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PubMed2002

Developmentally regulated interactions of human thymocytes with different laminin isoforms.

The gene family of heterotrimeric laminin molecules consists of at least 15 naturally occurring isoforms which are formed by five different alpha, three beta and three gamma subunits. The expression pattern of the individual laminin chains in the human thymus was comprehensively analysed in the present study. Whereas laminin isoforms containing the laminin alpha1 chain (e.g. LN-1) were not present in the human thymus, laminin isoforms containing the alpha2 chain (LN-2/4) or the alpha5 chain (LN-10/11) were expressed in the subcapsular epithelium and in thymic blood vessels. Expression of the laminin alpha4 chain seemed to be restricted to endothelial cells of the thymus, whereas the LN-5 isoform containing the alpha3 chain could be detected on medullary thymic epithelial cells and weakly in the subcapsular epithelium. As revealed by cell attachment assays, early CD4- CD8- thymocytes which are localized in the thymus beneath the subcapsular epithelium adhered strongly to LN-10/11, but not to LN-1, LN-2/4 or LN-5. Adhesion of these thymocytes to LN-10/11 was mediated by the integrin alpha6beta1. During further development, the cortically localized CD4+ CD8+ thymocytes have lost the capacity to adhere to laminin-10/11. Neither do these cells adhere to any other laminin isoform tested. However, the more differentiated single positive CD8+ thymocytes which were mainly found in the medulla were able to bind to LN-5 which is expressed by medullary epithelial cells. Interactions of CD8+ thymocytes with LN-5 were integrin alpha6beta4-dependent. These results show that interactions of developing human thymocytes with different laminin isoforms are spatially and developmentally regulated.

CD4-Positive T-Lymphocytes↗
PubMed2004

Contributions of the alpha6 integrins to breast carcinoma survival and progression.

This review summarizes recent findings that support a key role for the alpha6 integrins (alpha6beta1 and alpha6beta4) in the progression of breast carcinoma. The hypothesis that emerges from the existing data is that both of these integrins have the ability to sustain the survival of breast carcinoma cells, especially in stress conditions such as those that exist in the tumor microenvironment. The mechanisms by which these integrins promote survival appear to involve their ability to regulate the expression of vascular endothelial growth factor (VEGF), either at the level of transcription or translation. VEGF produced by breast carcinoma cells in response to alpha6 integrin regulation can function in an autocrine manner to promote survival signaling.

Breast Neoplasms↗
PubMed1993

Blood group antigens and integrins as biomarkers in head and neck cancer: is aberrant tyrosine phosphorylation the cause of altered alpha 6 beta 4 integrin expression?

Head and neck cancer is a capricious disease that varies greatly in its clinical behavior. The development of biomarkers that can distinguish between biologically aggressive and indolent tumors has been a long term goal of our laboratories. Predictive markers applicable to biopsy specimens should facilitate clinical management through early identification of patients at greatest risk for early relapse or metastatic spread. Two prominent cell surface markers that we identified by raising monoclonal antibodies to squamous cell carcinomas are blood group antigens and the A9 antigen/alpha 6 beta 4 integrin. Both of these markers are abnormally displayed in squamous cancers of the head and neck and serve as indicators of early relapse. Loss of blood group antigen expression is a stronger single indicator than is overexpression of the alpha 6 beta 4 integrin. However, use of both markers together is a stronger predictive indicator than is either alone. We know little about the function of the blood group antigens in squamous cells except that the mature antigens are associated with differentiation. Similarly, the function of the alpha 6 beta 4 integrin is also not fully understood. Integrin alpha 6 beta 4 is thought to serve as an extracellular matrix receptor, but its ligand has not been confirmed. In resting epithelium, the alpha 6 beta 4 integrin is polarized to the basal aspect of the basal cell as a component of the hemidesmosome, the anchoring structures of the epithelia. This basal polarization is lost in migrating normal squamous cells and squamous carcinomas. Tyrosine phosphorylation of the beta 4 subunit is absent or greatly reduced in malignant cells and this may be a critical signal for subcellular localization of alpha 6 beta 4 and cell anchoring. On the basis of our current experimental results, we postulate that tyrosine phosphorylation of the beta 4 subunit is a reversible signal that regulates cell migration in normal and malignant cells, and may therefore be an important initial event in the metastatic cascade.

ABO Blood-Group System↗
PubMed1993

Redistribution of the hemidesmosome components alpha 6 beta 4 integrin and bullous pemphigoid antigens during epithelial wound healing.

As basal cells of stratified squamous epithelia become migratory in response to wounding, they lose their cell-substrate adhesion junctions, the hemidesmosomes. We report here studies to determine the fate of the hemidesmosome components, alpha 6 beta 4 integrin and the bullous pemphigoid antigens (BPAGs), as recognized by bullous pemphigoid autoantisera (BPA), in migrating epithelium. In addition, we report studies to determine whether relative synthesis and amount of alpha 6 beta 4 is altered during migration. Mouse corneas with 1.5- to 2-mm-diameter central epithelial debridements were allowed to heal in vitro or in vivo for 1-18 h. In order to do preembedding immunoelectron microscopic localization of alpha 6 beta 4, sheets of stationary and migrating corneal epithelium were removed from their basal laminae after organ culture. BPA and antibodies to alpha 6 and beta 4 were used for immunofluorescence microscopy on frozen sections of intact corneas healing in vivo 1-18 h. Both alpha 6 and beta 4 were found to redistribute from their clustered location within hemidesmosomes to a more even distribution within the substrate-associated membrane of basal cells of the tip of the leading edge of migrating epithelium. Behind the tip of the leading edge, basal cells bound the integrin antibodies around their entire membrane. BPAGs moved from their location along the basal cell membrane of stationary epithelium to a diffuse location within the cytoplasm of migrating cells at the leading edge of migration. Quantitative immunoprecipitation and immunoblotting of alpha 6 beta 4 as well as beta 1 integrin from stationary and migrating epithelium were done to determine whether the synthesis or total amount of the integrins were altered during migration. The relative syntheses of alpha 6 beta 4 and beta 1 per milligram of protein or per cell do not appear to differ between stationary and migrating epithelium and the total amount of the beta 4 and beta 1 does not change despite increased rates of protein synthesis in migrating epithelium. Taken together, these studies suggest that as hemidesmosomes disassemble, their clustered integrin component distributes more evenly in the basal cell membrane, the components recognized by BPA and associated with intermediate filaments are released from the membrane, and these events occur in the absence of any measurable change in the synthesis or total amount of the alpha 6 beta 4 component.

Animals↗
PubMed2002

Regulation of the association of alpha 6 beta 4 with vimentin intermediate filaments in endothelial cells.

The adhesion of microvascular endothelial cells to their underlying basement membrane is important for the maintenance of vascular integrity. Most integrins function in endothelial cell adhesion by forming a transmembrane link between their basement membrane ligand and the actin microfilament cytoskeleton. The alpha 6 beta 4 laminin-binding integrin, however, associates with vimentin intermediate filaments (IFs) in microvascular endothelial cells and therefore is likely to uniquely contribute to the barrier function of the endothelium. In this study, we examined the regulation of alpha 6 beta 4-vimentin IF association. We first tested the requirement for alpha 6 beta 4-laminin interactions and actin microfilament assembly. We found that alpha 6 beta 4 associated with vimentin IFs when cells were adherent to either laminin 5 or fibronectin, indicating that this association can occur independent of alpha 6 beta 4-ligand interactions. Additionally, we found that alpha 6 beta 4 was associated with vimentin IFs prior to cell spreading, indicating that changes in the microfilament cytoskeleton associated with changes in cell shape are also not required. Thus, although the association of alpha 6 beta 4 with vimentin IFs may strengthen cell adhesion by providing endothelial cells with an additional transmembrane linkage between the basement membrane and the cytoskeleton, this association is not itself regulated by alpha 6 beta 4-mediated adhesion. Finally, we tested the role of plectin in the association of alpha 6 beta 4 with vimentin IFs. Plectin is known to bind in vitro to both IFs and the beta 4 cytoplasmic domain (beta 4 tail), suggesting that it may be important for this linkage. Therefore, we generated deletion mutants of the beta 4 tail and compared the ability of alpha 6 beta 4 containing these deletions to associate with vimentin IFs. We targeted the two regions of the beta 4 tail known to bind to plectin IN VITRO: the N-terminal and C-terminal plectin binding sites. We found that deletion of the N-terminal binding site inhibited the association of alpha 6 beta 4 with vimentin IFs. Thus, plectin-beta 4 tail interactions may play an important role in connecting alpha 6 beta 4 with vimentin IFs and may prove to be important targets in the regulation of this association in endothelial cells.

Animals↗
PubMed1988

MHC antigens expressed on 3LL metastatic variants: correlation with the expression of a TSP-180 protein.

In attempts to correlate metastatic potential with specific properties of tumor cells, homogeneous subpopulations, which are endowed with low or high metastatic potential, have been selected from Lewis lung carcinoma (3LL). In particular, since cell surface constituents are possibly involved in the metastatic process, changes in antigen expression have been correlated with the metastatic potential of 3LL variants. In this view, we quantitated the expression of MHC (Db,Kb) antigens and of a tumor specific protein (TSP) identified by the monoclonal antibody (MoAb) 135-13C on some "in vitro" and "in vivo" variants of 3LL. The MoAb 135-13C was found to recognize a TSP-180 protein that appears on the cell surface of several murine carcinomas, but is not detected on normal cells in culture. Studies of the MHC expression on these variants, by the use of the indirect immunofluorescent staining or the direct binding of the MoAb to H-2Db (28-14-8) and the MoAb to H-2Kb (28-13-3), demonstrate that "in vivo" and "in vitro" 3LL variants which, are endowed with a higher metastatic potential, express on the cell surface a higher amount of the Db antigen. By contrast, all the 3LL lines have few cells recognized by the MoAb to H-2Kb and express low amounts of this antigen on the cell surface. The direct binding to different tumor lines and the analysis of the immunoprecipitates from the cell lysates by the use of the MoAb 135-13C demonstrate that the TSP-180 protein is highly expressed on 3LL cells which possess high capacity to metastasize to the lung. The variations induced in 3LL metastatic phenotype by the injection of the variant lines in allogeneic mice (Balb/c, C3HeB:H-2d,H-2k, respectively) or after treatment with the specific MoAb 135-13C have, also, been studied. An attempt was made to correlate the changes in 3LL metastatic phenotype with the expression of the TSP-180 protein and of the MHC antigens. We conclude that a high expression on the cell surface of the Db antigen and of the TSP-180 protein, is associated with a high malignant phenotype of 3LL tumor cells.

Animals↗
PubMedDate not supplied

Stimulation of tumor cell growth in vitro by a monoclonal antibody to a tumor specific protein (TSP-180) present on the cell surface of 3LL cells.

Proliferation capacity and MHC class I antigen expression of two Lewis lung carcinoma (3LL) metastatic variants (C87, BC215) grown under defined experimental conditions (serum-free defined medium or 10 per cent serum) have been studied following exposure to MoAb 135-13C which recognizes on these cells a tumor surface protein of 180,000 daltons (TSP-180). The results of this study indicate that the high metastatic clone (C87) binds higher amounts of MoAb to TSP-180 and Db antigens than does the low metastatic one (BC215), while both clones express very low amounts of Kb antigens. 3LL clones grown in 10 per cent serum or adapted in serum-free, defined medium show the same metastatic phenotype and MHC class I antigen expression, but when grown in defined medium exhibit increased capacity to bind MoAb 135-13C. However, the relative binding rate of 3LL clones grown in 10 per cent serum or in defined medium is unchanged: the high metastatic clone always showing higher capacity to bind MoAb to TSP-180. Furthermore, comparison of EGF binding sites on the cell surface of 3LL clones, grown in different culture conditions, demonstrates that the C87 clone binds higher amounts of labelled EGF and that this amount increases in serum-free defined medium, exactly as reported for TSP-180. In addition, competition experiments demonstrated that MoAb 135-13C does not compete for EGF binding sites on 3LL cell surface. Studies on cell proliferation following exposure to MoAb 135-13C, revealed that the low metastatic clone (BC215) is more actively stimulated than the high metastatic one. Moreover, similar data were obtained after exposure of 3LL clones to physiological amounts of different growth factors (i.e. EGF, MSA, insulin). Analysis of MHC class I antigen expression following exposure to MoAb 135-13C indicated that MoAb 135-13C induces on the cell surface of the C87 clone a transient low modulation of Db antigens. These results suggest that 3LL cells endowed with lower metastatic potential are more dependent on the microenvironmental conditions than the high metastasizing ones, and that MoAb 135-13C binding to 3LL cell surface stimulates proliferation as reported for several known growth factors.

Animals↗
PubMed2006

ErbB2 makes beta 4 integrin an accomplice in tumorigenesis.

Integrins modulate signaling by growth factor receptors, but their role during tumorigenesis is not clear. Guo et al. (2006) now demonstrate that alpha 6 beta 4 integrin cooperates with ErbB2 in the formation of mammary tumors and discover distinct pathways that regulate cellular proliferation and adhesion downstream of the ErbB2-integrin complex.

Animals↗
PubMed2003

The role of alpha3beta1 integrin in determining the supramolecular organization of laminin-5 in the extracellular matrix of keratinocytes.

Analyses of mice with targeted deletions in the genes for alpha3 and beta1 integrin suggest that the alpha3beta1 integrin heterodimer likely determines the organization of the extracellular matrix within the basement membrane of skin. Here we tested this hypothesis using keratinocytes derived from alpha3 integrin-null mice. We have compared the organizational state of laminin-5, a ligand of alpha3beta1 integrin, in the matrix of wild-type keratinocytes with that of laminin-5 in the matrix of alpha3 integrin-null cells. Laminin-5 distributes diffusely in arc structures in the matrix of wild-type mouse keratinocytes, whereas laminin-5 is organized into linear, spike-like arrays by the alpha3 integrin-null cells. The fact that alpha3 integrin-null cells are deficient in their ability to assemble a proper laminin-5 matrix is also shown by their failure to remodel laminin-5 when plated onto surfaces coated with purified laminin-5 protein. In sharp contrast, wild-type keratinocytes organize exogenously added laminin-5 into discrete ring-like organizations. These findings led us next to assess whether differences in laminin-5 organization in the matrix of the wild-type and alpha3 integrin-null cells impact cell behavior. Our results indicate that alpha3 integrin-null cells are more motile than their wild-type counterparts and leave extensive trails of laminin-5 over the surface on which they move. Moreover, HEK 293 cells migrate significantly more on the laminin-5-rich matrix derived from the alpha3 integrin-null cells than on the wild-type keratinocyte laminin-5 matrix. In addition, alpha3 integrin-null cells show low strength of adhesion to surfaces coated with purified laminin-5 compared to wild-type cells although both the wild type and the alpha3 integrin-null keratinocytes adhere equally strongly to laminin-5 that has been organized into arrays by other epithelial cells. These data suggest: (1) that alpha3beta1 integrin plays an important role in determining the incorporation of laminin-5 into its proper higher-order structure within the extracellular matrix of keratinocytes and (2) that the organizational state of laminin-5 has an influence on laminin-5 matrix function.

Animals↗
PubMed2002

Detection and purification of instructive extracellular matrix components with monoclonal antibody technologies.

Historically, Mabs have been one of the most productive and reliable methods for the identification of adhesion receptors and adhesive ECM ligands. In large part, this is because Mabs can identify the function of the adhesion components within the context of the complex ECM or the cell surface. There are now many isoforms of laminin, collagen, and other ECM components that have been identified by molecular and Mab approaches. It is not clear when and where these isoforms are expressed at the protein level, nor what unique functions each ECM isoform may serve within the context of tissue. Undoubtedly, specific in vitro assays in combination with specific Mabs will help illuminate the instructive roles of ECM components for reporter cells within in vitro models and tissue. Delineation of cell responses to the instructive ECM will require additional high-resolution technologies including DNA microarrays and targeted disruption of ECM components.

Animals↗
PubMed2006

Laminin 5 regulates polycystic kidney cell proliferation and cyst formation.

Renal cyst formation is the hallmark of autosomal dominant polycystic kidney disease (ADPKD). ADPKD cyst-lining cells have an increased proliferation rate and are surrounded by an abnormal extracellular matrix (ECM). We have previously shown that Laminin 5 (Ln-5, a alpha(3)beta(3)gamma(2) trimer) is aberrantly expressed in the pericystic ECM of ADPKD kidneys. We report that ADPKD cells in primary cultures produce and secrete Ln-5 that is incorporated to the pericystic ECM in an in vitro model of cystogenesis. In monolayers, purified Ln-5 induces ERK activation and proliferation of ADPKD cells, whereas upon epidermal growth factor stimulation blocking endogenously produced Ln-5 with anti-gamma(2) chain antibody reduces the sustained ERK activation and inhibits proliferation. In three-dimensional gel culture, addition of purified Ln-5 stimulates cell proliferation and cyst formation, whereas blocking endogenous Ln-5 strongly inhibits cyst formation. Ligation of alpha(6)beta(4) integrin, a major Ln-5 receptor aberrantly expressed by ADPKD cells, induces beta(4) integrin phosphorylation, ERK activation, cell proliferation, and cyst formation. These findings indicate that Ln-5 is an important regulator of ADPKD cell proliferation and cystogenesis and suggest that Ln-5 gamma(2) chain and Ln-5-alpha(6)beta(4) integrin interaction both contribute to these phenotypic changes.

Cell Line↗
PubMed1991

Surface relocation of alpha 6 beta 4 integrins and assembly of hemidesmosomes in an in vitro model of wound healing.

A transmembrane extracellular matrix receptor of the integrin family, alpha 6 beta 4, is a component of the hemidesmosome, an adhesion complex of importance in epithelial cell-connective tissue attachment (Stepp, M. A., S. Spurr-Michaud, A. Tisdale, J. Elwell, and I. K. Gipson. 1990. Proc. Natl. Acad. Sci. USA. 87:8970-8974; Jones, J. C. R., M. A. Kurpakus, H. M. Cooper, and V. Quaranta. 1991. Cell Regulation. 2:427-438). Cytosolic components of hemidesmosomes include bullous pemphigoid (BP) antigens while extracellular components include a 125-kD component of anchoring filaments (CAF) and collagen type VII-containing anchoring fibrils. We have monitored the incorporation of the alpha 6 beta 4 integrins into forming hemidesmosomes in an in vitro wound-healing explant model. In epithelial cells recently migrated from the edges of unwounded sites over bare connective tissue, alpha 6 beta 4 first appears along the entire cell surface. At this stage, these cells contain little or no cytosolic hemidesmosomal components, at least as detectable by immunofluorescence using BP autoantibodies, whereas they are already positive for laminin and CAF. At a later stage, as cells become positive for cytosolic hemidesmosome components such as BP antigens as well as collagen type VII, alpha 6 beta 4 becomes concentrated along the basal pole of the epithelial cell where it abuts the connective tissue of the explant. Polyclonal antibodies to beta 4 do not interfere with the migration of epithelial cells in the explant. However, they prevent assembly of hemidesmosomal complexes and inhibit expression of collagen type VII in cells that have migrated over wound areas. In addition, they induce disruption of established hemidesmosomes in nonmigrating cells of the unwounded area of the explant. Monoclonal antibodies to alpha 6 have a more dramatic effect, since they completely detach epithelial cells in the unwounded area of the explant. Antibodies to CAF also detach epithelial cells in unwounded areas, apparently by inducing separation between epithelium and connective tissue at the lamina lucida of the basement membrane zone. These results suggest a model whereby polarization of alpha 6 beta 4 to the basal surface of the cells, perhaps induced by a putative anchoring filament-associated ligand, triggers assembly of hemidesmosome plaques.

Animals↗
PubMed1993

The monoclonal antibody BQ16 identifies the alpha 6 beta 4 integrin on bladder cancer.

Monoclonal antibody BQ16, raised against UM-UC-9, a human bladder cancer cell line, exhibited strong reactivity with most bladder carcinoma tissue samples and cell lines. In normal urothelium, BQ16 stained only the basal surface of urothelial cells at the junction with the lamina propria. BQ16 immunoprecipitated two protein bands of approximately 140 and 180 kDa (under non-reducing conditions), while on Western blots, BQ16 identified only the 140 kDa protein indicating that BQ16 binds to one chain of a dimeric protein complex. The dimeric structure, molecular size, and basal orientation of the BQ16 antigen prompted a comparison with the alpha 6 beta 4 integrin identified by monoclonal antibody UM-A9. In most tissues BQ16 and UM-A9 produced identical staining patterns. However, normal lymphocytes and certain bladder cancer cell lines were BQ16 positive but failed to react with UM-A9, indicating that the BQ16 and UM-A9 epitopes can be expressed independently. Pulse-chase immunoprecipitation experiments showed that the alpha 6 subunit was more prominent in early BQ16 precipitates and the beta 4 subunit was more prominent in early UM-A9 precipitates. Furthermore, preclearing cell extracts with the anti-alpha 6 antibody GoH3 removed all BQ16 reactivity and in UM-A9-negative, BQ16-positive cells, BQ16 precipitated the alpha 6 beta 1 complex. We conclude that BQ16 identifies the alpha 6 integrin subunit and that alpha 6 beta 4 integrin is strongly expressed in most bladder cancers.

Antibodies, Monoclonal↗
PubMed1992

Expression of integrin alpha 6 beta 4 in junctional epidermolysis bullosa.

The integrin alpha 6 beta 4 is a member of the integrin family of adhesion receptors. The integrin alpha 6 beta 4 is preferentially expressed in stratified squamous epithelia, where it is localized in hemidesmosomes. A reduced number of rudimentary hemidesmosomes is often found in skin from patients with junctional epidermolysis bullosa (JEB). In this study we have investigated the expression of alpha 6 beta 4 in skin specimens of patients with junctional (one non-lethal, two lethal) and dystrophic (two) epidermolysis bullosa, using immunofluorescent (IF) staining with five different monoclonal antibodies against the alpha 6 and beta 4 subunits. The intensity of IF staining of the integrin alpha 6 beta 4 and bullous pemphigoid antigen (BPA) was unreduced along the epidermal basement membrane zone (EBMZ) of all EB patients, compared to that in skin of healthy human controls. However, in the skin of two patients with lethal (Herlitz) JEB, who did not express GB3, IF staining of integrin alpha 6 beta 4 and BPA showed a "stitchy" discontinuous linear pattern along the EBMZ with interruptions at the borders of adjoining basal keratinocytes. The same results were obtained by immunoelectron microscopy. They corresponded with freeze-induced partial cell detachment from the basement membrane at the ultimate baso-lateral edge of the basal keratinocytes in lethal JEB skin. The basal lamellipodia at that location almost completely lacked tonofilaments and hemidesmosomes. Furthermore, in JEB there was a split between the intra- and extracellular epitopes of the integrin alpha 6 beta 4 receptor, whereas the integrin remains intact in salt-split skin. This suggests that the defect is in alpha 6 beta 4 itself or perhaps its ligand.

Adult↗
PubMed1992

Alpha-6 (CD 49f) integrin expression in genetic and acquired bullous skin diseases. A comparison of its distribution with bullous pemphigoid antigen.

Bullous pemphigoid (BP) antigen and alpha 6 integrin are hemidesmosome-associated glycoproteins of basal keratinocytes. In this work, the immunoreactivity of antibodies to BP and to alpha 6 in salt- or dispase-split human skin, and in 46 biopsy specimens of various genetic and autoimmune bullous dermatoses taken from various body sites, was studied by double-labeling immunofluorescence. In all specimens, both antigens localized at the same side of the blisters observed, i.e. the roof of the bulla in cases with a junctional or dermolytic cleavage, or the floor of the blister in those with intraepidermal cleavage. Immunostaining for alpha 6 was strong and present in all specimens studied, whereas the one obtained with the BP serum was absent from some specimens. These results show that the BP antigen and the alpha 6 integrin colocalize at the level of cleavage in bullous diseases; however, the more consistent and reproducible reactivity obtained with the anti-alpha 6 antibody suggests that this should be preferentially used in the immunohistochemical investigation of bullous dermatoses.

Antigens, Surface↗
PubMed2003

Multiphoton microscopy: an optical approach to understanding and resolving sulfur mustard lesions.

Sulfur mustard (SM; 2,2(')-dichloroethyl sulfide) is a percutaneous alkylating agent first used as a chemical weapon at Ypres, Belgium, in World War I. Despite its well-documented history, the primary lesions effecting dermal-epidermal separation and latent onset of incapacitating blisters remain poorly understood. By immunofluorescent imaging of human epidermal keratinocytes (HEK) and epidermal tissues exposed to SM (400 microM for 5 min), we have amassed unequivocal evidence that SM disrupts adhesion complex molecules, which are also disrupted by epidermolysis bullosa-type blistering diseases of the skin. Images of keratin 14 (K14) in control cells showed tentlike filament networks linking the HEK's basolateral anchoring sites to the dorsal surface of its nuclei. Images from 6-h postexposure profiles revealed early disruption (</=1 h) and progressive collapse of the K14 cytoskeleton. Collapse involved focal erosions, loss of functional asymmetry, and displacement of nuclei beneath a mat of jumbled filaments. In complementary studies, 1-h images showed statistically significant (p<0.01) decreases of 25 to 30% in emissions from labeled alpha(6)beta(4) integrin and laminin 5, plus disruption of their receptor-ligand organization. Results indicate that SM alkylation destabilizes dermal-epidermal attachments and potentiates vesication by disrupting adhesion complex molecules and associated signaling mechanisms required for their maintenance and repair.

Cell Adhesion Molecules↗
PubMed2004

Differential expression of collagen- and laminin-binding integrins mediates ureteric bud and inner medullary collecting duct cell tubulogenesis.

Inner medullary collecting ducts (IMCD) are terminally differentiated structures derived from the ureteric bud (UB). UB development is mediated by changes in the temporal and spatial expression of integrins and their respective ligands. We demonstrate both in vivo and in vitro that the UB expresses predominantly laminin receptors (alpha3beta1-, alpha6beta1-, and alpha6beta(4-integrins), whereas the IMCD expresses both collagen (alpha1beta1- and alpha2beta1-integrins) and laminin receptors. Cells derived from the IMCD, but not the UB, undergo tubulogenesis in collagen-I (CI) gels in an alpha1beta1- and alpha2beta1-dependent manner. UB cells transfected with the alpha2-integrin subunit undergo tubulogenesis in CI, suggesting that collagen receptors are required for branching morphogenesis in CI. In contrast, both UB and IMCD cells undergo tubulogenesis in CI/Matrigel gels. UB cells primarily utilize alpha3beta1- and alpha6-integrins, whereas IMCD cells mainly employ alpha1beta1 for this process. These results demonstrate a switch in integrin expression from primarily laminin receptors in the early UB to both collagen and laminin receptors in the mature IMCD, which has functional consequences for branching morphogenesis in three-dimensional cell culture models. This suggests that temporal and spatial changes in integrin expression could help organize the pattern of branching morphogenesis of the developing collecting system in vivo.

Animals↗