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ITGA1 (integrin, alpha 1)

Written2014-10Salah Boudjadi, Jean-François Beaulieu
Laboratory of Intestinal Physiopathology, Department of Anatomy, Cell Biology, Faculty of Medicine, Health Sciences, Universite de Sherbrooke, 3001 12th Avenue N, Sherbrooke, QC J1H 5N4, Canada

Abstract The α1 integrin subunit (SU) belongs to a large family of α and β subunits that are noncovalently linked to constitute αβ transmembrane units. To date, 18 α and 8 β subunits are known to form 24 αβ units (Takada et al., 2007; Barczyk et al., 2010) which are involved in cell-cell and cell-matrix attachment and can drive inside-out and outside-in cell signaling (Shattil et al., 2010). Integrins are known to participate in different cell processes including cell shape, differentiation, migration, survival and proliferation (Giancotti, 1997; Vachon, 2011; Beauséjour et al., 2012). The α1 SU was discovered in 1986 as the Very Late Antigen 1 (VLA1) and is highly expressed in activated lymphocytes in the joints of patients with rheumatoid arthritis (Hemler et al., 1986). In fibroblasts, α1 is known to activate the RAS/ERK proliferative pathway and has a pro-invasive function in certain cancers. In megakaryocyte differentiation α1 is silenced by DNA methylation but not histone modification (Cheli et al., 2007). Different transcription factors involved in cancer progression can bind to the ITGA1 promoter. Integrin α1 transcriptional regulation remains to be further defined.

(Note : for Links provided by Atlas : click)

Identity

Alias_namesintegrin
Alias_symbol (synonym)VLA1
CD49a
Other alias
HGNC (Hugo) ITGA1
LocusID (NCBI) 3672
Atlas_Id 40999
Location 5q11.2  [Link to chromosome band 5q11]
Location_base_pair Starts at 52788302 and ends at 52953655 bp from pter ( according to hg19-Feb_2009)  [Mapping ITGA1.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
ITGA1 (5q11.2) / PKIB (6q22.31)

DNA/RNA

 
  Figure 1. The human ITGA1 gene is located on chromosome 5 at locus q11.2 and contains 29 exons. Only exons 1 and 2 are presented in this diagram. The first intron of ITGA1, which is 69 kb, contains the two exons of the PELO gene. The proximal promoter sequence immediately preceeding the initiation transcription site (red line) includes a CpG island (underlined in orange) and is predicted to be methylated. This region contains possible regulatory elements for different transcription factors known to be involved in various cancers (see text below).
Description The ITGA1 gene is 165354 bp in length and contains 29 exons that encode a protein of 1179 aa.
Transcription Transcriptional regulation of the α1 integrin SU: transcriptional regulation of ITGA1 was first described in smooth muscle cells of the chicken in the proximal promoter of ITGA1 containing the CArG box for the serum response factor (SRF) (Obata et al., 1997). Cheli et al. also reported that ITGA1 expression is predominantly regulated by DNA methylation and not histone modification in human HEK293 cells (Cheli et al., 2007). The proximal promoter region of the ITGA1 gene contains CpG islands which are selectively and fully methylated during differentiation of mononuclear cells into the megakaryocyte lineage. This mechanism could be responsible for the silencing of ITGA1 expression in differentiated intestinal cells. Our in silico analysis of the proximal promoter of ITGA1 revealed the presence of a number of response elements for nuclear factors known to be implicated in cancer progression such as TCF/LEF and c-Myc (unpublished data). Further studies are needed to determine a functional relationship between these factors and ITGA1 expression.

Protein

Note Protein access number: P56199. NCBI reference sequence: NP_852478.1.
 
  Figure 2. αβ heterodimer domain composition. The two subunits have external domains, a transmembrane domain and a small cytoplasmic tail. α1 is the largest a subunit, but has the smallest cytoplasmic tail. It contains the I (inserted) domain implicated in collagen binding. α1 has no disulfide junctions (no cleavage under reduced conditions) and forms a heterodimer only with the β1 subunit. When inactive the integrin heterodimer is under a bent conformation. Once activated it becomes open and elongated which enhances ligand binding affinity (Arnaout et al., 2005; Shattil et al., 2010).
Expression Expression and localisation: the α1 integrin SU (figure 2) is highly expressed in various areas of the stroma. As reported previously, α1 is present in fibroblasts, endothelial cells and smooth muscle cells (Gardner, 2014). In the gut, α1 is expressed in myofibroblast cells surrounding the crypts of the colon and small intestinal mucosa (Boudjadi et al., 2013). α1 is present in epithelial cells of the endometrium, kidney and intestine. In the latter, α1 is present only in proliferating crypt cells while its exclusive partner β1 is constitutively expressed in all intestinal cells (Beaulieu, 1992; Boudjadi et al., 2013). In these cells, α1 is observed in the basolateral portion of the cytoplasmic membrane (figure 3).
 
  Figure 3. Immunohistochemical images showing examples of α1 integrin subunit expression in the gut. (A) Resection margin and (B) corresponding matched colorectal adenocarcinoma specimens. α1 is predominantly expressed in the proliferative cells of the crypt (A; red arrows) at the basolateral domain of normal epithelial cells, and also in the endothelial cells (A; black arrow). In adenocarcinomas, α1 is highly expressed in tumour epithelial cells (B; red arrows) and reactive stromal cells (B; black arrows). Scale bars = 50 μm.
Function α1β1 is the main cell receptor for collagen IV and with a lower affinity for collagen I, whereas α2β1 has a higher affinity for collagen I (Barczyk et al., 2010). α1β1 recognizes the GEFOGER sequence within the tertiary structure of collagen IV. It is important for cell anchorage to the extracellular matrix and is implicated in focal adhesions and cell migration. The presence of α1β1 in proliferating cells is supported by the reported role for α1, via caveolin-1 and Shc, in the downstream activation of the Ras/MEK/ERK proliferative pathway (Giancotti, 2000). In endothelial cells, using a selective mutagenesis approach, specific amino acids in the α1 cytoplasmic tail are shown to drive various functions and pathways. While Lys1147 is important only for tubulogenesis, Pro1142 and Leu1145 are required for ERK activation and cell proliferation. Lys1146 is involved in cell adhesion, migration (activation of p38 MAPK) and tubulogenesis (activation of p38 MAPK and PI3K). Interestingly, substitution of the Lys1151 positively charged amino acid at the COOH-terminus of the α1 tail results in a complete loss of the above functions. This positively charged amino acid could be required for α1 orientation relative to the β1 tail, compromising binding to signal molecules (Abair et al., 2008).

Mutations

Note No mutation known for human ITGA1 gene.

Implicated in

Note
  
Entity Lung cancer
Note In mouse models, the α1β1 integrin mediates cell invasion through the regulation of stromelysin-1 expression (Lochter et al., 1999) and, together with the Kras oncogenic factor, potentiates tumour growth and cell motility (Macias-Perez et al., 2008).
  
  
Entity Colorectal cancer
Note Integrin α1β1 is up-regulated in 65% of colon adenocarcinomas compared to matched margins. Expression is found to be higher in epithelial cells and the surrounding reactive cells (Boudjadi et al., 2013). Also, α1β1 is present in the early stages of colorectal cancer which could constitute a useful early diagnostic marker.
  
  
Entity Hepatocellular carcinoma
Note In a fibrotic microenvironment similar to that of hepatocellular carcinoma, α1β1 has been reported to be able to enhance cell invasion through the fibrotic matrix (Yang et al., 2003).
  

Bibliography

Functional analysis of the cytoplasmic domain of the integrin {alpha}1 subunit in endothelial cells.
Abair TD, Bulus N, Borza C, Sundaramoorthy M, Zent R, Pozzi A.
Blood. 2008 Oct 15;112(8):3242-54. doi: 10.1182/blood-2007-12-126433. Epub 2008 Jul 22.
PMID 18647959
 
Integrin structure, allostery, and bidirectional signaling.
Arnaout MA, Mahalingam B, Xiong JP.
Annu Rev Cell Dev Biol. 2005;21:381-410. (REVIEW)
PMID 16212500
 
Integrins.
Barczyk M, Carracedo S, Gullberg D.
Cell Tissue Res. 2010 Jan;339(1):269-80. doi: 10.1007/s00441-009-0834-6. Epub 2009 Aug 20. (REVIEW)
PMID 19693543
 
Differential expression of the VLA family of integrins along the crypt-villus axis in the human small intestine.
Beaulieu JF.
J Cell Sci. 1992 Jul;102 ( Pt 3):427-36.
PMID 1506425
 
Integrin/Fak/Src-mediated regulation of cell survival and anoikis in human intestinal epithelial crypt cells: selective engagement and roles of PI3-K isoform complexes.
Beausejour M, Noel D, Thibodeau S, Bouchard V, Harnois C, Beaulieu JF, Demers MJ, Vachon PH.
Apoptosis. 2012 Jun;17(6):566-78. doi: 10.1007/s10495-012-0713-6.
PMID 22402981
 
Integrin a1 subunit is up-regulated in colorectal cancer.
Boudjadi S, Carrier JC, Beaulieu JF.
Biomark Res. 2013 Mar 7;1(1):16. doi: 10.1186/2050-7771-1-16.
PMID 24252313
 
Transcriptional and epigenetic regulation of the integrin collagen receptor locus ITGA1-PELO-ITGA2.
Cheli Y, Kanaji S, Jacquelin B, Chang M, Nugent DJ, Kunicki TJ.
Biochim Biophys Acta. 2007 Sep-Oct;1769(9-10):546-58. Epub 2007 Jul 6.
PMID 17669516
 
Integrin a1b1.
Gardner H.
Adv Exp Med Biol. 2014;819:21-39. doi: 10.1007/978-94-017-9153-3_2. (REVIEW)
PMID 25023165
 
Complexity and specificity of integrin signalling.
Giancotti FG.
Nat Cell Biol. 2000 Jan;2(1):E13-4.
PMID 10620816
 
Very late activation antigens on rheumatoid synovial fluid T lymphocytes. Association with stages of T cell activation.
Hemler ME, Glass D, Coblyn JS, Jacobson JG.
J Clin Invest. 1986 Sep;78(3):696-702.
PMID 3018043
 
alpha1 and alpha2 integrins mediate invasive activity of mouse mammary carcinoma cells through regulation of stromelysin-1 expression.
Lochter A, Navre M, Werb Z, Bissell MJ.
Mol Biol Cell. 1999 Feb;10(2):271-82.
PMID 9950676
 
Loss of integrin alpha1beta1 ameliorates Kras-induced lung cancer.
Macias-Perez I, Borza C, Chen X, Yan X, Ibanez R, Mernaugh G, Matrisian LM, Zent R, Pozzi A.
Cancer Res. 2008 Aug 1;68(15):6127-35. doi: 10.1158/0008-5472.CAN-08-1395.
PMID 18676835
 
Smooth muscle cell phenotype-dependent transcriptional regulation of the alpha1 integrin gene.
Obata H, Hayashi K, Nishida W, Momiyama T, Uchida A, Ochi T, Sobue K.
J Biol Chem. 1997 Oct 17;272(42):26643-51.
PMID 9334246
 
The final steps of integrin activation: the end game.
Shattil SJ, Kim C, Ginsberg MH.
Nat Rev Mol Cell Biol. 2010 Apr;11(4):288-300. doi: 10.1038/nrm2871. (REVIEW)
PMID 20308986
 
The integrins.
Takada Y, Ye X, Simon S.
Genome Biol. 2007;8(5):215. (REVIEW)
PMID 17543136
 
Integrin signaling, cell survival, and anoikis: distinctions, differences, and differentiation.
Vachon PH.
J Signal Transduct. 2011;2011:738137. doi: 10.1155/2011/738137. Epub 2011 Jul 13.
PMID 21785723
 
Integrin alpha1beta1 and alpha2beta1 are the key regulators of hepatocarcinoma cell invasion across the fibrotic matrix microenvironment.
Yang C, Zeisberg M, Lively JC, Nyberg P, Afdhal N, Kalluri R.
Cancer Res. 2003 Dec 1;63(23):8312-7.
PMID 14678990
 

Citation

This paper should be referenced as such :
Salah Boudjadi, Jean-Franois Beaulieu
ITGA1 (integrin, alpha 1)
Atlas Genet Cytogenet Oncol Haematol. 2015;19(9):186-189.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/ITGA1ID40999ch5q11.html


External links

Nomenclature
HGNC (Hugo)ITGA1   6134
Cards
AtlasITGA1ID40999ch5q11
Entrez_Gene (NCBI)ITGA1  3672  integrin subunit alpha 1
AliasesCD49a; VLA1
GeneCards (Weizmann)ITGA1
Ensembl hg19 (Hinxton)ENSG00000213949 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000213949 [Gene_View]  chr5:52788302-52953655 [Contig_View]  ITGA1 [Vega]
ICGC DataPortalENSG00000213949
TCGA cBioPortalITGA1
AceView (NCBI)ITGA1
Genatlas (Paris)ITGA1
WikiGenes3672
SOURCE (Princeton)ITGA1
Genetics Home Reference (NIH)ITGA1
Genomic and cartography
GoldenPath hg38 (UCSC)ITGA1  -     chr5:52788302-52953655 +  5q11.2   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)ITGA1  -     5q11.2   [Description]    (hg19-Feb_2009)
EnsemblITGA1 - 5q11.2 [CytoView hg19]  ITGA1 - 5q11.2 [CytoView hg38]
Mapping of homologs : NCBIITGA1 [Mapview hg19]  ITGA1 [Mapview hg38]
OMIM192968   
Gene and transcription
Genbank (Entrez)AK300423 BC050277 BC137121 BC137122 BX640981
RefSeq transcript (Entrez)NM_181501
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)ITGA1
Cluster EST : UnigeneHs.644352 [ NCBI ]
CGAP (NCI)Hs.644352
Alternative Splicing GalleryENSG00000213949
Gene ExpressionITGA1 [ NCBI-GEO ]   ITGA1 [ EBI - ARRAY_EXPRESS ]   ITGA1 [ SEEK ]   ITGA1 [ MEM ]
Gene Expression Viewer (FireBrowse)ITGA1 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)3672
GTEX Portal (Tissue expression)ITGA1
Human Protein AtlasENSG00000213949-ITGA1 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP56199   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP56199  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP56199
Splice isoforms : SwissVarP56199
PhosPhoSitePlusP56199
Domaine pattern : Prosite (Expaxy)FG_GAP (PS51470)    INTEGRIN_ALPHA (PS00242)    VWFA (PS50234)   
Domains : Interpro (EBI)FG-GAP    Int_alpha_beta-p    Integrin_alpha    Integrin_alpha-2    Integrin_alpha_C_CS    Integrin_dom    VWF_A   
Domain families : Pfam (Sanger)FG-GAP (PF01839)    Integrin_alpha2 (PF08441)    VWA (PF00092)   
Domain families : Pfam (NCBI)pfam01839    pfam08441    pfam00092   
Domain families : Smart (EMBL)Int_alpha (SM00191)  VWA (SM00327)  
Conserved Domain (NCBI)ITGA1
DMDM Disease mutations3672
Blocks (Seattle)ITGA1
PDB (SRS)1PT6    1QC5    1QCY    2L8S    2M32    4A0Q   
PDB (PDBSum)1PT6    1QC5    1QCY    2L8S    2M32    4A0Q   
PDB (IMB)1PT6    1QC5    1QCY    2L8S    2M32    4A0Q   
PDB (RSDB)1PT6    1QC5    1QCY    2L8S    2M32    4A0Q   
Structural Biology KnowledgeBase1PT6    1QC5    1QCY    2L8S    2M32    4A0Q   
SCOP (Structural Classification of Proteins)1PT6    1QC5    1QCY    2L8S    2M32    4A0Q   
CATH (Classification of proteins structures)1PT6    1QC5    1QCY    2L8S    2M32    4A0Q   
SuperfamilyP56199
Human Protein Atlas [tissue]ENSG00000213949-ITGA1 [tissue]
Peptide AtlasP56199
HPRD01892
IPIIPI00743104   
Protein Interaction databases
DIP (DOE-UCLA)P56199
IntAct (EBI)P56199
FunCoupENSG00000213949
BioGRIDITGA1
STRING (EMBL)ITGA1
ZODIACITGA1
Ontologies - Pathways
QuickGOP56199
Ontology : AmiGOactivation of MAPK activity  acrosomal vesicle  receptor binding  protein binding  collagen binding  plasma membrane  focal adhesion  muscle contraction  cell-matrix adhesion  integrin-mediated signaling pathway  negative regulation of cell proliferation  integrin complex  external side of plasma membrane  cell surface  membrane  protein phosphatase binding  extracellular matrix organization  neutrophil chemotaxis  positive regulation of phosphoprotein phosphatase activity  integrin alpha1-beta1 complex  negative regulation of epidermal growth factor receptor signaling pathway  vasodilation  neuron projection  perikaryon  positive regulation of neuron apoptotic process  membrane raft  cellular extravasation  basal part of cell  metal ion binding  neuron projection morphogenesis  extracellular exosome  collagen binding involved in cell-matrix adhesion  
Ontology : EGO-EBIactivation of MAPK activity  acrosomal vesicle  receptor binding  protein binding  collagen binding  plasma membrane  focal adhesion  muscle contraction  cell-matrix adhesion  integrin-mediated signaling pathway  negative regulation of cell proliferation  integrin complex  external side of plasma membrane  cell surface  membrane  protein phosphatase binding  extracellular matrix organization  neutrophil chemotaxis  positive regulation of phosphoprotein phosphatase activity  integrin alpha1-beta1 complex  negative regulation of epidermal growth factor receptor signaling pathway  vasodilation  neuron projection  perikaryon  positive regulation of neuron apoptotic process  membrane raft  cellular extravasation  basal part of cell  metal ion binding  neuron projection morphogenesis  extracellular exosome  collagen binding involved in cell-matrix adhesion  
Pathways : KEGG   
REACTOMEP56199 [protein]
REACTOME PathwaysR-HSA-75892 [pathway]   
NDEx NetworkITGA1
Atlas of Cancer Signalling NetworkITGA1
Wikipedia pathwaysITGA1
Orthology - Evolution
OrthoDB3672
GeneTree (enSembl)ENSG00000213949
Phylogenetic Trees/Animal Genes : TreeFamITGA1
HOVERGENP56199
HOGENOMP56199
Homologs : HomoloGeneITGA1
Homology/Alignments : Family Browser (UCSC)ITGA1
Gene fusions - Rearrangements
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerITGA1 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)ITGA1
dbVarITGA1
ClinVarITGA1
1000_GenomesITGA1 
Exome Variant ServerITGA1
ExAC (Exome Aggregation Consortium)ENSG00000213949
GNOMAD BrowserENSG00000213949
Genetic variants : HAPMAP3672
Genomic Variants (DGV)ITGA1 [DGVbeta]
DECIPHERITGA1 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisITGA1 
Mutations
ICGC Data PortalITGA1 
TCGA Data PortalITGA1 
Broad Tumor PortalITGA1
OASIS PortalITGA1 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICITGA1  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDITGA1
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch ITGA1
DgiDB (Drug Gene Interaction Database)ITGA1
DoCM (Curated mutations)ITGA1 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)ITGA1 (select a term)
intoGenITGA1
NCG5 (London)ITGA1
Cancer3DITGA1(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM192968   
Orphanet
MedgenITGA1
Genetic Testing Registry ITGA1
NextProtP56199 [Medical]
TSGene3672
GENETestsITGA1
Target ValidationITGA1
Huge Navigator ITGA1 [HugePedia]
snp3D : Map Gene to Disease3672
BioCentury BCIQITGA1
ClinGenITGA1
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD3672
Chemical/Pharm GKB GenePA29935
Clinical trialITGA1
Miscellaneous
canSAR (ICR)ITGA1 (select the gene name)
Probes
Litterature
PubMed125 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineITGA1
EVEXITGA1
GoPubMedITGA1
iHOPITGA1
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Thu Oct 12 16:25:04 CEST 2017

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