Disease relevance of ITGA6

• Pyloric atresia-junctional epidermolysis bullosa syndrome (PA-JEB) is an autosomal recessive inherited rare blistering disorder caused by mutations in ITGA6 or ITGB4, genes encoding integrin alpha6 or beta4, respectively [1].
• These changes of integrin expression during tumour progression particularly, the data showing an increase of VLA-4, and a decrease of VLA-6 expression support the concept that integrins are a new additional set of prognostic markers which indicate predisposition to the development of metastases [2].
• Unexpectedly, the beta 1-integrins VLA-1 (1/51), VLA-2 (18/123), VLA-3 (5/43), VLA-6 (15/29) and the E-selectin (2/47) were expressed on > 70% blasts on a subset of leukemias of varied phenotype [3].
• Regarding integrin expression we found elevated levels of VLA-2 and VLA-6 in the highly invasive and metastatic cell lines compared with normal cultured melanocytes and nonmetastatic melanoma cell lines [4].
• We studied 23 renal cell carcinomas and two normal kidney tissues by immunohistochemistry using monoclonal antibodies against subunits of the VLA integrins (VLA-1 to VLA-6) and CD51 [5].

High impact information on ITGA6

• In vitro studies have shown that four members of the very late antigen (VLA) integrin family of adhesion molecules, VLA-3, VLA-4, VLA-5, and VLA-6, can bind to invasin [6].
• The presence of VLA-6, CD44v6, and ICAM-1 on melanoma cells was not associated with clinical outcome [7].
• In view of the role of the VLA-3 and VLA-6 as laminin receptors, this finding is in line with the production of laminin in active liver disease [8].
• Expression of the alpha6 beta4 integrin is altered at the dermal-epidermal basement-membrane zone; recently, mutations in the corresponding genes (ITGA6 and ITGB4) have been disclosed in a limited number of patients, premature termination codons in both alleles being characteristic of lethal variants [9].
• In this study we demonstrate, for the first time, a homozygous mutation in the alpha6 integrin gene (ITGA6) in a family with three affected individuals [10].

Biological context of ITGA6

• For this purpose, we first determined the genomic organization of ITGA6, and placed the gene on chromosome 2q by high resolution radiation hybrid mapping [10].
• Heteroduplex analysis of PCR products containing the individual exons of ITGA6, followed by direct nucleotide sequencing, revealed that the proband was homozygous for a G-to-T transversion in the +1 position of intron 12 [10].
• VLA6 up-regulation was transient, peaking in 6 min and returning to baseline in 1 h when tested in response to N-formyl-methionyl-leucyl-phenylalanine [11].
• Specific inhibitions of cell adhesion were performed, and it was demonstrated that VLA-6 was the major receptor involved in Langerhans cell adhesion to laminin [12].
• Antisera against the integrin (fibronectin) receptor, and monoclonal antibody to the integrin, VLA-6, inhibited cell interaction with laminin, as well as with peptides containing an RGD sequence [13].

Anatomical context of ITGA6

• Taken together, these data indicate that p67 LBP is an activation-induced surface structure on memory T cells that, together with VLA-6, mediates cellular adherence to laminin [14].
• Strong staining of capillaries was obtained in both normal and pathological tissue with antibodies to collagen type IV and its putative receptor VLA-1; laminin and its putative receptor VLA-6; and the common VLA beta 1-subunit [15].
• In the biopsies from nickel sulphate-induced lesions, the keratinocytes showed a tendency to less VLA-6 expression [16].
• VLA-6 was identified primarily in the basement membrane of vessels, glandular and surface epithelium in both patient groups [17].
• In active lesions decreased endothelial cell beta1/VLA-6 could result in their detachment from laminin thereby facilitating leukocyte transvascular migration and blood-brain barrier breakdown [18].

Associations of ITGA6 with chemical compounds

• Down-modulation of VLA-5 on the apical surface of monocytes by plating the cells onto surfaces precoated with anti-VLA-5 mAb also inhibited binding of beads coated with maltose-binding protein-FimD to monocytes, while precoating of the surfaces with mAb against VLA-6 or CR3 had no effect [19].
• By immunoelectron microscopy VLA-1, VLA-6, beta1, and laminin were distributed throughout endothelial cells; alpha(v) was adjacent to and on luminal surfaces; alpha(v) and VLA-1 were on intercellular junctions [18].
• Their phenotype indicated that they may be related to dermal DC rather than to LC, i.e., they were all CD11b-positive, and 72% were Factor XIIIa-positive, but they did not express E-cadherin nor VLA-6 [20].

Physical interactions of ITGA6

• The VLA-2 complex (alpha 2/beta 1) was found to act as collagen receptor on platelets and the VLA-6 complex (alpha 6/beta 1) as laminin receptor [21].

Regulatory relationships of ITGA6

• We postulated that VLA6 might be involved in neutrophil infiltration because it revealed as the most expressed beta1 integrins among VLA5, VLA4, and VLA3, which also appeared to define subsets within the blood neutrophil population [11].
• In chronic inactive lesions beta1, VLA-6 and alpha(v) were the same as controls but VLA-1 remained increased [18].

Other interactions of ITGA6

• Because VLA-5 and VLA-6 both closely resemble the previously defined Ic-IIa platelet protein complex, it is likely that there is more than one platelet "Ic" protein complexed with IIa [22].
• Specific association of CD63 with the VLA-3 and VLA-6 integrins [23].
• Approximately one third of the tumors stained positively for VLA6 and CD44, and fewer (27%) were positive for VLA2 [24].
• When combined, siRNAs against ITGA6, PAI-1, and KISS-1 could mimic the negative effect of siPTHrP on migration, whereas siKISS-1 and siPTHrP similarly reduced the proliferative activity of the cells [25].
• These findings suggest that VLA-6 and VLA-2 receptors mediate attachment of tumor cells to neoplastic BM material, which, in turn, may endow these cells with an increased ability to invade the extracellular matrix [26].

Analytical, diagnostic and therapeutic context of ITGA6

• Mutation detection strategy based on PCR amplification of genomic DNA, followed by heteroduplex analysis and direct nucleotide sequencing, did not reveal sequence variants in ITGA6 [27].
• VLA-6 was not readily seen in anti-VLA beta immunoprecipitations, apparently because the alpha 6 subunit is only loosely or partially associated with the VLA beta subunit [22].
• We have detected VLA-4 and VLA-5, but not VLA-3 and VLA-6 expressed on human CD3+CD4-CD8- gamma delta TCR T cells by flow cytometry [28].
• Immunoprecipitation analyses confirmed that VLA-2, VLA-3 and VLA-6 were expressed by basal keratinocytes [29].
• VLA-6 (CDw49f) is an important adhesion molecule in NK cell-mediated cytotoxicity following autologous or allogeneic bone marrow transplantation [30].

References