate AKT/mTOR pathway (Chung et al., 2002). Under hypoxic condition, the α6β1 integrin is required for transcriptional activation of VEGF via HIF-1 (Chung et al., 2004b). α6β4 integrin is implicated in invasion and metastasis of breast carcinoma cells via activation of PI3K/AKT pathway when it is mobilized from hemidesmosome into leading edges (Lipscomb et al., 2005).
Disease It is the most common cancer among women and the second leading cause of cancer deaths of women in US. Breast cancer is 100 times more common in women than in men. Despite of its mortality, it is mostly curable disease when it is detected at early stages. Microarray gene expression analysis defines four distinct sub-types of breast cancer, including hormone receptor (HR) positive luminal A and B, human epidermal growth receptor 2 (HER2/neu)-enriched and basal-like breast cancer (BLBC) (Perou et al., 2000). BLBC represent 17% to 37% of all breast cancers and is one of the most aggressive breast cancer sub-types with poor prognosis (Irvin and Carey, 2008). Expression of α6β4 integrin significantly correlates with BLBC (Lu et al., 2008)
Prognosis High expression of integrin α6 in women with breast cancer significantly correlated with reduced survival times (Friedrich et al., 1995; Chung et al., 2004a). Co-expression of α6β4 integrin and laminin in breast tumors has been correlated with poor prognosis (Tagliabue et al., 1998). Co-expression of both α6β4 integrin and Net1 (RhoA-specific guanine nucleotide exchange factor) is correlated with a high risk of distant metastasis in patients with hormone receptor-positive tumors (Gilcrease et al., 2009).
  
Entity Epidermolysis bullosa letalis with pyloric atresia (EB-PA)
Note EB-PA is a rare autosomal recessive genetic disease with a poor progonosis. It represents frequently lethal, epidermolysis bullosa with variable involvement of skin, nails, mucosa. EB-PA is caused by defects in ITGA6. The mutations in the genes encoding two subunit polypeptides of the α6β4 integrin (ITGA 6 and ITGA4) have been reported in the patients with EB-PA (Chung and Uitto, 2010).
Disease Mucocutaneous fragility, aplasia cutis congenita, and gastrointestinal atresia are common symptoms that affects the pylorus.
  
Entity Prostate cancer
Note Integrin α6β1 contributes to migration and invasion of protsate cancer cells through cell surface cleavage of integrin α6 in uPA induced manner (Rabinovitz et al., 1995; Demetriou et al., 2004; Pawar., 2007; Ports et al., 2009).
Disease It is the form of cancer that develops in a gland in the male reproductive system. While a majority of prostate cancer grow slowly, some cases of aggressive prostate cancer involve metastasis to the bones and lymph nodes. Prostate cancer usually occurs in older men. No early symptoms are reported in many cases of prostate cancer, but some patients may experience urinary symptoms and discomfort. Treatment options include surgery, chemotherapy, crytherapy, hormonal therapy, and/or radiation.
  

External links

Nomenclature
HGNC (Hugo)ITGA6   6142
Cards
AtlasITGA6ID41007ch2q31
Entrez_Gene (NCBI)ITGA6  3655  integrin, alpha 6
GeneCards (Weizmann)ITGA6
Ensembl (Hinxton)ENSG00000091409 [Gene_View]  chr2:173292314-173371181 [Contig_View]  ITGA6 [Vega]
AceView (NCBI)ITGA6
Genatlas (Paris)ITGA6
WikiGenes3655
SOURCE (Princeton)NM_000210 NM_001079818
Genomic and cartography
GoldenPath (UCSC)ITGA6  -  2q31.1   chr2:173292314-173371181 +  2q31.1   [Description]    (hg19-Feb_2009)
EnsemblITGA6 - 2q31.1 [CytoView]
Mapping of homologs : NCBIITGA6 [Mapview]
OMIM147556   226730   
Gene and transcription
Genbank (Entrez)AB208842 AK294436 AK296496 AK307777 AK311695
RefSeq transcript (Entrez)NM_000210 NM_001079818
RefSeq genomic (Entrez)AC_000134 NC_000002 NC_018913 NG_008853 NT_005403 NW_001838862 NW_004929305
Consensus coding sequences : CCDS (NCBI)ITGA6
Cluster EST : UnigeneHs.133397 [ NCBI ]
CGAP (NCI)Hs.133397
Alternative Splicing : Fast-db (Paris)GSHG0016992
Alternative Splicing GalleryENSG00000091409
Gene ExpressionITGA6 [ NCBI-GEO ]     ITGA6 [ SEEK ]   ITGA6 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP23229 (Uniprot)
NextProtP23229  [Medical]
With graphics : InterProP23229
Splice isoforms : SwissVarP23229 (Swissvar)
Domaine pattern : Prosite (Expaxy)FG_GAP (PS51470)    INTEGRIN_ALPHA (PS00242)   
Domains : Interpro (EBI)Int_alpha_beta-p    Integrin_alpha    Integrin_alpha-2    Integrin_alpha_C_CS   
Related proteins : CluSTrP23229
Domain families : Pfam (Sanger)Integrin_alpha2 (PF08441)   
Domain families : Pfam (NCBI)pfam08441   
Domain families : Smart (EMBL)Int_alpha (SM00191)  
DMDM Disease mutations3655
Blocks (Seattle)P23229
Human Protein AtlasENSG00000091409
Peptide AtlasP23229
HPRD00945
IPIIPI00010697   IPI00216221   IPI00216222   IPI00216224   IPI00216225   IPI00921080   IPI00921401   IPI00917593   IPI00915974   IPI00216223   
Protein Interaction databases
DIP (DOE-UCLA)P23229
IntAct (EBI)P23229
FunCoupENSG00000091409
BioGRIDITGA6
InParanoidP23229
Interologous Interaction database P23229
IntegromeDBITGA6
STRING (EMBL)ITGA6
Ontologies - Pathways
Ontology : AmiGOintegrin binding  protein binding  basement membrane  plasma membrane  plasma membrane  cell-substrate junction assembly  cell-matrix adhesion  integrin-mediated signaling pathway  blood coagulation  integrin complex  external side of plasma membrane  basal plasma membrane  positive regulation of cell-cell adhesion  hemidesmosome  extracellular matrix organization  hemidesmosome assembly  cellular response to extracellular stimulus  cell adhesion mediated by integrin  cell junction assembly  positive regulation of phosphorylation  odontogenesis of dentin-containing tooth  positive regulation of apoptotic process  positive regulation of transcription from RNA polymerase II promoter  filopodium assembly  metal ion binding  brown fat cell differentiation  leukocyte migration  negative regulation of extrinsic apoptotic signaling pathway  
Ontology : EGO-EBIintegrin binding  protein binding  basement membrane  plasma membrane  plasma membrane  cell-substrate junction assembly  cell-matrix adhesion  integrin-mediated signaling pathway  blood coagulation  integrin complex  external side of plasma membrane  basal plasma membrane  positive regulation of cell-cell adhesion  hemidesmosome  extracellular matrix organization  hemidesmosome assembly  cellular response to extracellular stimulus  cell adhesion mediated by integrin  cell junction assembly  positive regulation of phosphorylation  odontogenesis of dentin-containing tooth  positive regulation of apoptotic process  positive regulation of transcription from RNA polymerase II promoter  filopodium assembly  metal ion binding  brown fat cell differentiation  leukocyte migration  negative regulation of extrinsic apoptotic signaling pathway  
Pathways : KEGGPI3K-Akt signaling pathway    Focal adhesion    ECM-receptor interaction    Cell adhesion molecules (CAMs)    Hematopoietic cell lineage    Regulation of actin cytoskeleton    Toxoplasmosis    Pathways in cancer    Small cell lung cancer    Hypertrophic cardiomyopathy (HCM)    Arrhythmogenic right ventricular cardiomyopathy (ARVC)    Dilated cardiomyopathy   
REACTOMEITGA6
Protein Interaction DatabaseITGA6
Wikipedia pathwaysITGA6
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)ITGA6
SNP (GeneSNP Utah)ITGA6
SNP : HGBaseITGA6
Genetic variants : HAPMAPITGA6
1000_GenomesITGA6 
ICGC programENSG00000091409 
Somatic Mutations in Cancer : COSMICITGA6 
CONAN: Copy Number AnalysisITGA6 
Mutations and Diseases : HGMDITGA6
OMIM147556    226730   
GENETestsITGA6
Disease Genetic AssociationITGA6
Huge Navigator ITGA6 [HugePedia]  ITGA6 [HugeCancerGEM]
Genomic VariantsITGA6  ITGA6 [DGVbeta]
Exome VariantITGA6
dbVarITGA6
ClinVarITGA6
snp3D : Map Gene to Disease3655
General knowledge
Homologs : HomoloGeneITGA6
Homology/Alignments : Family Browser (UCSC)ITGA6
Phylogenetic Trees/Animal Genes : TreeFamITGA6
Chemical/Protein Interactions : CTD3655
Chemical/Pharm GKB GenePA29942
Clinical trialITGA6
Cancer Resource (Charite)ENSG00000091409
Other databases
Probes
Litterature
PubMed179 Pubmed reference(s) in Entrez
CoreMineITGA6
iHOPITGA6

Bibliography

Integrin alpha 6/beta 4 complex is located in hemidesmosomes, suggesting a major role in epidermal cell-basement membrane adhesion.
Sonnenberg A, Calafat J, Janssen H, Daams H, van der Raaij-Helmer LM, Falcioni R, Kennel SJ, Aplin JD, Baker J, Loizidou M, et al.
J Cell Biol. 1991 May;113(4):907-17.
PMID 2026654
 
High expression level of alpha 6 integrin in human breast carcinoma is correlated with reduced survival.
Friedrichs K, Ruiz P, Franke F, Gille I, Terpe HJ, Imhof BA.
Cancer Res. 1995 Feb 15;55(4):901-6.
PMID 7850807
 
Integrin alpha 6 expression in human prostate carcinoma cells is associated with a migratory and invasive phenotype in vitro and in vivo.
Rabinovitz I, Nagle RB, Cress AE.
Clin Exp Metastasis. 1995 Nov;13(6):481-91.
PMID 7586806
 
Beta4 integrin is required for hemidesmosome formation, cell adhesion and cell survival.
Dowling J, Yu QC, Fuchs E.
J Cell Biol. 1996 Jul;134(2):559-72.
PMID 8707838
 
Absence of integrin alpha 6 leads to epidermolysis bullosa and neonatal death in mice.
Georges-Labouesse E, Messaddeq N, Yehia G, Cadalbert L, Dierich A, Le Meur M.
Nat Genet. 1996 Jul;13(3):370-3.
PMID 8673141
 
A homozygous mutation in the integrin alpha6 gene in junctional epidermolysis bullosa with pyloric atresia.
Ruzzi L, Gagnoux-Palacios L, Pinola M, Belli S, Meneguzzi G, D'Alessio M, Zambruno G.
J Clin Invest. 1997 Jun 15;99(12):2826-31.
PMID 9185503
 
Prognostic value of alpha 6 beta 4 integrin expression in breast carcinomas is affected by laminin production from tumor cells.
Tagliabue E, Ghirelli C, Squicciarini P, Aiello P, Colnaghi MI, Menard S.
Clin Cancer Res. 1998 Feb;4(2):407-10.
PMID 9516929
 
Biology and function of hemidesmosomes.
Nievers MG, Schaapveld RQ, Sonnenberg A.
Matrix Biol. 1999 Feb;18(1):5-17. (REVIEW)
PMID 10367727
 
Molecular portraits of human breast tumours.
Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA, Fluge O, Pergamenschikov A, Williams C, Zhu SX, Lonning PE, Borresen-Dale AL, Brown PO, Botstein D.
Nature. 2000 Aug 17;406(6797):747-52.
PMID 10963602
 
The tetraspan molecule CD151, a novel constituent of hemidesmosomes, associates with the integrin alpha6beta4 and may regulate the spatial organization of hemidesmosomes.
Sterk LM, Geuijen CA, Oomen LC, Calafat J, Janssen H, Sonnenberg A.
J Cell Biol. 2000 May 15;149(4):969-82.
PMID 10811835
 
Protein kinase Cdelta-mediated phosphorylation of alpha6beta4 is associated with reduced integrin localization to the hemidesmosome and decreased keratinocyte attachment.
Alt A, Ohba M, Li L, Gartsbein M, Belanger A, Denning MF, Kuroki T, Yuspa SH, Tennenbaum T.
Cancer Res. 2001 Jun 1;61(11):4591-8.
PMID 11389095
 
EGF-R signaling through Fyn kinase disrupts the function of integrin alpha6beta4 at hemidesmosomes: role in epithelial cell migration and carcinoma invasion.
Mariotti A, Kedeshian PA, Dans M, Curatola AM, Gagnoux-Palacios L, Giancotti FG.
J Cell Biol. 2001 Oct 29;155(3):447-58. Epub 2001 Oct 29.
PMID 11684709
 
The alpha 6 beta 4 integrin and epithelial cell migration.
Mercurio AM, Rabinovitz I, Shaw LM.
Curr Opin Cell Biol. 2001 Oct;13(5):541-5. (REVIEW)
PMID 11544021
 
Integrin (alpha 6 beta 4) regulation of eIF-4E activity and VEGF translation: a survival mechanism for carcinoma cells.
Chung J, Bachelder RE, Lipscomb EA, Shaw LM, Mercurio AM.
J Cell Biol. 2002 Jul 8;158(1):165-74. Epub 2002 Jul 8.
PMID 12105188
 
Dynamics of the alpha6beta4 integrin in keratinocytes.
Geuijen CA, Sonnenberg A.
Mol Biol Cell. 2002 Nov;13(11):3845-58.
PMID 12429829
 
Contributions of the alpha6 integrins to breast carcinoma survival and progression.
Chung J, Mercurio AM.
Mol Cells. 2004a Apr 30;17(2):203-9. (REVIEW)
PMID 15179031
 
Hypoxia-induced vascular endothelial growth factor transcription and protection from apoptosis are dependent on alpha6beta1 integrin in breast carcinoma cells.
Chung J, Yoon S, Datta K, Bachelder RE, Mercurio AM.
Cancer Res. 2004b Jul 15;64(14):4711-6.
PMID 15256436
 
Extracellular alpha 6 integrin cleavage by urokinase-type plasminogen activator in human prostate cancer.
Demetriou MC, Pennington ME, Nagle RB, Cress AE.
Exp Cell Res. 2004 Apr 1;294(2):550-8.
PMID 15023541
 
Identification of human brain tumour initiating cells.
Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkelman RM, Cusimano MD, Dirks PB.
Nature. 2004 Nov 18;432(7015):396-401.
PMID 15549107
 
Mobilization and activation of a signaling competent alpha6beta4integrin underlies its contribution to carcinoma progression.
Lipscomb EA, Mercurio AM.
Cancer Metastasis Rev. 2005 Sep;24(3):413-23. (REVIEW)
PMID 16258729
 
Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma.
Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO; European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group.
N Engl J Med. 2005 Mar 10;352(10):987-96.
PMID 15758009
 
Integrin alpha6 cleavage: a novel modification to modulate cell migration.
Pawar SC, Demetriou MC, Nagle RB, Bowden GT, Cress AE.
Exp Cell Res. 2007 Apr 1;313(6):1080-9. Epub 2007 Jan 17.
PMID 17303120
 
What is triple-negative breast cancer?
Irvin WJ Jr, Carey LA.
Eur J Cancer. 2008 Dec;44(18):2799-805. doi: 10.1016/j.ejca.2008.09.034. Epub 2008 Nov 12. (REVIEW)
PMID 19008097
 
Analysis of integrin beta4 expression in human breast cancer: association with basal-like tumors and prognostic significance.
Lu S, Simin K, Khan A, Mercurio AM.
Clin Cancer Res. 2008 Feb 15;14(4):1050-8. doi: 10.1158/1078-0432.CCR-07-4116.
PMID 18281537
 
Coexpression of alpha6beta4 integrin and guanine nucleotide exchange factor Net1 identifies node-positive breast cancer patients at high risk for distant metastasis.
Gilcrease MZ, Kilpatrick SK, Woodward WA, Zhou X, Nicolas MM, Corley LJ, Fuller GN, Tucker SL, Diaz LK, Buchholz TA, Frost JA.
Cancer Epidemiol Biomarkers Prev. 2009 Jan;18(1):80-6. doi: 10.1158/1055-9965.EPI-08-0842.
PMID 19124484
 
Extracellular engagement of alpha6 integrin inhibited urokinase-type plasminogen activator-mediated cleavage and delayed human prostate bone metastasis.
Ports MO, Nagle RB, Pond GD, Cress AE.
Cancer Res. 2009 Jun 15;69(12):5007-14. doi: 10.1158/0008-5472.CAN-09-0354. Epub 2009 Jun 2.
PMID 19491258
 
Epidermolysis bullosa with pyloric atresia.
Chung HJ, Uitto J.
Dermatol Clin. 2010 Jan;28(1):43-54. doi: 10.1016/j.det.2009.10.005. (REVIEW)
PMID 19945615
 
Integrin alpha 6 regulates glioblastoma stem cells.
Lathia JD, Gallagher J, Heddleston JM, Wang J, Eyler CE, Macswords J, Wu Q, Vasanji A, McLendon RE, Hjelmeland AB, Rich JN.
Cell Stem Cell. 2010 May 7;6(5):421-32. doi: 10.1016/j.stem.2010.02.018.
PMID 20452317
 
Conditional ablation of integrin alpha-6 in mouse epidermis leads to skin fragility and inflammation.
Niculescu C, Ganguli-Indra G, Pfister V, Dupe V, Messaddeq N, De Arcangelis A, Georges-Labouesse E.
Eur J Cell Biol. 2011 Feb-Mar;90(2-3):270-7. doi: 10.1016/j.ejcb.2010.09.003. Epub 2010 Oct 20.
PMID 20965608
 
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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Contributor(s)

Written04-2013Young Hwa Soung, Jun Chung
Louisiana State University Health Sciences Center - Shreveport, Dept of Biochemistry and Molecular Biology, 1501 Kings Highway PO Box 33932, Shreveport, LA 71130-3932, USA

Citation

This paper should be referenced as such :
Soung YH, Chung J . ITGA6 (integrin, alpha 6). Atlas Genet Cytogenet Oncol Haematol. April 2013 .
URL : http://AtlasGeneticsOncology.org/Genes/ITGA6ID41007ch2q31.html

The various updated versions of this paper are referenced and archived by INIST as such :
http://documents.irevues.inist.fr/bitstream/handle/2042/51810/04-2013-ITGA6ID41007ch2q31.pdf   [ Bibliographic record ]

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indexed on : Mon Mar 31 09:06:54 CEST 2014

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