Journal articles: 'Integrin alpha6'

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Caniggia, I., J. Liu, R. Han, J. Wang, A. K. Tanswell, G. Laurie, and M. Post. "Identification of receptors binding fibronectin and laminin on fetal rat lung cells." American Journal of Physiology-Lung Cellular and Molecular Physiology 270, no. 3 (March 1, 1996): L459—L468. http://dx.doi.org/10.1152/ajplung.1996.270.3.l459.

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Fibronectin and laminin have been implicated in regulating lung morphogenesis. In the present study, the cell surface receptors involved in fetal lung cell binding to laminin and fibronectin were identified. Messages for alpha5- and beta1-integrin subunits were detected in both fetal lung epithelial cells and fibroblasts. The presence of alpha5 beta1 -integrin on both cell types was demonstrated by immunocytochemistry and confirmed by cell adhesion experiments with fibronectin and RGD-containing peptides. Epithelial cells adhered more readily to laminin than fibroblasts. The alpha4 beta1-integrin, and RGD-independent fibronectin receptor, was weakly expressed on either cell type. Both cell types expressed alpha6-integrin subunit mRNA and stained immunopositive for the alpha6-subunit. Although either cell type expressed nonintegrin 67-kDa laminin-elastin receptor mRNA, no positive immunoreactivity for this laminin-elastin binding protein was detected. None of these findings explain the enhanced attachment of distal fetal lung epithelial cells to laminin compared with fibroblasts. Previously, we have reported that epithelial cells were enriched in alpha3-integrin subunit mRNA and protein expression. Herein, we found that epithelial cell attachment to laminin was nearly completely inhibited by alpha3- but only partially by alpha6 -monoclonal antibodies. A peptide near the globular region at the long arm of the laminin A-chain, which contained the IKVAV sequence, and the laminin A-chain amino acid sequence representing the alpha3 beta1 -integrin binding site, inhibited the adherence of epithelial cells to laminin. Fetal lung epithelial cells attached to substrata coated with the alpha3 beta1-integrin binding site peptide and the peptide containing the IKVAV sequence. These data suggest that both fetal lung cell types bind to fibronectin via the fibronectin receptor, alpha5 beta1, and fetal lung epithelial cells interact with laminin via alpha3 beta1 and proteins that recognize the IKVAV-containing sequence on the laminin A-chain.

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Sastry, S. K., M. Lakonishok, D. A. Thomas, J. Muschler, and A. F. Horwitz. "Integrin alpha subunit ratios, cytoplasmic domains, and growth factor synergy regulate muscle proliferation and differentiation." Journal of Cell Biology 133, no. 1 (April 1, 1996): 169–84. http://dx.doi.org/10.1083/jcb.133.1.169.

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The role of integrins in muscle differentiation was addressed by ectopic expression of integrin alpha subunits in primary quail skeletal muscle, a culture system particularly amenable to efficient transfection and expression of exogenous genes. Ectopic expression of either the human alpha5 subunit or the chicken alpha6 subunit produced contrasting phenotypes. The alpha5-transfected myoblasts remain in the proliferative phase and are differentiation inhibited even in confluent cultures. In contrast, myoblasts that overexpress the alpha6 subunit exhibit inhibited proliferation and substantial differentiation. Antisense suppression of endogenous quail alpha6 expression inhibits myoblast differentiation resulting in sustained proliferation. These effects of ectopic alpha subunit expression are mediated, to a large extent, by the cytoplasmic domains. Ectopic expression of chimeric alpha subunits, alpha5ex/6cyto and alpha6ex/5cyto, produced phenotypes opposite to those observed with ectopic alpha5 or alpha6 expression. Myoblasts that express alpha5ex/6cyto show decreased proliferation while differentiation is partially restored. In contrast, the alpha6ex/5cyto transfectants remain in the proliferative phase unless allowed to become confluent for at least 24 h. Furthermore, expression of human alpha5 subunit cytoplasmic domain truncations, before and after the conserved GFFKR motif, shows that this sequence is important in alpha5 regulation of differentiation. Ectopic alpha5 and alpha6 expression also results in contrasting responses to the mitogenic effects of serum growth factors. Myoblasts expressing the human alpha5 subunit differentiate only in the absence of serum while differentiation of untransfected and alpha6-transfected myoblasts is insensitive to serum concentration. Addition of individual, exogenous growth factors to alpha5-transfected myoblasts results in unique responses that differ from their effects on untransfected cells. Both bFGF or TGFbeta inhibit the serum-free differentiation of alpha5-transfected myoblasts, but differ in that bFGF stimulates proliferation whereas TGF-beta inhibits it. Insulin or TGF-alpha promote proliferation and differentiation of alpha5-transfected myoblasts; however, insulin alters myotube morphology. TGF-alpha or PDGF-BB enhance muscle alpha-actinin organization into myofibrils, which is impaired in differentiated alpha5 cultures. With the exception of TGF-alpha, these growth factor effects are not apparent in untransfected myoblasts. Finally, myoblast survival under serum-free conditions is enhanced by ectopic alpha5 expression only in the presence of bFGF and insulin while TGF-alpha and TGF-beta promote survival of untransfected myoblasts. Our observations demonstrate (1) a specificity for integrin alpha subunits in regulating myoblast proliferation and differentiation; (2) that the ratio of integrin expression can affect the decision to proliferate or differentiate; (3) a role for the alpha subunit cytoplasmic domain in mediating proliferative and differentiative signals; and (4) the regulation of proliferation, differentiation, cytoskeletal assembly, and cell survival depend critically on the expression levels of different integrins and the growth factor environment in which the cells reside.

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Jacques, T. S., J. B. Relvas, S. Nishimura, R. Pytela, G. M. Edwards, C. H. Streuli, and C. ffrench-Constant. "Neural precursor cell chain migration and division are regulated through different beta1 integrins." Development 125, no. 16 (August 15, 1998): 3167–77. http://dx.doi.org/10.1242/dev.125.16.3167.

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Proliferation and tangential migration of neural precursor cells are essential determinants of CNS development. We have established cell culture models of both these processes using neural precursor cells grown as neurospheres. The pattern of migration that we observe in these cells is homotypic and occurs in the absence of a glial or neuronal scaffold, and is therefore equivalent to that previously described as chain migration. To determine the role of integrins in proliferation and migration, we have analysed the expression pattern of integrins on neurosphere cells and then performed blocking peptide and antibody experiments. Neurosphere cells express five major integrins, alpha5 beta1, alpha 6Abeta1, alphav beta1, alphav beta5 and alpha vbeta8 and, in addition, express low levels of alpha 6Bbeta1. Chain migration is inhibited by blocking the alpha 6beta1 integrin. Proliferation, by contrast, is inhibited by blocking the other beta1 integrins, alphav beta1 and alpha5 beta1. These results show that integrins are important regulators of neural precursor cell behaviour, with distinct beta1 integrins regulating proliferation and migration. They also demonstrate a novel role for the alpha6 beta1 integrin in the cell-cell interactions underlying homotypic chain migration.

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De Arcangelis, A., M. Mark, J. Kreidberg, L. Sorokin, and E. Georges-Labouesse. "Synergistic activities of alpha3 and alpha6 integrins are required during apical ectodermal ridge formation and organogenesis in the mouse." Development 126, no. 17 (September 1, 1999): 3957–68. http://dx.doi.org/10.1242/dev.126.17.3957.

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Integrins alpha6beta1 and alpha6beta4 are cell surface receptors for laminins. Integrin alpha6-null mice die at birth with severe skin blistering and defects in the cerebral cortex and in the retina. Integrin alpha3beta1 can associate with laminins and other ligands. Integrin alpha3-null mice also die at birth, with kidney and lung defects at late stages of development, and moderate skin blistering. To investigate possible overlapping functions between alpha3 and alpha6 integrins, we analyzed the phenotype of compound alpha3−/−/alpha6−/− mutant embryos. Double homozygous mutant embryos were growth-retarded and displayed several developmental defects not observed in the single mutant animals. First, limb abnormalities characterized by an absence of digit separation and the fusion of preskeletal elements were observed. Further analyses indicated a defect in the apical ectodermal ridge, an essential limb organizing center. In the double mutant, the ridge appeared flattened, and ridge cells did not show a columnar morphology. A strong reduction in ridge cell proliferation and alterations of the basal lamina underlying the ectoderm were observed. These results suggest that alpha3 and alpha6 integrins are required for the organization or compaction of presumptive apical ectodermal ridge cells into a distinct differentiated structure. Additional defects were present: an absence of neural tube closure, bilateral lung hypoplasia, and several abnormalities in the urogenital tract. Finally, an aggravation of brain and eye lamination defects was observed. The presence of novel phenotypes in double mutant embryos demonstrates the synergism between alpha3 and alpha6 integrins and their essential roles in multiple processes during embryogenesis.

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Leivo, I., T. Tani, L. Laitinen, R. Bruns, E. Kivilaakso, V. P. Lehto, R. E. Burgeson, and I. Virtanen. "Anchoring complex components laminin-5 and type VII collagen in intestine: association with migrating and differentiating enterocytes." Journal of Histochemistry & Cytochemistry 44, no. 11 (November 1996): 1267–77. http://dx.doi.org/10.1177/44.11.8918902.

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Anchoring complex component laminin-5 and its subunits laminin (Ln)-alpha3 and Ln-beta3 chains, Type VII collagen, and integrin chains alpha3, alpha6, and beta4 were studied in developing and adult human intestine and compared with findings on Ln-alpha1 and Ln-alpha2 chains. In adult human duodenum, jejunum, and ileum, Ln-5 detected with a polyclonal antiserum and Ln-alpha3 and Ln-beta3 chains, detected with monoclonal antibodies (MAbs), were restricted to the epithelial basement membranes (BMs) of villi, whereas Ln-alpha2 chain was seen only focally in crypt bottoms. In double labeling experiments, the stretch of crypt BM corresponding to the proliferative cell compartment was found to be devoid of both Ln-alpha3 and Ln-alpha2 chains. Double labeling for Ln-5 and proliferating cell nuclear antigen also showed an abrupt onset of Ln-5 expression exactly at the upper edge of the proliferative cell compartment. Type VII collagen was negligible in duodenum and showed a rising duodenal-ileal gradient localizing to villar BMs. Double labeling for Ln-5 and Type VII collagen, however, indicated only partial co-distribution in the intestine. Electron microscopy of ileum revealed both anchoring filaments and anchoring fibrils but no hemidesmosomal plaques. Our results demonstrate the expression of Ln-5 in BMs outside of stratified epithelia and indicate that Ln-5 in the intestine is associated with the compartment of migrating and differentiating enterocytes. Absence of hemidesmosomes and the presence of other anchoring complex components, such as Ln-5, Type VII collagen, and integrin chains alpha3, alpha6, and beta4, suggests unique properties for epithelial cell attachment in the intestine.

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Anderson, R., R. Fassler, E. Georges-Labouesse, R. O. Hynes, B. L. Bader, J. A. Kreidberg, K. Schaible, J. Heasman, and C. Wylie. "Mouse primordial germ cells lacking beta1 integrins enter the germline but fail to migrate normally to the gonads." Development 126, no. 8 (April 15, 1999): 1655–64. http://dx.doi.org/10.1242/dev.126.8.1655.

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Primordial germ cells are the founder cells of the gametes. They are set aside at the initial stages of gastrulation in mammals, become embedded in the hind-gut endoderm, then actively migrate to the sites of gonad formation. The molecular basis of this migration is poorly understood. Here we sought to determine if members of the integrin family of cell surface receptors are required for primordial germ cell migration, as integrins have been implicated in the migration of several other motile cell types. We have established a line of mice which express green fluorescent protein in germline cells that has enabled us to efficiently purify primordial germ cells at different stages by flow cytometry. We have catalogued the spectrum of integrin subunit expression by primordial germ cells during and after migration, using flow cytometry, immunocytochemistry and RT-PCR. Through analysis of integrin beta1(−/−)-->wild-type chimeras, we show that embryonic cells lacking beta1 integrins can enter the germline. However, integrin beta1(−/−) primordial germ cells do not colonize the gonad efficiently. Embryos with targeted deletion of integrin subunit alpha3, alpha6, or alphaV show no major defects in primordial germ cell migration. These results demonstrate a role for beta1-containing integrins in the development of the germline, although an equivalent role for * integrin subunit(s) has yet to be established.

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Manie, SN, A. Astier, D. Wang, JS Phifer, J. Chen, AI Lazarovits, C. Morimoto, and AS Freedman. "Stimulation of tyrosine phosphorylation after ligation of beta7 and beta1 integrins on human B cells." Blood 87, no. 5 (March 1, 1996): 1855–61. http://dx.doi.org/10.1182/blood.v87.5.1855.1855.

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Abstract B lymphocytes express several members of the integrin family of adhesion molecules that mediate cell-cell and cell-extracellular matrix interactions. In addition to beta1 integrins, predominantly alpha4 beta1, mature B cells also express alpha4 beta7, which is a receptor for vascular cell adhesion molecule-1 and fibronectin, and is also involved in the homing of B cells to mucosal sites through binding to a third ligand, mucosal address in cell adhesion molecule-1. Here we describe that crosslinking of alpha4 beta7 integrins on B cell lines and normal tonsillar B cells, induces tyrosine phosphorylation of multiple substrates of 105–130 kD, indicating that beta7 integrin plays a role as signaling molecule in B cells. This pattern of phosphorylated proteins was very similar to that induced following ligation of alpha4 beta1. Interestingly, ligation of alpha5 beta1 or alpha6 beta1 also stimulated the 105–125 kD group of phosphorylated proteins, whereas ligation of beta2 integrins did not. The focal adhesion tyrosine kinase p125FAK was identified as one of these substrates. Beta1 or beta7 mediated tyrosine phosphorylations were markedly decreased when the microfilament assembly was inhibited by cytochalasin B. These results suggest that intracellular signals initiated by different integrins in B cells may converge, to similar cytoskeleton-dependent tyrosine phosphorylated proteins.

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Manie, SN, A. Astier, D. Wang, JS Phifer, J. Chen, AI Lazarovits, C. Morimoto, and AS Freedman. "Stimulation of tyrosine phosphorylation after ligation of beta7 and beta1 integrins on human B cells." Blood 87, no. 5 (March 1, 1996): 1855–61. http://dx.doi.org/10.1182/blood.v87.5.1855.bloodjournal8751855.

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B lymphocytes express several members of the integrin family of adhesion molecules that mediate cell-cell and cell-extracellular matrix interactions. In addition to beta1 integrins, predominantly alpha4 beta1, mature B cells also express alpha4 beta7, which is a receptor for vascular cell adhesion molecule-1 and fibronectin, and is also involved in the homing of B cells to mucosal sites through binding to a third ligand, mucosal address in cell adhesion molecule-1. Here we describe that crosslinking of alpha4 beta7 integrins on B cell lines and normal tonsillar B cells, induces tyrosine phosphorylation of multiple substrates of 105–130 kD, indicating that beta7 integrin plays a role as signaling molecule in B cells. This pattern of phosphorylated proteins was very similar to that induced following ligation of alpha4 beta1. Interestingly, ligation of alpha5 beta1 or alpha6 beta1 also stimulated the 105–125 kD group of phosphorylated proteins, whereas ligation of beta2 integrins did not. The focal adhesion tyrosine kinase p125FAK was identified as one of these substrates. Beta1 or beta7 mediated tyrosine phosphorylations were markedly decreased when the microfilament assembly was inhibited by cytochalasin B. These results suggest that intracellular signals initiated by different integrins in B cells may converge, to similar cytoskeleton-dependent tyrosine phosphorylated proteins.

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Chen, L., V. Shick, M. L. Matter, S. M. Laurie, R. C. Ogle, and G. W. Laurie. "Laminin E8 alveolarization site: heparin sensitivity, cell surface receptors, and role in cell spreading." American Journal of Physiology-Lung Cellular and Molecular Physiology 272, no. 3 (March 1, 1997): L494—L503. http://dx.doi.org/10.1152/ajplung.1997.272.3.l494.

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Cell adhesion to amino acids 2179-2198 (SN-peptide) of the laminin-1 alpha1-chain is required for lung alveolar formation in vitro (M. L. Matter and G. W. Laurie. J. Cell Biol. 124: 1083-1090, 1994). The nature of the SN-peptide receptor(s) was probed with neutralizing anti-integrin monoclonal antibodies (MAb), cells lacking integrin subunits, soluble heparin, and SN-peptide columns. Cell adhesion and spreading studies confirmed the specificity of SN-peptide and revealed adhesion to be unaffected by inclusion of anti-beta1-, anti-alpha(2-6)- or anti-alpha(V)beta5-integrin MAb. Cells lacking beta1- or alpha6-integrin subunits were fully adherent. Adhesion was heparin, but not chondroitin sulfate or heparinase, sensitive, much as is alpha-dystroglycan-laminin-1 binding. Heparin eluted approximately 155- and 180-kDa cell-surface proteins from SN-peptide columns. An additional approximately 91-kDa protein was eluted by EDTA. All were unrecognized by anti-beta1-integrin MAb. SN-peptide therefore interacts with three cell-surface proteins for which the identity remains to be determined.

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Niessen, C. M., E. H. Hulsman, L. C. Oomen, I. Kuikman, and A. Sonnenberg. "A minimal region on the integrin beta4 subunit that is critical to its localization in hemidesmosomes regulates the distribution of HD1/plectin in COS-7 cells." Journal of Cell Science 110, no. 15 (August 1, 1997): 1705–16. http://dx.doi.org/10.1242/jcs.110.15.1705.

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The integrin alpha6 beta4 is a major component of hemidesmosomes, in which it mediates firm adhesion to laminin 5. Previous studies have shown that the incorporation of alpha6 beta4 into hemidesmosomes requires a 303 amino acid stretch of the cytoplasmic domain of beta4, comprising part of the first fibronectin type III (FNIII) repeat, the second FNIII repeat and the segment that connects the second to the third FNIII repeat (connecting segment). Now, we have further defined sequences within beta4 that are critical for its localization in hemidesmosomes and we demonstrate that these sequences also induce the redistribution of HD1/plectin into junctional complexes containing the integrin alpha6 beta4 in COS-7 cells, transfected with cDNAs encoding alpha6A and beta4. Truncation of the cytoplasmic domain of beta4 after amino acids 1,382 or 1,355 in the connecting segment, by which a potential tyrosine activation motif (TAM) is removed, does not prevent the localization of alpha6 beta4 in hemidesmosomes in the rat bladder carcinoma cell line 804G and neither did it eliminate the ability of alpha6 beta4 to change the subcellular distribution of HD1/plectin in COS-7 cells. In contrast, beta4 subunits in which the entire connecting segment had been deleted or which were truncated after amino acid 1,328, which removes almost the complete segment, had lost both of these functions. Furthermore, when beta4 subunits with either a deletion of the second FNIII repeat or a small deletion in this repeat were co-expressed with alpha6, the integrins were not localized in hemidesmosomes and did not induce the redistribution of HD1/plectin in COS-7 cells. Finally, the fourth FNIII repeat of beta4 could not replace the second in either of these activities. These findings establish that a region in beta4, which encompasses the second FNIII repeat and a stretch of 27 amino acids (1,329-1,355) of the connecting segment, is critical for the localization of alpha6beta4 in hemidesmosomes and that it regulates the distribution of HD1/plectin.

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Fleischmajer, R., A. Utani, E. D. MacDonald, J. S. Perlish, T. C. Pan, M. L. Chu, M. Nomizu, Y. Ninomiya, and Y. Yamada. "Initiation of skin basement membrane formation at the epidermo-dermal interface involves assembly of laminins through binding to cell membrane receptors." Journal of Cell Science 111, no. 14 (July 30, 1998): 1929–40. http://dx.doi.org/10.1242/jcs.111.14.1929.

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To study the mechanism of basement membrane formation, we determined by immunochemistry temporal and spatial expression of laminin-5 (Ln-5), laminin-1 (Ln-1) and their integrin receptors during early skin morphogenesis. A 3-dimensional skin culture was used that allows the study of the sequential molecular events of basement membrane formation at the epidermodermal interface. During early anchorage of keratinocytes to the extracellular matrix there is expression of Ln-5, BP-230 antigen and alpha3, beta1 integrin subunits. During epidermal stratification and prior to the formation of the lamina densa there is assembly of Ln-5, Ln-1, collagen IV and nidogen accompanied by keratinocyte basal clustering of alpha2, alpha3, alpha6, beta1, and beta4+ integrin subunits. The assembly pattern of Ln-1 and Ln-5 can be disturbed with functional antibodies against the beta1 (AIIB2) and alpha6 (GoH3) integrin subunits. Ln-1 assembly can also be disturbed with antibodies against its E8 domain and by competitive inhibition with a synthetic peptide (AG-73) derived from its G-4 domain. Quantitative RT-PCR showed that the dermis contributes about 80% of the laminin gamma)1 chain mRNA while 20% is produced by the epidermis which emphasizes its dual tissue origin and the major contribution of the mesenchyma in laminin production. The laminin gamma2 chain mRNA, present in Ln-5, was mostly of epidermal origin. This study presents evidence that during the initiation of basement membrane formation, laminins bind to keratinocyte plasma membrane receptors and thus may serve as nucleation sites for further polymerization of these compounds by a self-assembly process.

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Ferletta, M., and P. Ekblom. "Identification of laminin-10/11 as a strong cell adhesive complex for a normal and a malignant human epithelial cell line." Journal of Cell Science 112, no. 1 (January 1, 1999): 1–10. http://dx.doi.org/10.1242/jcs.112.1.1.

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Laminins are heterotrimeric proteins of basement membranes. More than 50 different trimers may exist. Laminin-10 (alpha5beta1gamma1 rather than laminin-1 (alpha1beta1gamma1) could be the most abundant isoform in the adult stage, and laminin-10 is made by several developing epithelial sheets. We show here that a much used commercial human preparation contains laminin-10 (alpha5beta1gamma1), some laminin-11 (alpha5beta2gamma1), but no laminin-1. Moreover, the laminin-10/11 mixture was found to be a strong adhesive for two human cell lines derived from epithelia. Antibodies against integrin beta1, alpha6 or alpha3 (at 50 microgram/ml) or dystroglycan did not inhibit cell attachment to laminin-10/11, although lower concentrations of anti-dystroglycan and integrin alpha6 antibodies inhibited cell binding to laminin-1.

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Yao, C. C., J. Breuss, R. Pytela, and R. H. Kramer. "Functional expression of the alpha 7 integrin receptor in differentiated smooth muscle cells." Journal of Cell Science 110, no. 13 (July 1, 1997): 1477–87. http://dx.doi.org/10.1242/jcs.110.13.1477.

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Expression of the alpha7 integrin is developmentally regulated and is thought to be tissue-specific for both skeletal and cardiac muscles. We now report that alpha7 is also strongly and ubiquitously expressed by various types of smooth muscle, including vascular, gastrointestinal and genitourinary smooth muscles. In addition, alpha7 was surface-expressed by a number of smooth muscle cell lines that maintained their differentiated phenotype following adaptation to culture. Studies with the mouse 9E11G smooth muscle cell line showed that the alpha7 integrin mediated both adhesion and motility of these cells on laminin 1 substrates. Alpha7 expression appears to correlate with the smooth-muscle-differentiated phenotype. The multipotential P19 mouse embryonic stem cell line lacks alpha7 but uses the alpha6 integrin to adhere to laminin 1. Following retinoic acid-induced P19 differentiation predominantly to the smooth muscle cell lineage, high expression of alpha7 was detected along with partial dependence on alpha7 for binding to laminin. The expression of alpha7 paralleled the induction of smooth-muscle-specific alpha-actin, as revealed by dual-labeling flow cytometry. In contrast, alpha7, which initially was highly expressed on the surface of vascular smooth muscle cell explants, was rapidly downregulated in smooth muscle cell outgrowths as they dedifferentiated into their synthetic phenotype. The results indicate that the expression of alpha7 integrin in smooth muscle cells is associated with their differentiated phenotype and mediates their interaction with laminins.

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Goissis, M. D., F. R. O. de Barros, M. G. Marques, C. M. Mendes, M. P. Milazzotto, C. H. C. Viana, M. E. O. A. Assumpção, and J. A. Visintin. "276 EXPRESSION OF CD9 AND ALPHA6-INTEGRIN IN PORCINE BLASTOCYSTS." Reproduction, Fertility and Development 21, no. 1 (2009): 235. http://dx.doi.org/10.1071/rdv21n1ab276.

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Establishment of embryonic stem cell (ESC) culture in pigs has not been achieved. Verification of pluripotency markers is necessary for validation of a pluripotent cell line. Not all markers observed in ESC from other species are characterized in swine embryos. The objective of this study was to characterize CD9 and α6-integrin expression in porcine blastocysts and to derive porcine ESC using Matrigel. In vitro or in vivo porcine blastocysts were submitted to total RNA extraction for RT-PCR, fixation for immunocytochemistry or immunosurgery for culture of inner cell mass. Expression of Oct-4, CD9, and α6-integrin was detected by PCR. CD9 and α6-integrin PCR products had their nucleotide sequence assessed and compared with public nucleotide database. CD9 product was identical to CD9 porcine sequences and α6-integrin product was similar to human and equine α6-integrin. Immunocytochemistry revealed Oct-4 expression in cytoplasm of the inner cell mass (ICM) and trophoblast cells. CD9 and α6-integrin were observed preferentially on trophoblast cells. No ESC colonies were obtained using co-culture on mouse embryonic fibroblasts (MEF) or on Matrigel. This study describes for the first time expression of CD9 and α6-integrin in porcine blastocysts. Financial support: Fapesp 05/57314-0.

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Gonçalves, R. F., R. P. Bertolla, R. A. Mortara, and V. H. Barnabe. "206 ALPHA6, BETA1, AND BETA3 INTEGRINS EXPRESSED BY SPERM MAY BE INVOLVED IN CATTLE FERTILIZATION." Reproduction, Fertility and Development 21, no. 1 (2009): 201. http://dx.doi.org/10.1071/rdv21n1ab206.

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Sperm-egg interaction is a complex molecular process leading to gamete fusion mediated by a series of molecular interactions. Some integrin subunits, which are adhesion molecules, are expressed on human and mouse sperm, but major questions about the roles of integrins in sperm-oocyte fusion remain unsolved. This study was conducted to determine the presence of integrin subunits on cattle (Bos indicus and Bos taurus) sperm, and whether fertilization might be affected by treating sperm with antibodies to integrin subunits. Frozen–thawed sperm, donated by ABS Pecplan, were centrifuged at 700g for 10 min and washed once in warm PBS (Nutricell®, Campinas, São Paulo, Brazil). Sperm were resuspended in PBS and treated with an equal volume of cold 4% paraformaldehyde (prepared fresh from formaldehyde) for 15 min on ice. All subsequent steps were conducted at RT. Fixed sperm were washed twice with PBS (10 000 rpm, 5 min) in an IEC Micromax (Needham, MA), and the pellet was resuspended in PBS containing 5% BSA. Samples of 1 mL, each containing 5 × 106 spermatozoa, were incubated overnight at 4°C with a monoclonal anti-integrin α6 immunoglobulin G (IgG), monoclonal anti-integrin β1 IgG, and monoclonal anti-integrin β3 IgG (Chemicon®). The next day, sperm were resuspended in Alexa Fluor® 488 goat anti-mouse IgG (Invitrogen). After being washed 3 times in PBS-BSA as before, a drop of sperm suspension was smeared on a slide, air-dried, mounted with antifade reagent with 4′,6-diamidino-2-phenylindole (Invitrogen), and covered with a coverslip for analysis. Frozen–thawed spermatozoa were washed by a 45/90% layered Percoll gradient centrifugation and incubated for 1 h in fertilization medium (FM; 1), FM with a monoclonal anti-integrin α6 IgG (2), FM with monoclonal anti-integrin β1 IgG (3), and FM with monoclonal anti-integrin β3 (4). In vitro-matured cattle oocytes were incubated (39°C, 5% CO2 in air) with 10 × 104 washed pretreated spermatozoa per 25 oocytes for 18 h. The oocytes were fixed in acid alcohol, stained with 1% acetate-orcein, and observed to determine the presence of pronuclei. Immunoreactive α6, β1, and β3 were concentrated at the apical segment of the acrosome in all bulls tested. There was no detectable fluorescence in any of the controls, and not all the sperm in an ejaculate were immunoreactive. Addition of anti-integrin α6, anti-integrin β1, and anti-integrin β3 decreased fertilization (P < 0.05) compared with the control: (1) 91.2 ± 2.0%; (2) 17.4 ± 2.0%; (3) 14.3 ± 2.0%; (4) 24.3 ± 2.0%. These findings show that α6, β1, and β3 integrins are expressed by cattle spermatozoa and may be involved in sperm-oocyte fusion and fertilization. This study was supported by FAPESP grants (2007/00363-5 and 2006/06008-0, Brazil). We acknowledge Nutricell and ABS Pecplan for their generous contribution.

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Desban, N., and J. L. Duband. "Avian neural crest cell migration on laminin: interaction of the alpha1beta1 integrin with distinct laminin-1 domains mediates different adhesive responses." Journal of Cell Science 110, no. 21 (November 1, 1997): 2729–44. http://dx.doi.org/10.1242/jcs.110.21.2729.

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In the present study, to further elucidate the molecular events that control neural crest cell migration, we have analyzed in vitro the adhesive and locomotory response of avian trunk neural crest cells to laminin-1 and searched for the integrin receptors involved in this process. Adhesion of crest cells on laminin-1 was comparable to that found on fibronectin or vitronectin. By contrast, migration was significantly greater on laminin-1 than on the other substrate molecules. Interaction of crest cells with laminin-1 involved two major cell-binding domains situated in different portions of the molecule, namely the E1′ and E8 fragments, which elicited different cellular responses. Cells were poorly spread on the E1′ fragment whereas, on E8, they were extremely flattened and cohesive. Either fragment supported cell locomotion, albeit not as efficiently as laminin-1. Immunoprecipitation and immunocytochemistry analyses revealed that crest cells expressed the alpha1beta1, alpha3beta1, alpha6beta1 and alpha vbeta3 integrins, as well as beta8 integrins, as presumptive laminin-1 receptors, but not alpha6beta4 and alpha2beta1. Immunofluorescence labeling of cultured cells showed that the alpha1, alpha v, beta1 and beta3 subunits were diffuse on the cell surface and in focal contacts. In contrast, alpha3 and beta8 were diffuse, while alpha6 was mostly intracytoplasmic and, secondarily, in focal contacts. Inhibition assays of cell adhesion and migration with function-perturbing antibodies demonstrated that alpha1beta1 played a predominant role in both adhesion and migration on laminin-1 and interacted with either binding sites in the E1′ and E8 fragments. Alpha vbeta3 was also implicated in neural crest cell migration. In contrast, alpha3beta1, alpha6beta1 and the beta8 integrins appeared to play only subsidiary roles in cell adhesion and migration. Finally, the ability of neural crest cells to interact with laminin-1 was found to increase with time in culture, possibly in correlation with changes in alpha3 distribution on the cell surface. In conclusion, our study indicates that (1) the preferential migration of neural crest cells along basal laminae can be accounted for by the ability of laminin-1 to promote migration with great efficiency; (2) interaction with laminin-1 involves two major cell binding domains that are both recognized by the alpha1beta1 integrin; (3) alpha1beta1 integrin can elicit different cellular responses depending on the laminin-1 domains with which it interacts; and (4) changes in the repertoire of integrins expressed by neural crest cells are consistent with the modulations of cell-substratum adhesion occurring throughout migration.

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Franchi, Alessandro, Roberto Santoro, Milena Paglierani, and Roberto Bondi. "Immunolocalization of alpha2, alpha5, and alpha6 integrin subunits in salivary tissue and adenomas of the parotid gland." Journal of Oral Pathology and Medicine 23, no. 10 (November 1994): 457–60. http://dx.doi.org/10.1111/j.1600-0714.1994.tb00444.x.

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Nievers, M. G., R. Q. Schaapveld, L. C. Oomen, L. Fontao, D. Geerts, and A. Sonnenberg. "Ligand-independent role of the beta 4 integrin subunit in the formation of hemidesmosomes." Journal of Cell Science 111, no. 12 (June 15, 1998): 1659–72. http://dx.doi.org/10.1242/jcs.111.12.1659.

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Recently, we have shown that a region within the beta4 cytoplasmic domain, encompassing the second fibronectin type III (FNIII) repeat and the first 27 amino acids of the connecting segment, is critical for the localization of alpha6 beta4 in hemidesmosomes. In addition, this region was shown to regulate the distribution of HD1/plectin in transfected cells. In order to investigate the function of the beta4 extracellular and cytoplasmic domains in the assembly and integrity of hemidesmosomes, we have constructed chimeric receptors consisting of the extracellular and transmembrane domains of the interleukin 2 receptor (IL2R), fused to different parts of the beta4 cytoplasmic domain. These chimeras are expressed as single subunits at the plasma membrane. The results show that the first and the second FNIII repeat, together with the first part of the connecting segment (in total a stretch of 241 amino acids spanning amino acids 1,115 to 1,356) are both essential and sufficient for the localization of beta4 in pre-existing hemidesmosomes. Moreover, expression of the IL2R/beta4 chimeric constructs in COS-7 and CHO cells, which do not express alpha6 beta4 or the bullous pemphigoid (BP) antigens but do express HD1/plectin, revealed that the stretch of 241 amino acids is sufficient for inducing the formation of type II hemidesmosomes. Expression of the IL2R/beta4 chimeras in a keratinocyte cell line derived from a patient lacking beta4 expression, showed that amino acids 1,115 to 1,356 can also induce the formation of type I hemidesmosomes. We further demonstrate that type I and II hemidesmosomes can also be formed upon adhesion of alpha6 beta4-expressing cells to fibronectin. These findings establish that the beta4 extracellular domain is not essential for the induction of hemidesmosome assembly. Moreover, they demonstrate that binding of alpha6 beta4 to ligand, and heterodimerization of alpha6 with beta4, are not required for hemidesmosome formation. This indicates that the assembly of hemidesmosomes can be regulated from within the cell.

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HOGERVORST, Frans, Ingrid KUIKMAN, Ad Geurts KESSEL, and Arnoud SONNENBERG. "Molecular cloning of the human alpha6 integrin subunit. Alternative splicing of alpha6 mRNA and chromosomal localization of the alpha6 and beta4 genes." European Journal of Biochemistry 199, no. 2 (July 1991): 425–33. http://dx.doi.org/10.1111/j.1432-1033.1991.tb16140.x.

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Pawar, Sangita C., Shona Dougherty, Michael E. Pennington, Manolis C. Demetriou, B. Dino Stea, Robert T. Dorr, and Anne E. Cress. "alpha6 Integrin Cleavage: Sensitizing human prostate cancer to ionizing radiation." International Journal of Radiation Biology 83, no. 11-12 (January 2007): 761–67. http://dx.doi.org/10.1080/09553000701633135.

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Viquez, Olga M., Eugenia M. Yazlovitskaya, Tianxiang Tu, Glenda Mernaugh, Pablo Secades, Karen K. McKee, Elizabeth Georges-Labouesse, et al. "Integrin alpha6 maintains the structural integrity of the kidney collecting system." Matrix Biology 57-58 (January 2017): 244–57. http://dx.doi.org/10.1016/j.matbio.2016.12.003.

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Evander, M., I. H. Frazer, E. Payne, Y. M. Qi, K. Hengst, and N. A. McMillan. "Identification of the alpha6 integrin as a candidate receptor for papillomaviruses." Journal of virology 71, no. 3 (1997): 2449–56. http://dx.doi.org/10.1128/jvi.71.3.2449-2456.1997.

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23

Gang, EunJi, Yao-Te Hsieh, Hye Na Kim, Yann Duchartre, Shishido Stephanie, Markus Muschen, Elizabeth Wayner, Nora Heisterkamp, Halvard Bonig, and Yong-Mi Kim. "Overcoming Drug Resistance of Pre-B ALL Cells By Targeting Integrin alpha6 Associated Cell-Adhesion Mediated Drug Resistance Using a Novel Antibody, P5G10." Blood 126, no. 23 (December 3, 2015): 2525. http://dx.doi.org/10.1182/blood.v126.23.2525.2525.

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Abstract Background. The presence of chemotherapy-resistant cells can be detected in the bone marrow (BM) and peripheral blood (PB) and is called minimal residual disease (MRD). The exact mechanism for cell adhesion-mediated drug resistance leading to MRD and how to therapeutically target MRD is unsolved.Integrin alpha-6 (alpha6) is expressed on normal hematopoietic cells but has recently been described as a novel marker for MRD+ ALL cells. We previously described a role of alpha6 as a critical molecule in drug resistance of ALL. Here we extend our studies evaluating a novel non-humanized antibody targeting alpha6, P5G10, as a novel therapy against drug resistant ALL. Method. For in vitro studies patient-derived (primary) pre-B ALL cells co-cultured with murine calvaria-derived mesenchymal stromal (OP9) cells or counter-ligand laminin-1. Annexin V/7-AAD staining was used for viability determination by flow cytometry. A NOD/SCID IL2Rγ-/- (NSG) xenograft model of primary pre-B ALL was used for in vivo experiments. Results. We evaluated integrin alpha6 blockade in four primary ALL cells (LAX7R, PDX2, TXL3, SFO2) using an anti-functional alpha6 antibody, P5G10, with and without the counter ligand laminin-1 or OP9. Alpha6 blockade de-adhered all four cases from laminin-1 compared to control-treated cells and percentage of adherence was significantly different (3.3%±0.6% vs. 77.7%±3.3%, p= 0.0002 for LAX7R; 10.5%±4.9% vs. 72.5%±0.7%, p= 0.003 for PDX2; 2.0%±1.3% vs. 66.9.6%±2.6%, p=0.0002 for TXL3; 9.6%±2.8% vs. 68.0%±5.7%, p=0.0006 for SFO2).. P5G10 de-adhered leukemia cells to a lesser degree from OP9-coated plates indicating that other adhesion molecules also contribute to leukemia cell adhesion. To determine the effect of alpha6 modulation in chemoresistant ALL, primary BCR-ABL1- ALL cells (LAX7R, SFO2) were treated with Vincristine, Dexamethasone and L-Asparaginase (VDL) and BCR-ABL1+ ALL cells (TXL3, PDX2) were treated with a tyrosine kinase inhibitor (TKI), Nilotinib (NTB). Primary ALL cells showed decreased viability after monotreatment with P5G10 in a short-term assay of 2 days with laminin-1 and were sensitized when P5G10 was combined with VDL or TKI, compared to TKI monotreatment (Cell viabilities were as follows: LAX7R, 13.9%±0.6% vs. 28.8%±2.6%, p=0.009; PDX2, 12.7%±1.4% vs. 19.9%±1.5%, p= 0.037: TXL3, 32.9%±2.6% vs. 48.3%±2.5%, p=0.026; and SFO2, 34.4%±7.9% vs. 47.6%±0.1%, p=0.047). Critically, in a long-term co-culture assay of primary ALL cells with OP9 cells, alpha6 blockade in combination with VDL or NTB lead to marked decrease in viability of ALL cells compared to VDL or NTB treatment (26.5%±10.0% vs. 74.2%±2.7%, p=0.002 for LAX7R and 33.5%±11.4% vs. 84.9%±15.1%, p=0.031 for SFO2 on day 17 post treatment, respectively). To determine if P5G10 induces mobilization of leukemia cells to the peripheral blood, patient-derived ALL cells, 3 cases (TXL3, PDX2 and LAX7R) were injected into NSG mice. After determination of engraftment of leukemia by flow cytometry of human CD45 in the PB, recipient mice were treated with 30mg/kg P5G10 or PBS control by i.v. or i.p. injection. The % of human CD45+ and CD19+ in peripheral blood (PB) was analyzed by flow cytometry before (pre), 1 and 3 days after (post) treatment with P5G10. In all 3 cases, we did not observe an increase of leukemia cells in the PB compared to before P5G10 treatment (Day 0) or compared to the control recipient mice. Critically, we determined, if P5G10 can restore chemosensitivity of leukemia cells in vivo. For this purpose, we injected luciferase-labeled LAX7R cells into NOD/SCID mice. Three days after leukemia cell injection leukemia cell-bearing mice received four weekly injections of 30mg/kg P5G10 or saline ± VDL. Mice treated with P5G10 survived similarly as untreated mice (PBS: MST = 39 days vs. P5G10: MST = 31 days; p=0.05). In marked contrast, mice treated with VDL plus P5G10 survived disease-free compared to chemotherapy-only treated mice until the experiment was terminated Day 186 post-leukemia injection (MST= 185 days vs. MST=71 days; p=0.0012). Human CD19 or CD45 was undetectable in the peripheral blood by flow cytometry in surviving P5G10+VDL-treated animals before they were sacrificed. Conclusion. Taken together, we demonstrate that alpha6 may be a novel therapeutic target in ALL and modulating the function of integrin alpha6 using P5G10 can overcome drug resistance in ALL. Disclosures No relevant conflicts of interest to declare.

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Husen, Giebel, and Rune. "Expression of the integrin subunits alpha5, alpha6 and beta1 in the testes of the common marmoset." International Journal of Andrology 22, no. 6 (December 1999): 374–84. http://dx.doi.org/10.1046/j.1365-2605.1999.00195.x.

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Zhu, Guang-Hui, Chen Huang, Zheng-Jun Qiu, Jun Liu, Zhi-Hua Zhang, Ning Zhao, Zheng-Zhong Feng, and Xiu-Hong Lv. "Expression and Prognostic Significance of CD151, c-Met, and Integrin alpha3/alpha6 in Pancreatic Ductal Adenocarcinoma." Digestive Diseases and Sciences 56, no. 4 (October 7, 2010): 1090–98. http://dx.doi.org/10.1007/s10620-010-1416-x.

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26

Neut, R. van der, A. S. Cachaco, S. Thorsteinsdottir, H. Janssen, D. Prins, J. Bulthuis, M. van der Valk, J. Calafat, and A. Sonnenberg. "Partial rescue of epithelial phenotype in integrin beta4 null mice by a keratin-5 promoter driven human integrin beta4 transgene." Journal of Cell Science 112, no. 22 (November 15, 1999): 3911–22. http://dx.doi.org/10.1242/jcs.112.22.3911.

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Integrin beta4 null mice exhibit extensive epidermal detachment, reminiscent of the human skin blistering disease junctional epidermolysis bullosa associated with pyloric atresia. Hemidesmosomes, the stable adhesion structures of squamous epithelia, are not formed in the absence of alpha6beta4. Null mutant mice die shortly after birth, but apart from their striking epithelial phenotype, no obvious developmental defects have been observed. To elucidate the cause of death in these mice, we generated transgenic mice with a heterologous construct consisting of the squamous epithelial-specific keratin-5 promoter and a human integrin beta4 subunit cDNA. The transgene was not expressed in the presence of endogenous beta4, probably as a result of competition for a limited pool of alpha6 subunits. In a beta4 null background, however, the transgene was expressed, and its expression pattern followed that of squamous epithelial-specific keratins. These rescued pups appeared healthy and ultrastructural analysis revealed that the interspecies heterodimer alpha6(mouse)/beta4(human) was sufficient to trigger the assembly of hemidesmosomes. After a variable period of up to 48 hours after birth these animals began to exhibit haemorrhages at the plantar and palmar areas. We observed the formation of small blisters and found that the transgene was not detectably expressed in this region, which is devoid of hair follicles. The rescued neonates became increasingly cyanotic and died soon after the onset of this phenomenon. We performed a developmental study of the expression of beta4 in the complete respiratory tract, but we found no correlation between the spatiotemporal distribution of beta4 and the onset of the respiratory insufficiency. It became clear, however, that there was a gradual detachment of squamous epithelia in the oral and nasal cavities which led to obstruction of the respiratory tract, suggesting that in beta4 null and rescued mice, neonatal death was a direct consequence of decreased adhesion properties of hairless squamous epithelia, rather than a developmental defect of the lungs.

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Bouvard, Claire, Adèle de Arcangelis, Blandine Dizier, Isabelle Galy-Fauroux, Anne-Marie Fischer, Elisabeth Georges Labouesse, and Dominique Helley. "Conditional ablation of alpha6 integrin subunit in mouse endothelium reduces post-ischemic angiogenesis." Vascular Pharmacology 56, no. 5-6 (May 2012): 308–9. http://dx.doi.org/10.1016/j.vph.2011.08.011.

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Krengel, Sven, Imke Stark, Christian Geuchen, Bettina Knoppe, Gabriele Scheel, Peter Schlenke, Andreas Gebert, Lutz Wunsch, Jurgen Brinckmann, and Michael Tronnier. "Selective down-regulation of the alpha6-integrin subunit in melanocytes by UVB light." Experimental Dermatology 14, no. 6 (June 2005): 411–19. http://dx.doi.org/10.1111/j.0906-6705.2005.00295.x.

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DiPersio, C. M., R. van der Neut, E. Georges-Labouesse, J. A. Kreidberg, A. Sonnenberg, and R. O. Hynes. "alpha3beta1 and alpha6beta4 integrin receptors for laminin-5 are not essential for epidermal morphogenesis and homeostasis during skin development." Journal of Cell Science 113, no. 17 (September 1, 2000): 3051–62. http://dx.doi.org/10.1242/jcs.113.17.3051.

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Continuous regeneration and homeostasis of the stratified epidermis requires coordinated regulation of cell proliferation, cell differentiation, and cell survival. Integrin-mediated cell adhesion to the extracellular matrix has important roles in regulating each of these processes. Integrins alpha3beta1 and alpha6beta4 are both receptors on epidermal keratinocytes for the basement membrane protein laminin-5, the major ligand for epidermal adhesion in mature skin. Ablation in mice of either alpha3beta1 or alpha6beta4, through null mutation of the gene encoding the alpha3, alpha6, or beta4 integrin subunit, results in epidermal blistering of varying severity. Our previous studies showed that, despite blistering, differentiation and stratification of the epidermis appeared essentially normal in mice that lacked either alpha3beta1 or alpha6beta4. However, these studies did not definitively address the specific developmental importance of each integrin, since they may have overlapping and/or compensatory functions. Given the individual importance of alpha3beta1 or alpha6beta4 in maintaining the dermo-epidermal junction in mature skin, we sought to determine the importance of these integrins for embryonic skin development and epidermal morphogenesis. In the current study, we analyzed skin development in mutant embryos that completely lack both integrins alpha3beta1 and alpha6beta4. Although alpha3beta1/alpha6beta4-deficient embryos displayed epidermal blistering by stage E15.5 of development, they also retained regions of extensive epidermal adhesion to the basement membrane through stage E16.5, indicating alternative adhesion mechanisms. Apoptosis was induced in detached epidermis of alpha3beta1/alpha6beta4-deficient embryos, exemplifying vividly the importance of epithelial attachment to the basement membrane for cell survival. However, apoptotic cells were completely absent from attached epidermis of alpha3beta1/alpha6beta4-deficient embryos, showing that epithelial adhesion that occurred independently of alpha3beta1 and alpha6beta4 also protected cells from apoptosis. Remarkably, in the absence of the known laminin-5 binding integrins (alpha3beta1, alpha6beta4, and alpha6beta1), keratinocytes retained the capacity to proliferate in the epidermis, and epidermal stratification and skin morphogenesis appeared normal prior to blister formation. These findings show that while alpha3beta1 and alpha6beta4 are both required for integrity of the dermo-epidermal junction, neither one is essential for epidermal morphogenesis during skin development.

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KOWALSKI-CHAUVEL, Aline, Valerie GOUAZE-ANDERSSON, Laurent BARICAULT, Elodie MARTIN, Caroline DELMAS, Christine TOULAS, Elizabeth COHEN-JONATHAN-MOYAL, and Catherine SEVA. "Alpha6-Integrin Regulates FGFR1 Expression through the ZEB1/YAP1 Transcription Complex in Glioblastoma Stem Cells Resulting in Enhanced Proliferation and Stemness." Cancers 11, no. 3 (March 22, 2019): 406. http://dx.doi.org/10.3390/cancers11030406.

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Glioblastoma (GBM) is the most lethal primary brain tumor in adults and is known to be particularly aggressive and resistant to anti-cancer therapies, mainly due to the presence of GBM stem cells (GBMSC). By in vitro approaches supported by analysis from patients’ databases, we determined how α6-integrin and Fibroblast Growth Factor Receptor 1 (FGFR1) work in concert to regulate proliferation and stemness of GBMSC. We showed that α6-integrin regulates the expression of FGFR1 and its target gene Fokhead Box M1 (FOXM1) via the ZEB1/YAP1 transcription complex. These results were in accordance with the positive correlation observed in GBM between α6-integrin expression and its target genes ZEB1/YAP1, FGFR1, and FOXM1 in the databases, TCGA and Rembrandt. In addition, the clinical data demonstrate that GBM patients with high levels of the five genes signature, including α6-integrin, ZEB1/YAP1, FGFR1 and FOXM1, have a significantly shorter overall survival. In vitro, we observed a similar decrease in the expression of stemness-related factors, neurospheres forming capacity, as well as spheroids growth when α6-integrin or FGFR1 was blocked individually with specific siRNA, whereas the combination of both siRNA led to a significantly higher inhibition of spheres formation. These data suggest that co-administration of anti-FGFR1 and anti-α6-integrin could provide an improved therapeutic response in GBMSC.

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Jensen, U. B., S. Lowell, and F. M. Watt. "The spatial relationship between stem cells and their progeny in the basal layer of human epidermis: a new view based on whole-mount labelling and lineage analysis." Development 126, no. 11 (June 1, 1999): 2409–18. http://dx.doi.org/10.1242/dev.126.11.2409.

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In order to examine the spatial organisation of stem cells and their progeny in human epidermis, we developed a method for whole-mount epidermal immunofluorescence labelling using high surface beta1 integrin expression as a stem cell marker. We confirmed that there are clusters of high beta1 integrin-expressing cells at the tips of the dermal papillae in epidermis from several body sites, whereas alpha6 integrin expression is more uniform. The majority of actively cycling cells detected by Ki67 or bromodeoxyuridine labelling were found in the beta1 integrin-dull, transit amplifying population and integrin-negative, keratin 10-positive cells left the basal layer exclusively from this compartment. When we examined p53-positive clones in sun-exposed epidermis, we found two types of clone that differed in size and position in a way that was consistent with the founder cell being a stem or transit amplifying cell. The patterning of the basal layer implies that transit amplifying cells migrate over the basement membrane away from the stem cell clusters. In support of this, isolated beta1 integrin-dull keratinocytes were more motile on type IV collagen than beta1 integrin-bright keratinocytes and EGFP-labelled stem cell clones in confluent cultured sheets were compact, whereas transit amplifying clones were dispersed. The combination of whole-mount labelling and lineage marking thus reveals features of epidermal organisation that were previously unrecognised.

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Ruzzi, L., L. Gagnoux-Palacios, M. Pinola, S. Belli, G. Meneguzzi, M. D'Alessio, and G. Zambruno. "A homozygous mutation in the integrin alpha6 gene in junctional epidermolysis bullosa with pyloric atresia." Journal of Clinical Investigation 99, no. 12 (June 15, 1997): 2826–31. http://dx.doi.org/10.1172/jci119474.

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Abesamis, Kim Ivan A., Camille S. Bagoyo, and Neil Andrew D. Bascos. "Investigating the Effect of a Non-Conservative Mutation (G273D) on Integrin Alpha6-Beta4 Binding Interactions." Biophysical Journal 120, no. 3 (February 2021): 267a. http://dx.doi.org/10.1016/j.bpj.2020.11.1709.

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Wu, Xin Yi, K. K. H. Svoboda, and V. Trinkaus-Randall. "Distribution of F-actin, vinculin and integrin subunits (alpha6 and beta4) in response to corneal substrata." Experimental Eye Research 60, no. 4 (April 1995): 445–58. http://dx.doi.org/10.1016/s0014-4835(05)80101-0.

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Wang, Yanfang, Sylvia Shenouda, Somesh Baranwal, Rajamani Rathinam, Prachi Jain, Lili Bao, Siddhartha Hazari, Srikanta Dash, and Suresh K. Alahari. "Integrin subunits alpha5 and alpha6 regulate cell cycle by modulating the chk1 and Rb/E2F pathways to affect breast cancer metastasis." Molecular Cancer 10, no. 1 (2011): 84. http://dx.doi.org/10.1186/1476-4598-10-84.

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Ambrose, Helen E., and Simon D. Wagner. "alpha6-Integrin is expressed on germinal centre B cells and modifies growth of a B-cell line." Immunology 111, no. 4 (April 2004): 400–406. http://dx.doi.org/10.1111/j.1365-2567.2004.01824.x.

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Szony, B. J. "Interleukin-10 receptors are expressed by basement membrane anchored, alpha6 integrin+ cytotrophoblast cells in early human placenta." Molecular Human Reproduction 5, no. 11 (November 1, 1999): 1059–65. http://dx.doi.org/10.1093/molehr/5.11.1059.

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Nigam, S., C. E. Weston, C. H. Liu, and E. E. Simon. "The actin cytoskeleton and integrin expression in the recovery of cell adhesion after oxidant stress to a proximal tubule cell line (JTC-12)." Journal of the American Society of Nephrology 9, no. 10 (October 1998): 1787–97. http://dx.doi.org/10.1681/asn.v9101787.

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This study examines the role of the actin cytoskeleton and integrin expression in the recovery of cell adhesion in the proximal tubule cell line JTC-12 after peroxide injury. The cells were exposed to 10, 20, or 50 mM hydrogen peroxide for 10 min and then allowed to recover. Viability measurements by trypan blue exclusion confirmed that the injury was largely nonlethal with 85% viability at 1 h even at 50 mM peroxide. ATP levels fell immediately after the peroxide incubation in all groups to approximately 10% of normal, but already showed some recovery by 1 h and full recovery in the 10 and 20 mM groups by 24 h. Cell adhesion to extracellular matrix immediately after injury was depressed at 20 and 50 mM peroxide, but by 12 h was abnormal only at 50 mM peroxide and at 24 h was essentially normal at all peroxide concentrations. Immediately after exposure to 10 mM peroxide, there were subtle abnormalities in the actin cytoskeleton (thickening of fibrils) as assessed by phalloidin staining, with more pronounced effects at 20 and 50 mM. At 1 h, many cells showed collapse of the actin cytoskeleton to the periphery. There was some recovery at 4 h; by 12 h, the actin cytoskeleton showed further recovery, although was still abnormal (coarsened microfilaments), especially at 20 and 50 mM peroxide. By 24 h, the actin cytoskeleton showed only subtle coarsening. Integrin surface expression was assessed by flow cytometry. The alpha6 subunit on cells exposed to 20 mM peroxide was unchanged at 1 h and 4 h, but by 12 h had increased to 118.5+/-4.5% and by 24 h to 146+/-13.4% of control levels. The expression of the beta1 and alphaVbeta3 integrins remained unchanged. Thus, despite coarsening of the actin cytoskeleton and depressed ATP levels, cell adhesion recovered from oxidant stress. Abnormal cell adhesion after injury was not a consequence of a decrease in integrin expression, and recovery of cell adhesion was not a consequence of the modest and selective increase in integrin expression.

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Deugnier, M. A., M. M. Faraldo, P. Rousselle, J. P. Thiery, and M. A. Glukhova. "Cell-extracellular matrix interactions and EGF are important regulators of the basal mammary epithelial cell phenotype." Journal of Cell Science 112, no. 7 (April 1, 1999): 1035–44. http://dx.doi.org/10.1242/jcs.112.7.1035.

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The mammary epithelium is composed of a luminal epithelium and a basal layer containing myoepithelial cells and undifferentiated precursors. Basal cells express specific protein markers, such as keratin 14 (K14) and P-cadherin. To study the factors that regulate the basal mammary epithelial cell phenotype, we have established two clonal derivatives of the mouse HC11 cell line, BC20 and BC44, expressing high levels of K14 and P-cadherin. Unlike the parental HC11 cells, these basal cells did not produce beta-casein in response to lactogenic hormone treatment; however their phenotype appeared to be plastic. Cultured in EGF-free medium, they exhibited enhanced cell-extracellular matrix adhesions and deficient cell-cell junctions, whereas long-term treatment with EGF induced a decrease of focal contact number and establishment of cell-cell junctions, resulting in downregulation of K14 and P-cadherin expression at the protein and mRNA levels. To determine whether cell-extracellular matrix interactions mediated by integrins have a role in the regulation of the expression of K14 and P-cadherin, the amounts of transcripts for the two proteins were analysed in the basal cells, which were plated on the function-blocking antibodies against beta1 and alpha6 integrin chains, on fibronectin and on laminin 5. The amount of P-cadherin transcript was 2- to 4-fold higher in cells plated on the function-blocking anti-integrin antibodies and on the extracellular matrix proteins, as compared to cells plated on poly-L-lysine, whereas the K14 transcript levels were not significantly modified in response to adhesion. The data demonstrate that integrin-mediated cell interaction with extracellular matrix is directly implicated in the control of P-cadherin expression, and that EGF and cell-extracellular matrix adhesion events are important regulators of the basal mammary epithelial cell phenotype.

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Pons, S., J. L. Trejo, J. R. Martinez-Morales, and E. Marti. "Vitronectin regulates Sonic hedgehog activity during cerebellum development through CREB phosphorylation." Development 128, no. 9 (May 1, 2001): 1481–92. http://dx.doi.org/10.1242/dev.128.9.1481.

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During development of the cerebellum, Sonic hedgehog (SHH) is expressed in migrating and settled Purkinje neurons and is directly responsible for proliferation of granule cell precursors in the external germinal layer. We have previously demonstrated that SHH interacts with vitronectin in the differentiation of spinal motor neurons. Here, we analysed whether similar interactions between SHH and extracellular matrix glycoproteins regulate subsequent steps of granule cell development. Laminins and their integrin receptor subunit alpha6 accumulate in the outer most external germinal layer where proliferation of granule cell precursors is maximal. Consistent with this expression pattern, laminin significantly increases SHH-induced proliferation in primary cultures of cerebellar granule cells. Vitronectin and its integrin receptor subunits alpha(v) are expressed in the inner part of the external germinal layer where granule cell precursors exit the cell cycle and commence differentiation. In cultures, vitronectin is able to overcome SHH-induced proliferation, thus allowing granule cell differentiation. Our studies indicate that the pathway in granule cell precursors responsible for the conversion of a proliferative SHH-mediated response to a differentiation signal depends on CREB. Vitronectin stimulates phosphorylation of cyclic-AMP responsive element-binding protein (CREB), and over-expression of CREB is sufficient to induce granule cell differentiation in the presence of SHH. Taken together, these data suggest that granule neuron differentiation is regulated by the vitronectin-induced phosphorylation of CREB, a critical event that terminates SHH-mediated proliferation and permits the differentiation program to proceed in these cells.

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Melker, Anneinieke A., and Arnoud Sonnenberg. "The Role of the Cytoplasmic Domain of alpha6 Integrin in the Assembly and Function of alpha6beta1 and alpha6beta4." European Journal of Biochemistry 241, no. 1 (October 1996): 254–64. http://dx.doi.org/10.1111/j.1432-1033.1996.0254t.x.

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Buck, V. U., M. T. Kohlen, A. K. Sternberg, B. Rösing, J. Neulen, R. E. Leube, and I. Classen-Linke. "Steroid hormones and human choriogonadotropin influence the distribution of alpha6-integrin and desmoplakin 1 in gland-like endometrial epithelial spheroids." Histochemistry and Cell Biology 155, no. 5 (January 27, 2021): 581–91. http://dx.doi.org/10.1007/s00418-020-01960-z.

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AbstractIn human glandular endometrial epithelial cells, desmosomal and adherens junction proteins have been shown to extend from a subapically restricted lateral position to the entire lateral membrane during the implantation window of the menstrual cycle. Similarly, a menstrual cycle stage-dependent redistribution of the extracellular matrix adhesion protein α6-integrin has been reported. These changes are believed to be important for endometrial receptiveness and successful embryo implantation. To prove the hypothesis that steroid hormones and human choriogonadotropin can induce the redistribution of these adhesion molecules, we used the human endometrial cell line Ishikawa in a 3D culture system. Gland-like spheroids were grown in reconstituted basement membrane (Matrigel™). The lumen-bearing spheroids were treated for 2 or 4 days with ovarian steroids or human choriogonadotropin and then assessed by immunofluorescence microscopy. In addition, human endometrial biopsies were obtained from patients, who were in therapy for assisted reproductive technology, and were examined in parallel. Lateral redistribution of the desmosomal plaque protein desmoplakin 1 was observed in the spheroids treated either with progesterone, medroxyprogesterone acetate or human choriogonadotropin. Furthermore, the extracellular matrix adhesion protein α6-integrin showed an increased lateral membrane localization upon gestagen stimulation in the 3D culture system. The results of this study demonstrate that the 3D endometrial Ishikawa cell culture might be suited as an experimental model system to prove the effect of hormonal changes like those occurring during the window of implantation.

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Nummela, P., M. Kielosto, K. Ravanko, K. Järvinen, M. Yin, and E. Hölttä. "433 Up-regulation of thymosin beta4, integrin alpha6, and cathepsin L is critical for the high invasiveness of fibrosarcoma cells." European Journal of Cancer Supplements 8, no. 5 (June 2010): 111. http://dx.doi.org/10.1016/s1359-6349(10)71234-9.

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Stanton, H., J. Gavrilovic, S. J. Atkinson, M. P. d'Ortho, K. M. Yamada, L. Zardi, and G. Murphy. "The activation of ProMMP-2 (gelatinase A) by HT1080 fibrosarcoma cells is promoted by culture on a fibronectin substrate and is concomitant with an increase in processing of MT1-MMP (MMP-14) to a 45 kDa form." Journal of Cell Science 111, no. 18 (September 15, 1998): 2789–98. http://dx.doi.org/10.1242/jcs.111.18.2789.

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We have assessed the effect of fibronectin and laminin-1 on the expression of molecules involved in the activation pathway of MMP-2, a key proteinase in tissue remodelling. HT1080 fibrosarcoma cells cultured on fibronectin were shown to activate endogenous MMP-2, to a level comparable with that elicited by treatment with phorbol ester. In contrast, the MMP-2 expressed by HT1080 cells cultured on laminin-1 was mainly in the pro- (inactive form). Culture of the cells on peptide fragments of fibronectin derived from the central cell binding domain also promoted MMP-2 activation, indicating that signals via fibronectin binding to integrin receptors may be involved. HT1080 cells cultured on immobilised antibodies to the alpha5 and beta1 integrin subunits secreted levels of active MMP-2 similar to those observed for full length fibronectin, whereas cells cultured on an antibody to the alpha6 integrin subunit secreted mainly proMMP-2. The data demonstrate that the activation of MMP-2 by HT1080 cells is regulated by the nature of the extracellular matrix, and that signals via the alpha5beta1 integrin receptor may be involved in the fibronectin induced up-regulation of MMP-2 activation. We then assessed the effect of fibronectin on the components of the putative MT1-MMP/TIMP-2 ‘receptor’ complex implicated in MMP-2 activation. Levels of TIMP-2 protein expressed by HT1080 cells did not vary detectably between cells cultured on fibronectin or laminin-1. However, the expression of MT1-MMP protein was up-regulated when the cells were cultured on fibronectin, which could be attributed to an increase in levels of a truncated 45 kDa form. Parallel studies using gelatin zymography demonstrated that the up-regulation of the production of the 45 kDa band was concomitant with MMP-2 activation. Inhibitor studies revealed that the truncation of MT1-MMP to a 45 kDa form is MMP mediated, although not inhibited by TIMP-1. In vitro, the 45 kDa form could be generated by cleavage of membrane-bound native MT1-MMP with several recombinant MMPs, including both active MT1-MMP and MMP-2. The implication that either MMP-2 or MT1-MMP can process MT1-MMP to 45 kDa, raises the possibility that truncation of MT1-MMP represents a self-regulatory end-point in the activation pathway of MMP-2.

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Pilling, Galvin, Robins, Sewell, and Mahida. "Expression of alpha5 (CD49e) and alpha6 (CD49f) Integrin Subunits on T Cells in the Circulation and the Lamina Propria of Normal and Inflammatory Bowel Disease Colonic Mucosa." Scandinavian Journal of Immunology 48, no. 4 (October 1998): 425–28. http://dx.doi.org/10.1046/j.1365-3083.1998.00424.x.

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Landi, I. "The alpha6 beta1 integrin is necessary for the matrix-dependent activation of FAK and MAP kinase and the migration of hepatocarcinoma cells." Journal of Hepatology 34 (April 2001): 89. http://dx.doi.org/10.1016/s0168-8278(01)80316-0.

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Landi, I., A. Mazzocca, and V. Carloni. "The alpha6 beta1 integrin is necessary for the matrix-dependent activation of FAK and MAP kinase and the migration of hepatocarcinoma cells." Journal of Hepatology 34 (April 2001): 89. http://dx.doi.org/10.1016/s0168-8278(01)81191-0.

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48

Laidler, P., D. Gil, A. Pituch-Noworolska, D. Ciołczyk, D. Ksiazek, M. Przybyło, and A. Lityńska. "Expression of beta1-integrins and N-cadherin in bladder cancer and melanoma cell lines." Acta Biochimica Polonica 47, no. 4 (December 31, 2000): 1159–70. http://dx.doi.org/10.18388/abp.2000_3968.

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Changes in the expression of integrins and cadherins might contribute to the progression, invasion and metastasis of transitional cell cancer of the bladder and of melanomas. The expression of alpha5 (P < 0.001), alpha2 and beta1 (P < 0.05 - P < 0.001) integrin subunits in melanoma cells from noncutaneous metastatic sites (WM9, A375) were significantly increased as compared to cutaneous primary tumor (WM35) and metastatic (WM239) cell lines. These differences might be ascribed to the invasive character of melanoma cells and their metastasis to the noncutaneous locations. The significantly heterogeneous expression of beta1 integrin subunit in two malignant bladder cancer cell lines (T24 and Hu456) and nonsignificant differences in the expression of alpha2, alpha3, and alpha5 subunits between malignant and non-malignant human bladder cell lines do not allow an unanimous conclusion on the role of these intergrin subunits in the progression of transitional cancer of bladder. The adhesion molecule, expressed in all studied melanoma and bladder cell lines, that reacted with anti-Pan cadherin monoclonal antibodies was identified as N-cadherin except in the HCV29 non-malignant ureter cell line. However, neither this nor any other bladder or melanoma cell line expressed E-cadherin. The obtained results imply that the replacement of E-cadherin by N-cadherin accompanied by a simultaneous increase in expression of alpha2, alpha3 and alpha5 integrin subunits clearly indicates an increase of invasiveness of melanoma and, to a lesser extent, of transitional cell cancer of bladder. High expression of N-cadherin and alpha5 integrin subunit seems to be associated with the most invasive melanoma phenotype.

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Morohoshi, Kazunori, Ryo Mochinaga, Tsukasa Watanabe, Ryojun Nakajima, and Toshio Harigaya. "16 kDa vasoinhibin binds to integrin alpha5 beta1 on endothelial cells to induce apoptosis." Endocrine Connections 7, no. 5 (May 2018): 630–36. http://dx.doi.org/10.1530/ec-18-0116.

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Many functions of vasoinhibins have been reported, but its receptor has not been clarified yet. Vasoinhibins, 11–18 kDa N-terminal fragments of prolactin, have anti-angiogenic activity and act on endothelial cells to induce apoptosis and to inhibit migration and proliferation, which are opposite to the effects of prolactin. Although vasoinhibins bind to the prolactin receptor, its binding activity is very weak compared to prolactin. Therefore, in this study, we evaluated the binding activity between 16 kDa vasoinhibin and integrin beta1, alpha5 beta1, alpha1 beta1 and alphaV beta3 to identify a specific receptor for vasoinhibins. Moreover, we examined whether 16 kDa vasoinhibin induced apoptosis through integrin beta1 and alpha5 beta1 in endothelial cells. In this study, binding assays and co-immunoprecipitation experiments demonstrated that 16 kDa vasoinhibin could bind strongly to integrin beta1 and alpha5 beta1. Moreover, neutralizing with integrin beta1 and alpha5 beta1 antibody could inhibit 16 kDa vasoinhibin-induced apoptosis in endothelial cells. These findings suggest that vasoinhibins can act on endothelial cells through integrin alpha5 beta1 to induce apoptosis.

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Wada, J., A. Kumar, Z. Liu, E. Ruoslahti, L. Reichardt, J. Marvaldi, and Y. S. Kanwar. "Cloning of mouse integrin alphaV cDNA and role of the alphaV-related matrix receptors in metanephric development." Journal of Cell Biology 132, no. 6 (March 15, 1996): 1161–76. http://dx.doi.org/10.1083/jcb.132.6.1161.

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Metanephrogenesis has been a long-standing model to study cell-matrix interactions. A number of adhesion molecules, including matrix receptors (i.e., integrins), are believed to be involved in such interactions. The integrins contain alpha and beta s ubunits and are present in various tissues in different heterodimeric forms. In this study, one of the members of the integrin superfamily, alphaV, was characterized, and its relevance in murine nephrogenesis was investigated. Mouse embryonic renal cDNA libraries were prepared and screened for alphaV, and multiple clones were isolated and sequenced. The deduced amino acid sequence of the alpha-v cDNA clones and hydropathic analysis revealed that it has a typical signal sequence and extracellular, transmembrane, and cytoplasmic domains, with multiple Ca2+ binding sites. No A(U)nA mRNA instability motifs were present. Conformational analysis revealed no rigid long-range-ordered structure in murine alphaV. The alphaV was expressed in the embryonic kidney at day 13 of the gestation, with a transcript size of approximately 7 kb. Its expression increased progressively during the later gestational stages and in the neonatal period. It was distributed in the epithelial elements of developing nephrons and was absent in the uninduced mesenchyme. In mature metanephroi, the expression was relatively high in the glomeruli and blood vessels, as compared to the tubules. Various heterodimeric associations of alphaV, i.e., with beta1, beta3, beta5, and beta6, were observed in metanephric tissues. Inclusion of alphaV-antisense-oligodeoxynucleotide or -antibody in metanephric culture induced dysmorphogenesis of the kidney with reduced population of the nephrons, disorganization of the ureteric bud branches, and reduction of mRNA and protein expressions of alphaV. The expressions of integrin beta3, beta5, and beta6 were unaltered. These findings suggest that the integrin alphaV is developmentally regulated, has a distinct spatio-temporal expression, and is relevant in the mammalian organogenesis.

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Journal articles on the topic 'Integrin alpha6'

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