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PubMed1998

Linking integrin alpha6beta4-based cell adhesion to the intermediate filament cytoskeleton: direct interaction between the beta4 subunit and plectin at multiple molecular sites.

Recent studies with patients suffering from epidermolysis bullosa simplex associated with muscular dystrophy and the targeted gene disruption in mice suggested that plectin, a versatile cytoskeletal linker and intermediate filament-binding protein, may play an essential role in hemidesmosome integrity and stabilization. To define plectin's interactions with hemidesmosomal proteins on the molecular level, we studied its interaction with the uniquely long cytoplasmic tail domain of the beta4 subunit of the basement membrane laminin receptor integrin alpha6beta4 that has been implicated in connecting the transmembrane integrin complex with hemidesmosome-anchored cytokeratin filaments. In vitro binding and in vivo cotransfection assays, using recombinant mutant forms of both proteins, revealed their direct interaction via multiple molecular domains. Furthermore, we show in vitro self-interaction of integrin beta4 cytoplasmic domains, as well as disruption of intermediate filament network arrays and dislocation of hemidesmosome-associated endogenous plectin upon ectopic overexpression of this domain in PtK2 and/or 804G cells. The close association of plectin molecules with hemidesmosomal structures and their apparent random orientation was indicated by gold immunoelectron microscopy using domain-specific antibodies. Our data support a model in which plectin stabilizes hemidesmosomes, via directly interlinking integrin beta4 subunits and cytokeratin filaments.

Animals↗
PubMed1996

Changes in integrin and E-cadherin expression in neoplastic versus normal thyroid tissue.

UNLABELLED: BACK: The functional organization of polarized epithelia depends mostly on adhesion molecules belonging to the integrin and cadherin families. These molecules either recognize basement membrane components, such as laminins, or form intercellular junctions via homotypic interactions. Such tissue organization is often disrupted upon neoplastic transformation, and the resulting loss of functional polarization and cell cohesion might be a prerequisite for the invasive and metastatic behavior of carcinomas. PURPOSE: We studied modifications on thyroid adhesive mechanisms at various stages of neoplastic progression in terms of adhesion molecule expression, topography, and functional regulation by tyrosine kinases. Starting from this working hypothesis, we sought to identify one or more biological markers that would be suggestive of malignant transformation and poorer prognosis and that could be developed as a reliable indicator(s) in early diagnostic steps. METHODS: The study was carried out on both surgical samples and the corresponding fine-needle aspiration biopsy smears (numbers of specimens collected: 19 adenomas, seven follicular carcinomas, 13 papilary carcinomas, and 39 normal tissues). Immunohistochemistry of tissue sections and smears and immuno-precipitation and western blot analysis of protein extracts were done with a battery of monoclonal and polyclonal antibodies. Northern blotting was performed on RNA extracts from frozen tissue samples and use of an integrin subunit beta4 complementary DNA probe. RESULTS: Our findings can be summarized as follows: 1) In normal thyroid cells, the cooperative role of integrin alpha6beta4 and laminin 5/kalinin in hemidesmosome-mediated adhesion adhesion is missing, and recognition of the basal lamina occurs via integrin alpha3beta1 and laminin 1 and/or 2 (this pattern being maintained in adenomas but altered in carcinomas regardless of their histotype or differentiation grade); 2) only in carcinomas with clinical and/or histologic aggressiveness do neoexpression of integrin subunit beta4 and loss of laminin 2/merosin occur, indicating de novo assembly of integrin alpha6beta4; 3) pericellular redistribution and cytoskeletal disconnection of the E-cadherin-catenin complex occur; and 4) basal E-cadherin tyrosine phosphorylation decreases in carcinomas as compared with that in normal and adenomatous tissue. CONCLUSION: The malignant progression of thyroid tumors involves marked rearrangement of cell-basement membrane and cell-cell adhesion molecules and changes in their cytoskeleton linkage. These rearrangements are also easily and reproducibly detected on fine-needle aspiration biopsy smears. IMPLICATIONS: Immunodetection of adhesion molecules in sections and/or fine-needle smears may complement the toolbox of thyroid surgical pathologists; it may expand the possibilities of achieving a correct early diagnosis of thyroid tumors and of gaining some prognostic information on thyroid tumors.

Adenocarcinoma, Follicular↗
PubMed1998

Thymocyte contact or monoclonal antibody-mediated clustering of 3beta1 or 6beta4 integrins activate interleukin-6 (IL-6) transcription factors (NF-kappaB and NF-IL6) and IL-6 production in human thymic epithelial cells.

T-cell precursors develop within the thymus in contact with multiple supportive elements, among which thymic epithelial cells (TEC) are known to exert a dominant role in their homing, survival, and functional differentiation. All these functions are supported by cell-cell contacts and cytokine release. Signaling events triggered in lymphoid cells by adhesion to TEC are well characterized, but little is known about the opposite phenomenon. To address this issue, we derived cultures of TEC from human normal thymus. TEC monolayers were cocultured with thymocytes and immunostained with monoclonal antibodies (MoAbs) to integrin (2, 3, 4, and 6) and beta (beta1 and beta4) chains. Optical and confocal analysis showed that integrins were polarized on TEC at discrete surface locations: 6beta4 lined the basal surface of TEC monolayers, whereas 3beta1 was found mostly at TEC-TEC contacts; it is noteworthy that both 3beta1 and 6beta4 became highly enriched also at the boundaries with adherent thymocytes. Functional studies performed with MoAbs anti-beta1 and -beta4 integrins showed that beta1, and, to a much lower extent, beta4 heterodimers are involved in the TEC-thymocyte adhesion. Thymocyte contact or MoAb-mediated ligation of 3, 6, beta1, and beta4 integrins was investigated as a potential inducer of intracellular signaling in TEC. Thymocyte adhesion or cross-linking of MoAbs bound to integrins clustered at the TEC/thymocyte contact sites led to activation of interleukin-6 (IL-6) gene transcription factors, namely NF-IL6 serine phosphorylation and NF-kappaB nuclear targeting, as well as to increased IL-6 secretion. We propose that integrin clustering occurring during TEC-thymocyte contacts modulates in TEC the gene expression of a cytokine involved in thymocyte growth and functional differentiation.

Antibodies, Monoclonal↗
PubMed2006

The cleavage plane of corneal epithelial adhesion complex in traumatic recurrent corneal erosion.

PURPOSE: To determine the anatomic cleavage plane of the corneal epithelial adhesion complex in eyes with traumatic recurrent corneal erosion (RCE). METHODS: A loosened sheet of corneal epithelium was obtained from corneal epithelial wounds in eight patients with traumatic RCE, before each patient underwent phototherapeutic keratectomy. Three control groups were employed in the study, including normal corneal epithelial sheets obtained by mechanical separation, normal corneal tissues obtained by partial lamellar keratectomy during pterygial surgery, and corneal tissues from three residual corneoscleral rims of corneas donated for transplantation. Immunofluorescence staining was performed using monoclonal antibodies against integrins beta1 and beta4, laminin 5, and collagen VII to identify abnormalities in specific layers of the adhesion complex. RESULTS: In both experimental and control specimens, the suprabasal and basal cells stained positive for integrin beta1, and basal cells stained positive for integrin beta4. Similarly, a continuous line along the base of each epithelial sheet and each control specimen stained positive for laminin 5, a major basement membrane component. In contrast, in all controls there was a continuous linear staining pattern along the basement membrane of stain positive for collagen VII, a marker for the presence of fibrils that anchor corneal basement membrane to Bowman's layer, but epithelial sheets from eyes with RCE showed either a discontinuous line stained positive for collagen VII (three out of eight specimens) or no positively stained areas (five out of eight specimens). The results indicated the cleavage plane of RCE was located at collagen VII layer, between basement membrane and Bowman's layer. CONCLUSIONS: This study identified a defect in collagen fibrils that anchor the corneal epithelium basement membrane to Bowman's layer as the cause of corneal epithelial loss in cases of traumatic RCE. As hemidesmosomes do not seem to be impaired, a treatment specific to restore anchoring fibril function might prove helpful.

Adult↗
PubMed2000

Expression of alpha(v)beta6 integrin in oral leukoplakia.

The distribution of alpha(v)beta6 integrin was examined in oral leukoplakia, lichen planus and squamous cell carcinomas using immunohistochemistry. Controls included oral mucosal wounds, chronically inflamed and normal oral mucosa. Integrins beta1, beta3, beta4, beta5, fibronectin and tenascin were also studied. The integrin alpha(v)beta6 was highly expressed throughout the whole lesion of 90% of the squamous cell carcinomas but was not present in any of the normal specimens. alpha(v)beta6 integrin was also expressed in 41% of the leukoplakia specimens, and 85% of the lichen planus samples, but in none of the tissues with inflammatory hyperplasia or chronic inflammation. The expression of beta1 integrins was localized in the basal layer, and that of the beta4 at the cell surface facing the basement membrane of all specimens. The integrins beta3 and beta5 were absent from all normal and leukoplakia specimens. Fibronectin and tenascin were present in the connective tissue underneath the epithelium of all the sections, and their expression was similar in both alpha(v)beta6-positive and alpha(v)beta6-negative tissues. A group of 28 leukoplakia patients were followed 1-4 years after first diagnosis. In this group, initially alpha(v)beta6 integrin-positive leukoplakia specimens had high tendency for disease progression while alpha(v)beta6-negative specimens did not progress. These results suggest that the expression of alpha(v)beta6 integrin could be associated in the malignant transformation of oral leukoplakias.

Antibodies, Monoclonal↗
PubMed2005

Integrin expression in developing human salivary glands.

The development and complete differentiation of salivary glands is a complex process that involves a large number of co-ordinated events. Little is known about the molecular basis for salivary gland development. However, we have reported previously that integrins appear to play a role. Integrins are heterodimeric transmembrane receptors consisting of one alpha and one beta subunit that play a pivotal role in the interaction of cells with the extracellular matrix. Such interactions regulate the organisation of cells of tissues and organs during development as well as cell proliferation and differentiation. Using immunohistochemistry and Western and Northern blot analysis, we mapped the localisation and expression of integrins beta1, beta3 and beta4 in human salivary glands obtained from foetuses ranging from weeks 4-24 of gestation and compared it with adult salivary glands. Integrin beta1 first appeared during the canalisation stage and during the differentiation stage. A message first appeared at week 6 of development. The expression of beta4 integrin protein and message was observed only in the late stage of differentiation. Integrin beta3 was not detected in the developing glands; however, integrins beta1, beta3 and beta4 were all expressed in adult salivary gland tissues. The data suggest that integrins, particularly beta1, have a role to play in salivary gland development and differentiation.

Adult↗
PubMed2001

Expression of type XII collagen and hemidesmosome-associated proteins in keratoconus corneas.

PURPOSE: Keratoconus is a disease characterized by thinning of the central and paracentral cornea and scarring in advanced cases. This study was performed to examine the expression of type XII collagen, proteins associated with hemidesmosomes, and beta1 integrin in keratoconus corneas. METHODS: Corneal buttons were collected from normal subjects and patients with keratoconus and other corneal diseases. Immunofluorescence staining was performed on frozen sections for type XII collagen, bullous pemphigoid antigen (BP180), and integrin subunits alpha6, beta4, and beta1. RESULTS: To varying degrees, all proteins examined were expressed in normal human corneas. The staining intensity of type XII collagen was diminished in keratoconus corneas in the epithelial basement membrane zone and the stromal matrix. No significant variation was found in either the staining patterns or intensities for BP180, or integrins alpha6, beta4, and beta1. CONCLUSIONS: The level of type XII collagen was reduced in the epithelial basement membrane zone and stromal matrices in keratoconus corneas. These alterations may affect critical interactions of the corneal epithelium with the under-lying basement membrane, and cell-matrix interactions and matrix organization in the stroma.

Adolescent↗
PubMed1998

Integrins in thyroid tissue: upregulation of alpha2beta1 in anaplastic thyroid carcinoma.

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.

Cadherins↗
PubMed1998

Decreased mRNA expression of several basement membrane components in basal cell carcinoma.

The biologic factors that control the behavior of basal cell carcinoma are poorly understood. This study was undertaken to elucidate the mechanisms responsible for the altered protein levels of several basement membrane components found in basal cell carcinoma. RNA was isolated from papulonodular basal cell carcinoma, normal human epidermal keratinocytes, and normal human skin, reverse transcribed to cDNA and amplified by the polymerase chain reaction utilizing primers specific for the 230 kDa bullous pemphigoid antigen (BPAG1), the 180 kDa bullous pemphigoid antigen (BPAG2), the alpha6 and beta4 chains of the alpha6beta4 integrin complex, and the beta3 chain of laminin 5. Southern blots probed with internal oligonucleotides confirmed that each polymerase chain reaction was specific for the basement membrane component amplified. The mRNA expressions of basement membrane components were indistinguishable between normal human epidermal keratinocytes and normal human skin, and subsequent experiments used normal human epidermal keratinocytes as controls. Quantitation of polymerase chain reaction products indicated that all basement membrane specific mRNA were significantly decreased in basal cell carcinoma as compared with normal human epidermal keratinocytes. The mean polymerase chain reaction product intensities were significantly less in the basal cell carcinoma as compared with the normal human epidermal keratinocytes at the following levels: p < 0.001 for alpha6 and beta4 integrins and the beta3 chain of laminin 5; p < 0.01 for BPAG1; and p < 0.05 for BPAG2. Our results demonstrate that decreased protein levels of basement membrane components in basal cell carcinoma are due at least partially to a downregulation of basement membrane mRNA species. We speculate that these alterations may lead to a structurally incompetent basement membrane that facilitates the basal cell carcinoma ability to invade tissues.

Antigens, CD↗
PubMed1999

Activation of p53 function in carcinoma cells by the alpha6beta4 integrin.

The interaction of integrins with extracellular matrix is known to promote cell survival by inhibiting apoptotic signaling. In contrast, we demonstrate here that the alpha6beta4 integrin induces apoptosis in carcinoma cells by stimulating p53 function. Specifically, we show that expression of alpha6beta4 in carcinoma cells that lack this integrin stimulates an increase in the transactivating function of p53 as demonstrated by the ability of this integrin to up-regulate the expression of a p53-sensitive reporter gene as well as the endogenous p53 response gene, bax. In addition, we report that alpha6beta4 triggers apoptosis in carcinoma cells that express wild-type but not mutant p53 and that these alpha6beta4 functions are inhibited by a dominant negative p53 construct. Importantly, we provide a link between integrin signaling and p53 activation by demonstrating that the clustering of alpha6beta4 with a beta4 integrin-specific antibody promotes p53-dependent apoptosis in cells that express both alpha6beta4 and wild-type p53. These studies are the first to demonstrate that a specific integrin can promote apoptosis by activating p53. Moreover, given the ability of alpha6beta4 to stimulate invasion (Shaw, L. M., Rabinovitz, I., Wang, H. F., Toker, A., and Mercurio, A. M. (1997) Cell 91, 949-960), these studies suggest that the ability of alpha6beta4 to promote carcinoma progression will be enhanced in tumor cells that express mutant, inactive forms of p53.

Antigens, Surface↗
PubMed1998

Stimulation of extracellular matrix components in the normal brain by invading glioma cells.

Malignant gliomas are characterized by an extensive invasion of tumor cells into the normal brain parenchyma. A substantial amount of data indicates that cell movement in general is regulated by specific interactions between extracellular matrix components and specific cell-surface receptors. In the present work, multicellular spheroids from 4 human glioma cell lines (U-373Mg, A-172Mg, U-251Mg and HF-66) were confronted with normal rat brain cell aggregates in vitro, which resulted in a progressive invasion of tumor cells into the brain aggregates. The co-cultures were then sectioned and immuno-stained for specific extracellular matrix components (laminin, fibronectin and collagen type IV) and for specific cell-surface receptors which bind to these components (integrins beta1, beta4, alpha3, alpha6). In addition, flow-cytometric measurements and Northern blot analyses showed expression of several different integrins within the cell lines. The alpha3 subunit was expressed strongly in all cell lines. Whereas the beta1 subunit was expressed weakly in exponentially growing monolayer cultures, it showed a pronounced expression in multicellular spheroids, indicating that the integrin expression may vary depending on the micro-environment within a tumor. Furthermore, normal brain tissue was able to produce laminin when confronted with the glioma cells, which also was observed for fibronectin and collagen type IV. The relevance of our observations to the in vivo situation was investigated further by immuno-staining 5 human glioma biopsy samples for laminin. In some areas of the tumors, specific deposits of laminin were observed. In conclusion, we have shown that normal brain tissue has the ability to produce extracellular matrix components, such as laminin, collagen type IV and fibronectin, when confronted with invading glioma cells. Our results show that the glioma cells express specific integrins which can interact with these extracellular matrix components. Such interactions may facilitate tumor cell migration and invasion.

Animals↗
PubMed2003

Butyrate inhibits pancreatic cancer invasion.

Pancreatic cancer is the most deadly gastrointestinal malignancy because of its propensity for local invasion and early metastasis. Integrin chains, in particular beta4, can promote invasion in other cancers. The effect of sodium butyrate (NaBT), which induces differentiation in transformed cells, on integrin expression is unknown. The purpose of this study was to determine patterns of integrin expression in pancreatic cancer cells and investigate the effect of NaBT on integrin expression and invasion. Integrin expression was assessed in the less invasive MIA-PaCa-2 and PANC-1 and more invasive L3.6, AsPC-1, and SUIT-2 human pancreatic cancer cell lines by ribonuclease (RNase) protection assay. Western blotting and immunofluorescent staining for beta4 expression was determined after NaBT treatment. Matrigel invasion chambers were used to assess pancreatic cancer cell invasion. beta4 and beta7 integrin expression was highest in L3.6, AsPC-1, and SUIT-2 cells. NaBT reduced the expression of beta4 integrin in AsPC-1 cells including less cell surface beta4. Invasion of AsPC-1 cells was also reduced by NaBT. Expression of beta4 is higher in more aggressive pancreatic cancer cells; NaBT inhibits beta4 expression and invasion. NaBT may represent a novel strategy to inhibit pancreatic cancer invasion and improve the prognosis of this deadly disease.

Adenocarcinoma↗
PubMedDate not supplied

Differential modulation of integrin expression in chondrocytes during expansion for tissue engineering.

Cartilage tissue engineering has an important role to play in the generation of graft material for reconstructive surgery. In cultured chondrocytes, the dedifferentiation of cells seems unavoidable for multiplication. Dedifferentiated cells produce matrix of less quality. Normal cartilage is composed of chondrocytes, which are embedded within an extracellular matrix (ECM). The ECM plays a key role in controlling cellular characteristics and contains the integrins as a large family of heterodimeric cell adhesion receptors involved in cell-cell and cell-matrix interactions. In this study, the characteristic changes of integrin expression and expression of matrix proteins during the course of dedifferentiation of chondrocytes in cell culture for 1, 6 and 21 days, analyzed at the mRNA level by microarray analysis and at the protein level by immunohistochemistry, are described. The components of the fibronectin receptor, integrin beta1,alpha5, in conjunction with the ligand fibronectin, were up-regulated during dedifferentiation. Integrin beta3 was expressed in the grey area. The components of the vitronectin-receptor, integrin alpha2b, alpha v, as well as integrin beta5, were activated on day 21, but neither vitronectin nor osteopontin were expressed by the cells. With ongoing dedifferentiation, activation of the GPIIb/GPIIIa receptor was found. The integrins beta2, beta4, beta6, beta8 and alpha2, alpha4, alpha6, alpha7 and alpha11 were never expressed. ILK, CD47 and ICAP1, as components of the intracellular signalling cascade of several integrins, were activated with ongoing dedifferentiation. In conclusion, a candidate for signal transmission during dedifferentiation is the fibronectin receptor (integrin alpha5beta1) in conjunction with its ligand fibronectin. Other receptors, e.g. for vitronectin and osteopontin (alphaVbeta3) or laminin (alpha6beta1) or their ligands, do not seem to be involved in signal transmission for dedifferentiation. In addition, the GPIIb/IIIa-receptor seems to assist the process of dedifferentiation. Intracellularly, ILK, ICAP1 and CD47 might assist the transduction of the integrin-dependent signals.

Cell Culture Techniques↗
PubMed2000

Selective upregulation of a functional beta7 integrin on differentiating eosinophils.

BACKGROUND: The sequence of adhesion-molecule expression during eosinophil differentiation remains unclear. METHODS: We analyzed the surface expression of alpha4, beta1, and beta7 integrins and compared it to established myeloid developmental markers, using the eosinophilic cell line HL-60 clone 15, as well as cord and peripheral blood differentiation assays. RESULTS: Cells induced to eosinophil differentiation by treatment with butyric acid, IL-5, and GM-CSF showed a significant upregulation of beta7 integrin expression coincident with a marked upregulation of CD35 and attenuation of CD33 and beta1 integrin expression. In addition, adhesion of induced HL-60 clone 15 cells to fibronectin was attenuated by a beta7 integrin antibody. CONCLUSIONS: Our data show that protein synthesis-dependent upregulation of the functional beta7 integrin occurs under conditions when beta4 and beta1 integrins are fully expressed, indicating a sequential appearance of specific adhesion molecules on differentiating eosinophil progenitors.

Antigens, CD↗
PubMed2005

Integrins in slow-cycling corneal epithelial cells at the limbus in the mouse.

Adult corneal epithelial stem cells (CESCs) have been shown to reside at the periphery of the cornea at a site called the corneoscleral junction or limbus. Although studies have shown that these cells are slow cycling, their molecular characteristics are not well understood. Using a whole-mount procedure, we show that whereas alpha9-integrin is present in a subset of the basal cells at the corneal limbus and absent in the central cornea, beta1-, beta4-, alpha3-, and alpha6-integrins are more highly expressed overall in central corneal basal cells. To characterize CESCs based on their slow-cycling nature, we simultaneously evaluated 5-bromo-2-deoxyuridine (BrdU) label-retaining cells (LRCs) and integrin expression (alpha9, beta1, and beta4) in a total of 1,889 cells at the limbus of adult mice that had been injected as neonates with BrdU. Whereas the LRCs were usually observed adjacent to alpha9-integrin-positive cells, most LRCs were alpha9-integrin-negative and expressed high levels of beta1- and beta4-integrin. In addition, we observed more BrdU-positive LRCs at the superior and inferior quadrants of adult mouse corneas than at the nasal and temporal quadrants, and determined that 0.94 to 3.6% of the limbal basal cells were slow cycling. We conclude from these data that the slow-cycling LRCs in the adult mouse cornea are enriched in cells that express high levels of beta1- and beta4-integrin and little alpha9-integrin.

Animals↗
PubMed2006

In vitro analysis of integrin expression during chondrogenic differentiation of mesenchymal stem cells and chondrocytes upon dedifferentiation in cell culture.

Tissue engineering represents a promising method for generating chondrogenic grafts for reconstructive surgery. In cultured chondrocytes, the dedifferentiation of cells seems unavoidable for multiplication. Stem cells, however, displaying unlimited self-renewal and the capacity to differentiate towards chondrocytes, might be usable after further characterization. As the interactions between the extracellular matrix and the cellular compartment can alter the cellular behaviour, we investigated the expression of integrins using microarray analysis during chondrogenic differentiation of human mesenchymal stem cells (MSC) in comparison with de-differentiating human chondrocytes (HC) harvested during septoplasty. During chondrogenic differentiation of MSC, the fibronectin-receptor (Integrin beta1alpha5), fibronectin and the GPIIb/IIIa-receptor were downregulated. The components of the vitronectin-receptor (Integrin alphavbeta3) and CD47 were constantly expressed and ILK was downregulated. Vitronectin and osteopontin were not expressed by the cells. In HC, Integrin beta1alpha5 in conjunction with the ligand fibronectin were upregulated during dedifferentiation, Integrin alphavbeta3 as well as the GBIIb/IIIa-receptor were activated on day 21 but neither vitronectin nor osteopontin were expressed by the cells. The integrins, beta2, beta4, beta6, beta8 and alpha2, alpha4, alpha6, alpha7, alpha11, were not expressed at any time. ILK, CD47, and ICAP were activated with ongoing dedifferentiation. In conclusion, a candidate for signal-transmission is the fibronectin receptor (integrin alpha5beta1) in conjunction with its ligand fibronectin. Other receptors, e.g. for vitronectin and osteopontin (alphavbeta3), or their ligands do not seem to be involved in signal transmission for dedifferentiation. The GPIIb/IIIa-receptor might assist the process of dedifferentiation. Intracellularly, ILK, ICAP1 and CD47 might be involved in the transduction of integrin-dependent signals.

Cell Differentiation↗
PubMed2004

Expression of integrin subunits alpha2, alpha3, alpha5, alphav, beta1, beta3 and beta4 in different histological types of ameloblastoma compared with dental germ, dental lamina and adult lining epithelium.

OBJECTIVE: To analyze integrin expression and distribution in different histological types of ameloblastoma, compared with dental germ, dental lamina and adult lining epithelium. MATERIALS AND METHODS: Three-micrometer sections from paraffin-embedded specimens were evaluated employing a streptavidin-biotin immunohistochemical method and anti-integrin alpha2, alpha3, alpha5, alphav, beta1, beta3 and beta4 antibodies. RESULTS: All integrins were present in all specimens, exhibiting different patterns. In follicular ameloblastoma, the integrin staining was stronger in the periphery while integrin alpha2 was not present in the central cells. Acanthomatous ameloblastoma showed a similar pattern, with positive staining for integrins alpha3, alpha5, alphav, beta1 and beta4 in the metaplastic cells. In the unicystic, integrin staining was uniform except for integrins alpha5 and beta3 which showed weaker staining in the upper layers. In the plexiform ameloblastoma, dental germ and lamina integrin staining was uniform. In the adult lining epithelium, staining for integrins alpha2, alpha5 and beta4 was confined to the basal layer, while integrins alphav and beta3 were present in the basal and parabasal, with integrins alpha3 and beta1 in the upper layers. CONCLUSION: Acanthomatous, follicular and unicystic ameloblastomas showed integrin staining patterns similar to the adult lining epithelium while the plexiform ameloblastoma was similar to the dental germ and lamina.

Adult↗
PubMed2006

Dissociation of the complex between CD151 and laminin-binding integrins permits migration of epithelial cells.

Laminin-binding integrins form a complex with CD151, a member of the tetraspanin family suggested to be involved in the regulation of cell migration. In the epidermis, CD151 is localized with alpha3beta1 and alpha6beta4 integrins at cell-cell and cell-matrix contacts, respectively, characteristic structures of non-migrating cells. Taking advantage of a monoclonal antibody against CD151, TS151r, which epitope overlaps with the tetraspanin integrin-binding site, we have investigated the role of CD151 in epithelial cell migration. Under standard culture conditions, the migratory capacity of epithelial HaCaT cells on laminins is low, apparently due to endogenous laminin 5. However, challenging HaCaT cells with TS151r allows a re-arrangement of the actin cytoskeleton, dismantling of cell-cell and beta4 integrin-mediated cell-matrix contacts and cell migration. In vivo, free CD151 is absent in resting epithelial cells of interfollicular epidermis, and all CD151 is bound to integrins in intercellular and cell-matrix contacts. By contrast, free CD151 is present at intercellular contacts in the epithelial sheet lining the deeper region of anagen hair follicles, which is considered to contain migrating cells. Together, these results strongly suggest that dissociation of the CD151-integrin complex permits remodeling of epithelial cell interactions with the extracellular matrix and cell migration.

Antigens, CD↗