ITGA1 (integrin, alpha 1)

2014-10-01 Salah Boudjadi , Jean-François Beaulieu Affiliation

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

Identity

HGNC

ITGA1

LOCATION

5q11.2

LOCUSID

3672

ALIAS

CD49a,VLA1

FUSION GENES

Show Gene Fusions

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)

100

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Focal adhesion	KEGG	ko04510
ECM-receptor interaction	KEGG	ko04512
Hematopoietic cell lineage	KEGG	ko04640
Regulation of actin cytoskeleton	KEGG	ko04810
Focal adhesion	KEGG	hsa04510
ECM-receptor interaction	KEGG	hsa04512
Hematopoietic cell lineage	KEGG	hsa04640
Regulation of actin cytoskeleton	KEGG	hsa04810
Hypertrophic cardiomyopathy (HCM)	KEGG	ko05410
Hypertrophic cardiomyopathy (HCM)	KEGG	hsa05410
Arrhythmogenic right ventricular cardiomyopathy (ARVC)	KEGG	ko05412
Arrhythmogenic right ventricular cardiomyopathy (ARVC)	KEGG	hsa05412
Dilated cardiomyopathy	KEGG	ko05414
Dilated cardiomyopathy	KEGG	hsa05414
PI3K-Akt signaling pathway	KEGG	hsa04151
PI3K-Akt signaling pathway	KEGG	ko04151
Hemostasis	REACTOME	R-HSA-109582
Platelet Adhesion to exposed collagen	REACTOME	R-HSA-75892
Muscle contraction	REACTOME	R-HSA-397014
Smooth Muscle Contraction	REACTOME	R-HSA-445355
Extracellular matrix organization	REACTOME	R-HSA-1474244
Laminin interactions	REACTOME	R-HSA-3000157
Integrin cell surface interactions	REACTOME	R-HSA-216083
Developmental Biology	REACTOME	R-HSA-1266738
Axon guidance	REACTOME	R-HSA-422475
Semaphorin interactions	REACTOME	R-HSA-373755
Other semaphorin interactions	REACTOME	R-HSA-416700
L1CAM interactions	REACTOME	R-HSA-373760
CHL1 interactions	REACTOME	R-HSA-447041

Protein levels (Protein atlas)

Not detected

Low

Medium

High

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