ITGA1 (integrin, alpha 1)
2014-10-01 Salah Boudjadi , Jean-François Beaulieu AffiliationLaboratory 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.
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.
Proteins
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
Entity name
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 name
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 name
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).
Article Bibliography
| Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|
| 18647959 | 2008 | Functional analysis of the cytoplasmic domain of the integrin {alpha}1 subunit in endothelial cells. | Abair TD et al |
| 16212500 | 2005 | Integrin structure, allostery, and bidirectional signaling. | Arnaout MA et al |
| 19693543 | 2010 | Integrins. | Barczyk M et al |
| 1506425 | 1992 | Differential expression of the VLA family of integrins along the crypt-villus axis in the human small intestine. | Beaulieu JF et al |
| 22402981 | 2012 | 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. | Beauséjour M et al |
| 24252313 | 2013 | Integrin α1 subunit is up-regulated in colorectal cancer. | Boudjadi S et al |
| 17669516 | 2007 | Transcriptional and epigenetic regulation of the integrin collagen receptor locus ITGA1-PELO-ITGA2. | Cheli Y et al |
| 25023165 | 2014 | Integrin α1β1. | Gardner H et al |
| 10620816 | 2000 | Complexity and specificity of integrin signalling. | Giancotti FG et al |
| 3018043 | 1986 | Very late activation antigens on rheumatoid synovial fluid T lymphocytes. Association with stages of T cell activation. | Hemler ME et al |
| 9950676 | 1999 | alpha1 and alpha2 integrins mediate invasive activity of mouse mammary carcinoma cells through regulation of stromelysin-1 expression. | Lochter A et al |
| 18676835 | 2008 | Loss of integrin alpha1beta1 ameliorates Kras-induced lung cancer. | Macias-Perez I et al |
| 9334246 | 1997 | Smooth muscle cell phenotype-dependent transcriptional regulation of the alpha1 integrin gene. | Obata H et al |
| 20308986 | 2010 | The final steps of integrin activation: the end game. | Shattil SJ et al |
| 17543136 | 2007 | The integrins. | Takada Y et al |
| 21785723 | 2011 | Integrin signaling, cell survival, and anoikis: distinctions, differences, and differentiation. | Vachon PH et al |
| 14678990 | 2003 | Integrin alpha1beta1 and alpha2beta1 are the key regulators of hepatocarcinoma cell invasion across the fibrotic matrix microenvironment. | Yang C et al |
Other Information
Locus ID:
NCBI: 3672
MIM: 192968
HGNC: 6134
Ensembl: ENSG00000213949
Variants:
dbSNP: 3672
ClinVar: 3672
TCGA: ENSG00000213949
COSMIC: ITGA1
RNA/Proteins
| Gene ID | Transcript ID | Uniprot |
|---|---|---|
| ENSG00000213949 | ENST00000282588 | P56199 |
| ENSG00000213949 | ENST00000650673 | A0A494C0F7 |
Expression (GTEx)
Pathways
Protein levels (Protein atlas)
References
| Pubmed ID | Year | Title | Citations |
|---|---|---|---|
| 35013194 | 2022 | The catalytic activity of TCPTP is auto-regulated by its intrinsically disordered tail and activated by Integrin alpha-1. | 17 |
| 35060996 | 2022 | Erianin Controls Collagen-Mediated Retinal Angiogenesis via the RhoA/ROCK1 Signaling Pathway Induced by the alpha2/beta1 Integrin-Collagen Interaction. | 4 |
| 36301458 | 2022 | Hsa_circ_0043949 reinforces temozolomide resistance via upregulating oncogene ITGA1 axis in glioblastoma. | 5 |
| 36517525 | 2022 | The effects of inhibition and siRNA knockdown of collagen-binding integrins on human umbilical vein endothelial cell migration and tube formation. | 3 |
| 35013194 | 2022 | The catalytic activity of TCPTP is auto-regulated by its intrinsically disordered tail and activated by Integrin alpha-1. | 17 |
| 35060996 | 2022 | Erianin Controls Collagen-Mediated Retinal Angiogenesis via the RhoA/ROCK1 Signaling Pathway Induced by the alpha2/beta1 Integrin-Collagen Interaction. | 4 |
| 36301458 | 2022 | Hsa_circ_0043949 reinforces temozolomide resistance via upregulating oncogene ITGA1 axis in glioblastoma. | 5 |
| 36517525 | 2022 | The effects of inhibition and siRNA knockdown of collagen-binding integrins on human umbilical vein endothelial cell migration and tube formation. | 3 |
| 34566986 | 2021 | CD49a Identifies Polyfunctional Memory CD8 T Cell Subsets that Persist in the Lungs After Influenza Infection. | 13 |
| 34906278 | 2021 | Nanofluorescence Probes to Detect miR-192/Integrin Alpha 1 and Their Correlations with Retinoblastoma. | 1 |
| 34566986 | 2021 | CD49a Identifies Polyfunctional Memory CD8 T Cell Subsets that Persist in the Lungs After Influenza Infection. | 13 |
| 34906278 | 2021 | Nanofluorescence Probes to Detect miR-192/Integrin Alpha 1 and Their Correlations with Retinoblastoma. | 1 |
| 32753478 | 2020 | An interspecies translation model implicates integrin signaling in infliximab-resistant inflammatory bowel disease. | 11 |
| 32986180 | 2020 | Alginate oligosaccharide protects endothelial cells against oxidative stress injury via integrin-α/FAK/PI3K signaling. | 6 |
| 32753478 | 2020 | An interspecies translation model implicates integrin signaling in infliximab-resistant inflammatory bowel disease. | 11 |
Citation
Salah Boudjadi ; Jean-François Beaulieu
ITGA1 (integrin, alpha 1)
Atlas Genet Cytogenet Oncol Haematol. 2014-10-01
Online version: http://atlasgeneticsoncology.org/gene/40999/new-content/meetings/
