ITGA1 (integrin, alpha 1)

	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number of response elements for nuclear factors known to be implicated in cancer progression such as TCF/LEF and c-Myc (unpublished data).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.

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).

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