Journal articles: 'Integrin alpha6beta4'

1

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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2

Mainiero, F., A. Pepe, M. Yeon, Y. Ren, and F. G. Giancotti. "The intracellular functions of alpha6beta4 integrin are regulated by EGF." Journal of Cell Biology 134, no. 1 (July 1, 1996): 241–53. http://dx.doi.org/10.1083/jcb.134.1.241.

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Upon ligand binding, the alpha6beta4 integrin becomes phosphorylated on tyrosine residues and combines sequentially with the adaptor molecules Shc and Grb2, linking to the ras pathway, and with cytoskeletal elements of hemidesmosomes. Since alpha6beta4 is expressed in a variety of tissues regulated by the EGF receptor (EGFR), we have examined the effect of EGF on the cytoskeletal and signaling functions of alpha6beta4. Experiments of immunoblotting with anti-phosphotyrosine antibodies and immunoprecipitation followed by phosphoamino acid analysis and phosphopeptide mapping showed that activation of the EGFR causes phosphorylation of the beta4 subunit at multiple tyrosine residues, and this event requires ligation of the integrin by laminins or specific antibodies. Immunoprecipitation experiments indicated that stimulation with EGF does not result in association of alpha6beta4 with Shc. In contrast, EGF can partially suppress the recruitment of Shc to ligated alpha6beta4. Immunofluorescent analysis revealed that EGF treatment does not induce increased assembly of hemidesmosomes, but instead causes a deterioration of these adhesive structures. Finally, Boyden chamber assays indicated that exposure to EGF results in upregulation of alpha6beta4-mediated cell migration toward laminins. We conclude that EGF-dependent signals suppress the association of activated alpha6beta4 with both signaling and cytoskeletal molecules, but upregulate alpha6beta4-dependent cell migration. The changes in alpha6beta4 function induced by EGF may play a role during wound healing and tumorigenesis.

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3

Homan, S. M., A. M. Mercurio, and S. E. LaFlamme. "Endothelial cells assemble two distinct alpha6beta4-containing vimentin-associated structures: roles for ligand binding and the beta4 cytoplasmic tail." Journal of Cell Science 111, no. 18 (September 15, 1998): 2717–28. http://dx.doi.org/10.1242/jcs.111.18.2717.

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The alpha6beta4 laminin binding integrin functions in the assembly of type I hemidesmosomes, which are specialized cell-matrix adhesion sites found in stratified epithelial cells. Although endothelial cells do not express all the components of type I hemidesmosomes, endothelial cells can express the alpha6beta4 integrin. Because endothelial cells lose expression of alpha6beta4 in culture, we expressed recombinant alpha6beta4 in the dermal microvascular endothelial cell line, HMEC-1, to test whether endothelial cells can assemble adhesion structures containing alpha6beta4. Using immunofluorescence microscopy, we found that recombinant alpha6beta4 concentrates specifically in a novel fibrillar structure on the basal surface of endothelial cells in the absence of an exogenous laminin substrate. This localization is regulated by an intracellular mechanism, because the beta4 cytoplasmic domain is sufficient to direct a reporter domain (IL-2R) to the fibrillar structures independently of recombinant alpha6beta4. In addition, this IL-2R-beta4 chimera is sufficient to recruit the intermediate filament-associated protein HD1/plectin to these fibrillar structures and this also occurs in the absence of recombinant alpha6beta4. The fibrillar localization pattern, as well as the recruitment of HD1/plectin, requires the first and second fibronectin type III repeats and the connecting segment of the beta4 tail. In addition, when endothelial cells are provided a laminin 5-rich matrix, recombinant alpha6beta4 redistributes from the fibrillar structure to type I hemidesmosome-like structures. The beta4 cytoplasmic domain can also direct a reporter domain to these type I hemidesmosome-like structures; however, this process is dependent upon the expression of recombinant alpha6beta4 Biochemical analysis indicates that both the fibrillar and the type I hemidesmosome-like structures are associated with the vimentin intermediate filament cytoskeleton. Thus, the results illustrate that endothelial cells have the essential components necessary to assemble at least two distinct alpha6beta4-containing and vimentin-associated structures on their basal surface and that the alpha6beta4 cytoplasmic tail and the availability of specific alph6beta4 ligands regulate receptor localization to these structures.

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4

Xia, Y., S. G. Gil, and W. G. Carter. "Anchorage mediated by integrin alpha6beta4 to laminin 5 (epiligrin) regulates tyrosine phosphorylation of a membrane-associated 80-kD protein." Journal of Cell Biology 132, no. 4 (February 15, 1996): 727–40. http://dx.doi.org/10.1083/jcb.132.4.727.

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Detachment of basal keratinocytes from basement membrane signals a differentiation cascade. Two integrin receptors alpha6beta4 and alpha3beta1 mediate adhesion to laminin 5 (epiligrin), a major extracellular matrix protein in the basement membrane of epidermis. By establishing a low temperature adhesion system at 4 degrees C, we were able to examine the exclusive role of alpha6beta4 in adhesion of human foreskin keratinocyte (HFK) and the colon carcinoma cell LS123. We identified a novel 80-kD membrane-associated protein (p80) that is tyrosine phosphorylated in response to dissociation of alpha6beta4 from laminin 5. The specificity of p80 phosphorylation for laminin 5 and alpha6beta4 was illustrated by the lack of regulation of p80 phosphorylation on collagen, fibronectin, or poly-L-lysine surfaces. We showed that blocking of alpha3beta1 function using inhibitory mAbs, low temperature, or cytochalasin D diminished tyrosine phosphorylation of focal adhesion kinase but not p80 phosphorylation. Therefore, under our assay conditions, p80 phosphorylation is regulated by alpha6beta4, while motility via alpha3beta1 causes phosphorylation of focal adhesion kinase. Consistent with a linkage between p80 dephosphorylation and alpha6beta4 anchorage to laminin 5, we found that phosphatase inhibitor sodium vanadate, which blocked the p80 dephosphorylation, prevented the alpha6beta4-dependent cell anchorage to laminin 5 at 4degreesC. In contrast, adhesion at 37 degrees C via alpha3beta1 was unaffected. Furthermore, by in vitro kinase assay, we identified a kinase activity for p80 phosphorylation in suspended HFKs but not in attached cells. The kinase activity, alpha6beta4, and its associated adhesion structure stable anchoring contacts were all cofractionated in the Triton-insoluble cell fraction that lacks alpha3beta1. Thus, regulation of p80 phosphorylation, through the activities of p80 kinase and phosphatase, correlates with alpha6beta4-SAC anchorage to laminin 5 at 4 degrees C in epithelial cells of the skin and intestine. Transmembrane signaling through p80 is an early tyrosine phosphorylation event responsive to and possibly required for anchorage to laminin 5 by HFK and LS123 epithelial cells.

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5

Orian-Rousseau, V., D. Aberdam, P. Rousselle, A. Messent, J. Gavrilovic, G. Meneguzzi, M. Kedinger, and P. Simon-Assmann. "Human colonic cancer cells synthesize and adhere to laminin-5. Their adhesion to laminin-5 involves multiple receptors among which is integrin alpha2beta1." Journal of Cell Science 111, no. 14 (July 30, 1998): 1993–2004. http://dx.doi.org/10.1242/jcs.111.14.1993.

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In the mature gut, laminin-5 is expressed at the basal aspect of the differentiating epithelial cells. In vitro, we show that three more or less differentiated human colonic cancer HT29 cell lines produce and deposit laminin-5; they predominantly synthesize and secrete the 440 kDa form of laminin-5 that comprises the unprocessed 155 kDa gamma2 chain, as determined by immunoprecipitation analysis. In contrast, the highly differentiated colon carcinoma Caco-2 cells produce almost no laminin-5. Using anti-integrin antibodies, we show that adhesion of the two colonic cancer cell lines to laminin-5 is mediated by multiple integrin receptors including those for alpha3beta1, alpha6beta1 and alpha6beta4 integrins like in other cell types. In addition, the implication of integrin alpha2beta1 in this adhesion process is demonstrated for the first time. This has been shown by cell adhesion inhibition experiments, solid phase assays and confocal analysis. Together with previous in situ observations, these data provide a baseline knowledge for the understanding of the regulation of laminin-5 in normal and pathological intestine.

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6

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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7

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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8

Ashton, G. H. S., P. Sorelli, J. E. Mellerio, F. M. Keane, R. A. J. Eady, and J. A. Mcgrath. "alpha6beta4 integrin abnormalities in junctional epidermolysis bullosa with pyloric atresia." British Journal of Dermatology 144, no. 2 (February 2001): 408–14. http://dx.doi.org/10.1046/j.1365-2133.2001.04038.x.

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9

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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10

Goldfinger, L. E., S. B. Hopkinson, G. W. deHart, S. Collawn, J. R. Couchman, and J. C. Jones. "The alpha3 laminin subunit, alpha6beta4 and alpha3beta1 integrin coordinately regulate wound healing in cultured epithelial cells and in the skin." Journal of Cell Science 112, no. 16 (August 15, 1999): 2615–29. http://dx.doi.org/10.1242/jcs.112.16.2615.

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Previously, we demonstrated that proteolytic processing within the globular domain of the alpha3 subunit of laminin-5 (LN5) converts LN5 from a cell motility-inducing factor to a protein complex that can trigger the formation of hemidesmosomes, certain cell-matrix attachment sites found in epithelial cells. We have prepared a monoclonal antibody (12C4) whose epitope is located toward the carboxy terminus of the globular domain of the alpha3 laminin subunit. This epitope is lost from the alpha3 subunit as a consequence of proteolytic processing. Antibody 12C4 stains throughout the matrix of cells that fail to process the alpha3 laminin subunit, but does not recognize the matrix of confluent cultures of MCF-10A cells, which efficiently process their alpha3 laminin chain. In subconfluent populations of MCF-10A cells, 12C4 only stains matrix deposited at the outer edges of cell colonies. In these cells, integrin alpha3beta1 occasionally colocalizes with the staining generated by the 12C4 antibody but alpha6beta4 integrin does not. In wounded MCF-10A cell cultures, the 12C4 antibody stains the extracellular matrix beneath those cells at the very edge of the cellular sheet that moves to cover the wound site. A similar phenomenon is observed in human skin wounds, since we also detect expression of the unprocessed alpha3 laminin subunit at the leading tip of the sheet of epidermal cells that epithelializes skin wounds in vivo. In addition, using alpha3 laminin subunit and integrin function-inhibiting antibodies, we provide evidence that LN5 and its two integrin receptors (alpha6beta4 and alpha3beta1) appear necessary for wound healing to occur in MCF-10A cell culture wounds. We propose a model for healing of wounded epithelial tissues based on these results.

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11

Witkowski, C. M. "Altered surface expression and increased turnover of the alpha6beta4 integrin in an undifferentiated carcinoma." Carcinogenesis 21, no. 2 (February 1, 2000): 325–30. http://dx.doi.org/10.1093/carcin/21.2.325.

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12

Guaguere, E., K. Berg, F. Degorce-Rubiales, A. Spadafora, and G. Meneguzzi. "FC-26 Junctional epidermolysis bullosa in a Charolais calf with deficient expression of integrin alpha6beta4." Veterinary Dermatology 15, s1 (August 2004): 28. http://dx.doi.org/10.1111/j.1365-3164.2004.411_26.x.

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13

Koster, J. "Analysis of the interactions between BP180, BP230, plectin and the integrin alpha6beta4 important for hemidesmosome assembly." Journal of Cell Science 116, no. 2 (December 4, 2002): 387–99. http://dx.doi.org/10.1242/jcs.00241.

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14

Rigot, V., M. Lehmann, F. Andre, N. Daemi, J. Marvaldi, and J. Luis. "Integrin ligation and PKC activation are required for migration of colon carcinoma cells." Journal of Cell Science 111, no. 20 (October 15, 1998): 3119–27. http://dx.doi.org/10.1242/jcs.111.20.3119.

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The activation of protein kinases C (PKCs) is an essential step in integrin-dependent cell adhesion and spreading. In this report we examined the effect of the phorbol ester PMA, a PKC activator, on adhesion, spreading and migration of a colon carcinoma cell line, HT29-D4. Treatment with PMA increased the rate of cell spreading and induced the migration of these cells towards purified matrix proteins in haptotaxis assays on Boyden chambers. PMA-induced effects were the result of PKCs activation, as shown by using the inactive isomer 4alpha-PMA and PKCs inhibitors. The involvement of integrins in the phorbol ester-induced cell migration was demonstrated both by the absence of migration of cells plated on membranes coated with poly-L-lysine and by the use of function blocking antibodies. Thus, interactions between alpha 2beta1, alpha3beta1, alpha6beta4, alpha vbeta5, alphavbeta6 integrins and their specific ligands are necessary for the PKC-mediated migration. However, adhesion, immunoprecipitation and immunocytofluorometry experiments clearly showed that HT29-D4 cell haptotaxis induced by PKC activation is not a consequence of quantitative or qualitative changes in the cell surface integrins. We also demonstrated that PKCs were able to activate the MAP kinase pathway and that the impediment of MAP kinase activation resulted in the loss of cell migration. Moreover, stimulation of the insulin-like growth factor I signalling pathway led to MAP kinase activation and to the induction of cell migration. In addition, the growth factor-induced motility of HT29-D4 cells was affected both by PKC and MAP kinase cascade inhibitors. It thus appears that both integrin ligation and MAP kinase activation by PKCs are required to promote the migration of HT29-D4 cells.

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15

Thuma, Florian, Honoré Ngora, and Margot Zöller. "The metastasis-associated molecule C4.4A promotes tissue invasion and anchorage independence by associating with the alpha6beta4 integrin." Molecular Oncology 7, no. 5 (May 15, 2013): 917–28. http://dx.doi.org/10.1016/j.molonc.2013.05.002.

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16

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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17

Perrin, C., A. Pisani, M. Demarchez, J. F. Michiel, and J. P. Ortonne. "VLA and alpha6beta4 integrin expression in neuroendocrine carcinomas of the skin (their xenografts on nude mice and a corresponding primary culture)." Journal of Cutaneous Pathology 23, no. 3 (June 1996): 223–28. http://dx.doi.org/10.1111/j.1600-0560.1996.tb01470.x.

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18

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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19

Dogic, D., P. Rousselle, and M. Aumailley. "Cell adhesion to laminin 1 or 5 induces isoform-specific clustering of integrins and other focal adhesion components." Journal of Cell Science 111, no. 6 (March 15, 1998): 793–802. http://dx.doi.org/10.1242/jcs.111.6.793.

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Laminin 1 (alpha1beta1gamma1) and laminin 5 (alpha3beta3gamma2) induce cell adhesion with different involvement of integrins: both are ligands for the alpha6beta1 integrin, while alpha3beta1 integrin has affinity for laminin 5 only. These two laminin isoforms therefore provide good models to investigate whether alpha3beta1 and alpha6beta1 integrins play different roles in signal transduction and in focal adhesion formation. Laminin 1 or 5 induced adhesion of normal human skin fibroblasts to a similar extent but promoted different overall cell shapes. On laminin 1 the fibroblasts formed mainly filopodia-like structures, while on laminin 5 they developed lamellipodias. Staining of fibrillar actin with fluorescein-phalloidin revealed a similar organisation of the actin cytoskeleton on both substrates. However, integrin subunits and several cytoskeletal linker proteins, including vinculin, talin, and paxillin, showed an isoform-specific arrangement into focal adhesions. On laminin 1 they were recruited into thick and short aggregates localized at the termini of actin stress fibers, while on laminin 5 they appeared as dots or streaks clustered on a long portion of actin microfilaments. To test whether the differing affinity of laminin 1 or 5 for alpha3beta1 integrin would explain the formation of morphologically different focal adhesions, cells were seeded on laminin 1 under conditions in which alpha3beta1 integrins were occupied by a function-blocking antibody. This resulted in the formation of focal adhesions similar to that observed on laminin 5, where the integrin is occupied by its natural ligand. These results provide the first evidence for a cross-talk between alpha3beta1 and alpha6beta1 integrins and indicate that occupancy of alpha3beta1 integrins results in a trans-dominant regulation of alpha6beta1 integrin clustering and of focal adhesions. It suggests that recruitment of integrins and cytoskeletal linker proteins are laminin isoform-specific and that tissue specific expression of laminin isoforms might modulate cell behavior by the activation of distinct sets of integrins and by the induction of distinct molecular assemblies within the cell adhesion signaling complexes.

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Champliaud, M. F., G. P. Lunstrum, P. Rousselle, T. Nishiyama, D. R. Keene, and R. E. Burgeson. "Human amnion contains a novel laminin variant, laminin 7, which like laminin 6, covalently associates with laminin 5 to promote stable epithelial-stromal attachment." Journal of Cell Biology 132, no. 6 (March 15, 1996): 1189–98. http://dx.doi.org/10.1083/jcb.132.6.1189.

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Stable attachment of external epithelia to the basement membrane and underlying stroma is mediated by transmembrane proteins such as the integrin alpha6beta4 and bullous pemphigoid antigen 2 within the hemidesmosomes along the basolateral surface of the epithelial cell and their ligands that include a specialized subfamily of laminins. The laminin 5 molecule (previously termed kalinin/nicein/epiligrin) is a member of this epithelial-specific subfamily. Laminin 5 chains are not only considerably truncated within domains III-VI, but are also extensively proteolytically processed in vitro and in vivo. As a result, the domains expected to be required for the association of laminins with other basement membrane components are lacking in the mature laminin 5 molecule. Therefore, the tight binding of laminin 5 to the basement membrane may occur by a unique mechanism. To examine laminin 5 in tissue, we chose human amnion as the source, because of its availability and the similarity of the amniotic epithelial basement membrane with that of skin. We isolated the laminin 5 contained within the basement membrane of human amnion. In addition to monomeric laminin 5, we find that much of the laminin 5 isolated is covalently adducted with laminin 6 (alpha3beta1gamma1) and a novel laminin isotype we have termed laminin 7 (alpha3beta2gamma1). We propose that the association between laminin 5 and laminins 6 and 7 is a mechanism used in amnion to allow stable association of laminin 5 with the basement membrane. The beta2 chain is seen at the human amniotic epithelial-stromal interface and at the dermal-epidermal junction of fetal and adult bovine skin by immunofluorescence, but is not present, or only weakly present, in neonatal human skin.

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21

Barraud-Lange, Virginie, Nathalie Naud-Barriant, Line Saffar, Liliane Gattegno, Beatrice Ducot, Anne-Sophie Drillet, Morgane Bomsel, Jean-Philippe Wolf, and Ahmed Ziyyat. "Alpha6beta1 integrin expressed by sperm is determinant in mouse fertilization." BMC Developmental Biology 7, no. 1 (2007): 102. http://dx.doi.org/10.1186/1471-213x-7-102.

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22

Le Bellego, F., C. Pisselet, C. Huet, P. Monget, and D. Monniaux. "Laminin-alpha6beta1 integrin interaction enhances survival and proliferation and modulates steroidogenesis of ovine granulosa cells." Journal of Endocrinology 172, no. 1 (January 1, 2002): 45–59. http://dx.doi.org/10.1677/joe.0.1720045.

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This study aimed to determine the physiological role of laminin (LN) and its receptor, alpha(6)beta(1) integrin, in controlling the functions of granulosa cells (GC) during follicular development in sheep ovary. Immunohistochemistry experiments showed the presence of increasing levels of LN (P<0.0001), and high levels of mature alpha(6)beta(1) integrin in GC layers of healthy antral follicles during the follicular and the preovulatory phases of the estrous cycle. In vitro, the addition of a function-blocking antibody raised against alpha(6) subunit (anti-alpha(6) IgG) to the medium of ovine GC cultured on LN impaired cell spreading (P<0.0001), decreased the proliferation rate (P<0.05) and increased the apoptosis rate (P<0.05). Furthermore, addition of anti-alpha(6) IgG enhanced estradiol (E2) secretion by GC in the presence or absence of follicle-stimulating hormone (FSH), luteinizing hormone or insulin-like growth factor-I in culture medium (P<0.0001), and inhibited progesterone (P4) secretion in basal conditions or in the presence of low (0.5 ng/ml) FSH concentrations only (P<0.0001). The anti-alpha(6) IgG effect was specific to an interaction of LN with alpha(6)beta(1) integrin since it was ineffective on GC cultured on heat-denatured LN, RGD (arginine-glycine-aspartic acid) peptides and non-coated substratum. Hence, this study established that alpha(6)beta(1) integrin 1) was expressed in GC of antral follicles, 2) mediated the actions of LN on survival, proliferation and steroidogenesis of GC, and 3) was able to dramatically modulate P4 and E2 secretion by GC in vitro. It is suggested that during the follicular and the preovulatory phases of the estrous cycle, the increasing levels of LN in GC of large antral follicles might support their final development to ovulation.

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Koks, C. A. M. "Adhesion of menstrual endometrium to extracellular matrix: the possible role of integrin alpha6beta1 and laminin interaction." Molecular Human Reproduction 6, no. 2 (February 1, 2000): 170–77. http://dx.doi.org/10.1093/molehr/6.2.170.

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Fehlner-Gardiner, Christine C., Shashi Uniyal, and Bosco M. C. Chan. "Integrin VLA-6 (alpha6beta1) is transiently expressed during the development of mouse bone marrow-derived mast cells." Development, Growth and Differentiation 38, no. 6 (December 1996): 673–86. http://dx.doi.org/10.1046/j.1440-169x.1996.t01-5-00011.x.

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Bosco, D., P. Meda, P. A. Halban, and D. G. Rouiller. "Importance of cell-matrix interactions in rat islet beta-cell secretion in vitro: role of alpha6beta1 integrin." Diabetes 49, no. 2 (February 1, 2000): 233–43. http://dx.doi.org/10.2337/diabetes.49.2.233.

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Barraud-Lange, Virginie, Côme Ialy-Radio, Céline Chalas, Isabelle Holtzmann, Jean-Philippe Wolf, Sandrine Barbaux, and Ahmed Ziyyat. "Partial Sperm beta1 Integrin Subunit Deletion Proves Its Involvement in Mouse Gamete Adhesion/Fusion." International Journal of Molecular Sciences 21, no. 22 (November 11, 2020): 8494. http://dx.doi.org/10.3390/ijms21228494.

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We have previously shown, using antibodies, that the sperm alpha6beta1 integrin is involved in mouse gamete fusion in vitro. Here we report the conditional knockdown of the sperm Itgb1 gene. It induced a drastic failure of sperm fusogenic ability with sperm accumulation in the perivitelline space of in vitro inseminated oocytes deleted or not for the Itgb1 gene. These data demonstrate that sperm, but not oocyte, beta1 integrin subunit is involved in gamete adhesion/fusion. Curiously, knockdown males were fertile in vivo probably because of the incomplete Cre-mediated deletion of the sperm Itgb1 floxed gene. Indeed, this was shown by Western blot analysis and confirmed by both the viability and litter size of pups obtained by mating partially sperm Itgb1 deleted males with females producing completely deleted Itgb1 oocytes. Because of the total peri-implantation lethality of Itgb1 deletion in mice, we assume that sperm that escaped the Itgb1 excision seemed to be preferentially used to fertilize in vivo. Here, we showed for the first time that the deletion, even partial, of the sperm Itgb1 gene makes the sperm unable to normally fertilize oocytes. However, to elucidate the question of the essentiality of its role during fertilization, further investigations using a mouse expressing a recombinase more effective in male germ cells are necessary.

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Tavella, S., G. Bellese, P. Castagnola, I. Martin, D. Piccini, R. Doliana, A. Colombatti, R. Cancedda, and C. Tacchetti. "Regulated expression of fibronectin, laminin and related integrin receptors during the early chondrocyte differentiation." Journal of Cell Science 110, no. 18 (September 15, 1997): 2261–70. http://dx.doi.org/10.1242/jcs.110.18.2261.

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We have investigated the expression and localization of fibronectin, laminin, and their receptors, and we used an in vitro chick chondrocyte differentiation model to define a time hierarchy for their appearance in early chondro-genesis and to determine their role in the cell condensation process. By serum fibronectin depletion/reconstitution, or GRGDSP peptide competition experiments, we show that fibronectin contributes to the initial cell-cell interactions that occur during condensation. In later stages, a down-regulation of both fibronectin and of its alpha5beta1 integrin receptor occur, as demonstrated by mRNA and protein kinetics. Immunolocalisation studies suggest that the reduction of fibronectin in discrete areas is involved in local activation of the cell differentiation program. Furthermore, we show that laminin is expressed during the in vitro cell condensation process in areas that are negative for fibronectin staining. The types of laminin as well as the timing of expression have been determined by northern blot and RT-PCR analyses. The highest levels of expression are coincident with maximal cell aggregation. The alpha3beta1 laminin receptor, highly expressed in dedifferentiated cells, follows later on the ligand trend. During in vitro chondrogenesis, a down-regulation in the B isoform, and an up-regulation of the A isoform, of the alpha subunit of the alpha6beta1 laminin receptor occurs. Immunolocalisation studies suggest that laminin is involved in the definition of differentiating areas as opposed to non differentiating areas of the condensed region, i.e. the periphery, which eventually gives rise to the perichondrium.

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Chen, Jui-Chieh, Yu-Ju Chen, Chih-Yang Lin, Yi-Chin Fong, Chin-Jung Hsu, Chun-Hao Tsai, Jen-Liang Su, and Chih-Hsin Tang. "Amphiregulin enhances alpha6beta1 integrin expression and cell motility in human chondrosarcoma cells through Ras/Raf/MEK/ERK/AP-1 pathway." Oncotarget 6, no. 13 (March 18, 2015): 11434–46. http://dx.doi.org/10.18632/oncotarget.3397.

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Geberhiwot, T., D. Assefa, J. Kortesmaa, S. Ingerpuu, C. Pedraza, Z. Wondimu, J. Charo, et al. "Laminin-8 (alpha4beta1gamma1) is synthesized by lymphoid cells, promotes lymphocyte migration and costimulates T cell proliferation." Journal of Cell Science 114, no. 2 (January 15, 2001): 423–33. http://dx.doi.org/10.1242/jcs.114.2.423.

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Laminins are a growing family of large heterotrimeric proteins with cell adhesive and signalling functions. They are major components of basement membranes and are found in many organs, including the vasculature and other compartments of bone marrow, thymus, lymph nodes and spleen. However, expression, recognition and use of laminin isoforms by lymphoid cells are poorly understood. In the present study, lymphoid T cells (Jurkat) were found to synthesize laminin alpha4, beta1 and gamma1 mRNAs and polypeptides and to assemble the chains into laminin-8. Lymphoblastoid B (NAD-20) cells, lymphoid NK (NKL) cells and blood lymphocytes also contained laminin-8 and, after cell permeabilization, practically all blood lymphocytes reacted with mAbs to laminin beta1 and gamma1 chains. Following stimulation, blood lymphocytes secreted laminin-8, and this laminin isoform, but not laminin-10/11(alpha5beta1gamma1/alpha5beta2gamma1), promoted chemokine-induced migration of the cells. In an activation-dependent manner, purified blood CD4 T cells adhered to immobilized laminin-8 and laminin-10/11 by using alpha6beta1 integrin, but minimally to laminin-1 (alpha1beta1gamma1). Accordingly, laminin-8 and laminin-10/11, but not laminin-1, strongly costimulated proliferation of the T cells via the same integrin. Thus, lymphoid cells are able to synthesize and secrete complete laminin molecules. In addition, synthesis of laminin-8 and recognition of laminin-8 and -10/11 by lymphocytes indicate relevance of these laminin isoforms in lymphocyte physiology.

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Chen, Jui-Chieh, Yu-Ju Chen, Chih-Yang Lin, Yi-Chin Fong, Chin-Jung Hsu, Chun-Hao Tsai, Jen-Liang Su, and Chih-Hsin Tang. "Correction: Amphiregulin enhances alpha6beta1 integrin expression and cell motility in human chondrosarcoma cells through Ras/Raf/MEK/ERK/AP-1 pathway." Oncotarget 8, no. 15 (April 10, 2017): 25830. http://dx.doi.org/10.18632/oncotarget.16998.

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Gang, Eun Ji, Yao-Te Hsieh, Huimin Geng, Jennifer Pham, Markus Muschen, Adele de Arcangelis, Cheryl L. Willman, et al. "Functional Modulation of VLA6 in BCR-ABL1+ Pre-B Acute Lymphoblastic Leukemia." Blood 120, no. 21 (November 16, 2012): 2565. http://dx.doi.org/10.1182/blood.v120.21.2565.2565.

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Abstract Abstract 2565 Chemotherapy drug resistance in acute lymphoblastic leukemia (ALL) remains a major problem, resulting in reduced treatment efficacy and relapse. The bone marrow environment (BME) has been shown to promote resistance of leukemia cells towards chemotherapy, which has been attributed to several proteins, including integrins. Our analysis of 207 children with high-risk (BCR/ABL1−) pre-B ALL revealed that high expression of the laminin-binding integrin VLA6 (alpha6beta1) portends poor clinical outcomes in patients with minimal residual disease (MRD+) on day 29 of induction. In addition, our comparative analysis of pre-B leukemia and normal B-cells revealed that VLA6 is preferentially upregulated on BCR/ABL1+ pre-B ALL blasts. Alterations in adhesion properties have been described for BCR/ABL1+ (p210) chronic myeloid leukemia. The role of integrins and integrin VLA6 in particular for cell adhesion-mediated drug resistance (CAM-DR) in BCR/ABL1+ (p210) ALL has not been addressed. With respect to its role for normal immature hematopoietic cells, contradictory observations have been reported. Therefore, we hypothesized that VLA6-mediated adhesion of ALL cells to the bone marrow stromal niche contributes to drug resistance. We evaluated the role of VLA6 in BCR-ABL1+ leukemia using two of our established models of leukemia, a conditional knockout model of VLA6 in murine BCR-ABL1+ leukemia and a xenograft model of human BCR-ABL1+ leukemia. VLA6fl/fl cells were oncogenically transformed using BCR-ABL1 (p210) and cultured under lymphoid-skewing conditions. Induction of pre- B (B220+ CD19+) ALL was confirmed by flow cytometry. Subsequent transduction with CreERT2 or EmptyERT2 generated leukemia cells in which VLA6 ablation could be induced (CreERT2) or not (EmptyERT2) by addition of Tamoxifen. Conditional ablation of VLA6 in vitro decreased adhesion significantly compared to undeleted controls (19.7%±8.1% vs. 87.7%±6.0%; p=0.00041) and increased apoptosis of murine BCR-ABL1+ leukemia cells as determined by analysis of Annexin V−/7-AAD− viable cells by flow cytometry (VLA6 deleted vs. undeleted: 35.3%±1.1% vs. 75.1%±1.2%; p=0.0001). Moreover, VLA6 deletion sensitized murine ALL to a tyrosine kinase inhibitor (TKI), Nilotinib (p=0.022, 45.6%±2.4% vs. 73.3%±13.0%). To test the effect of VLA6 deletion on leukemic progression in vivo, VLA6 BCR/ABL1+ pre-B (B220+ CD19+) CreERT2+ or control transduced ALL cells were transferred into NOD/SCID mice. 3 days thereafter, VLA6 deletion was induced by Tamoxifen administration to all animals in 2 cycles for 5 days. In vivo deletion of VLA6 in delayed leukemia progression compared to VLA6 competent controls from a median survival time (MST) of 30 days post-leukemia injection to a MST of 43 days post-leukemia injection (p=0.008 Log-rank test). In vivo deletion of VLA6 in combination with Nilotinib treatment delayed leukemia progression compared to VLA6 competent, as Nilotinib-treated control animals have uniformly died of leukemia with a MST of 39.5 days, however the Nilotinib treated VLA6 deleted group is completely alive and is still being monitored (p=0.0025). When VLA6 was ablated before transfer and recipients were observed for leukemia progression, the recipients of VLA6–deficient murine leukemia cells also showed attenuated leukemia progression compared to recipients of VLA6 competent cells. Moreover, we show that VLA6 blockade de-adheres primary ALL cells from their cognate counter receptor laminin in vitro, and sensitizes primary ALL cells to TKI Taken together, modulating the function of VLA6 in ALL offers a new approach to overcome drug resistance in ALL. Given that VLA6 is probably largely redundant for normal immature hematopoiesis, this approach may be preferable over targeting of other integrins in BCR/ABL1+ leukemias on which VLA6 is expressed. Disclosures: No relevant conflicts of interest to declare.

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Nicholls, P. K., P. G. Stanton, K. L. Walton, R. I. McLachlan, L. O'Donnell, and C. A. Harrison. "148. HORMONALLY REGULATED miRNAS TARGET THE TUBULOBULBAR COMPLEX IN THE TESTIS." Reproduction, Fertility and Development 22, no. 9 (2010): 66. http://dx.doi.org/10.1071/srb10abs148.

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Spermatogenesis is absolutely dependent on follicle stimulating hormone (FSH) and androgens; acute suppression of these hormones inhibits germ cell development and thus sperm production. The removal of intercellular junctions and release of spermatids by the Sertoli cell, a process known as spermiation, is particularly sensitive to acute hormone suppression(1). To define the molecular mechanisms that mediate FSH and androgen effects in the testis, we investigated the expression and hormonal regulation of micro-RNAs (miRNA), small non-coding RNAs that regulate protein translation and modify cellular responses. By array analysis, we identified 23 miRNAs that were upregulated >2-fold in stage VIII seminiferous tubules following hormone suppression, and in vitro in primary Sertoli cells. We subsequently validated the expression and hormonal regulation of several miRNAs, including miR-23b, -30d and -690 by quantitative PCR in primary Sertoli cells. Bioinformatic analysis of potential targets of hormonally-suppressed miRNAs identified genes associated with Focal adhesions (54 genes, P = –ln(17.97)) and the Regulation of the actin cytoskeleton (52 genes, P = –ln(10.16)), processes known to be intimately associated with adhesion of spermatids to Sertoli cells(2, 3). Furthermore, this analysis identified numerous components of the testicular tubulobulbar complex (TBC) as being targets of hormonally sensitive miRNAs. The TBC is a podosome-like structure between Sertoli and adjacent spermatids in the testis, which internalises intact inter-cellular junctions by endocytotic mechanisms prior to spermiation(4). We then demonstrate the hormonal regulation of predicted miRNA target proteins, and validate novel inhibitory miRNA interactions with Pten, nWASP, Eps15 and Picalm by luciferase knockdown in vitro. We hypothesise that hormonally suppressed miRNAs inhibit TBC function, and subsequently, endocytosis of intercellular junctions. In conclusion, we have demonstrated that hormonal suppression in the testis stimulates the expression of a subset of Sertoli cell miRNAs that are likely regulators of cell adhesion protein networks involved in spermiation. (1) Saito K, O’Donnell L, McLachlan RI, Robertson DM 2000 Spermiation failure is a major contributor to early spermatogenic suppression caused by hormone withdrawal in adult rats. Endocrinology 141: 2779–2.(2) O’Donnell L, Stanton PG, Bartles JR, Robertson DM 2000 Sertoli cell ectoplasmic specializations in the seminiferous epithelium of the testosterone-suppressed adult rat. Biol Reprod 63: 99–108.(3) Beardsley A, Robertson DM, O’Donnell L 2006 A complex containing alpha6beta1-integrin and phosphorylated focal adhesion kinase between Sertoli cells and elongated spermatids during spermatid release from the seminiferous epithelium. J Endocrinol 190(3): 759–70.(4) Young JS, Guttman JA, Vaid KS, Vogl AW 2009 Tubulobulbar complexes are intercellular podosome-like structures that internalize intact intercellular junctions during epithelial remodeling events in the rat testis. Biol Reprod 80: 162–74.

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Grossman, H. B., C. Lee, J. Bromberg, and M. Liebert. "Expression of the alpha6beta4 integrin provides prognostic information in bladder cancer." Oncology Reports, January 1, 2000. http://dx.doi.org/10.3892/or.7.1.13.

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Dahlman, T., L. Grimelius, G. Wallin, K. Rubin, and K. Westermark. "Integrins in thyroid tissue: upregulation of alpha2beta1 in anaplastic thyroid carcinoma." European Journal of Endocrinology, January 1, 1998, 104–12. http://dx.doi.org/10.1530/eje.0.1380104.

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OBJECTIVE: To evaluate the integrin pattern in the normal thyroid gland and in different pathological disorders including malignant tumors, because the aggressiveness of several malignant tumors correlates with alterations in the expression of one or more integrins. DESIGN: We examined the expression of integrins and E-cadherin immunohistochemically in a large and well-defined sample of normal and pathological human thyroid tissue. METHODS: Cryosections of 58 thyroid tissue specimens from normal tissue, thyrotoxicosis, nodular goiter, oxyphilic adenoma, follicular adenoma, follicular carcinoma, papillary carcinoma and anaplastic carcinoma, and three lymph node metastases were investigated immunohistochemically using monoclonal antibodies specifically recognizing the integrin beta1-, beta4-, alpha1-, alpha2-, alpha3-, alpha5- and alpha6-subunits, or E-cadherin. RESULTS: All thyroid epithelial cells expressed integrin beta1- and alpha3-subunits. Immunostaining of the beta4-subunit and the alpha6-subunits was found only in tumors. The staining pattern in the three lymph node metastases from papillary carcinomas did not differ from that in their primaries. Anaplastic carcinomas demonstrated neoexpression of the integrin alpha2-subunit. E-cadherin was detected in all tissues except anaplastic carcinomas. CONCLUSIONS: Neoexpression of alpha6beta4 was seen in most malignant tumors, whereas alpha2 was exclusively found in anaplastic carcinomas. In the latter, a loss of E-cadherin expression was also seen. These changes in cell adhesion molecule expression strongly suggest an association with the acquisition of proliferative and invasive properties.

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Gilcrease, Michael Z., Xiao Zhou, Xiaolin Lu, Wendy A. Woodward, Brian E. Hall, and Phillip J. Morrissey. "Alpha6beta4 integrin crosslinking induces EGFR clustering and promotes EGF-mediated Rho activation in breast cancer." Journal of Experimental & Clinical Cancer Research 28, no. 1 (May 26, 2009). http://dx.doi.org/10.1186/1756-9966-28-67.

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Vafa, A., Y. Zhang, R. A. Sikes, and S. R. Marengo. "Overexpression of p185erbB2/neu in the NbE prostatic epithelial cell line increases cellular spreading and the expression of integrin alpha6beta1." International Journal of Oncology, December 1, 1998. http://dx.doi.org/10.3892/ijo.13.6.1191.

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Journal articles on the topic 'Integrin alpha6beta4'

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