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PubMed1996

Lack of integrin alpha-chain endoproteolytic cleavage in furin-deficient human colon adenocarcinoma cells LoVo.

In the present report the biosynthesis of the integrin alpha-chains endowed with constitutive endoproteolytic cleavage was evaluated in LoVo cells where furin, a subtilisin-like convertase involved in post-translational endoproteolytic processing, is not functional. It was found that cell-surface alpha 3, alpha 6 and alpha v subunits were not processed endoproteolytically into heavy and light chains as they were in HT29-D4 cells, a furin-competent cell line. Complete removal of N-linked oligosaccharides and pulse-chase experiments confirmed that the cleavage of the alpha 6 integrin subunit occurring 45 min after translation in HT29 cells did not take place in LoVo cells. Apart from cleavage deficiency, alpha 6 subunit glycosylation, association with beta 4 subunits and targeting to the plasma membrane seemed comparable in LoVo and HT29 cells. The pro-alpha 6 and the pro-alpha 3 subunits immunopurified from LoVo cells were highly sensitive to endoproteolysis by recombinant furin. Furin cleavage was calcium dependent and resulted in the conversion of the 140 kDa pro-alpha 6 into a 120 kDa heavy chain. These results suggest strongly that furin is involved in the endoproteolytic processing of cleavable integrin alpha subunits.

ADP Ribose Transferases↗
PubMed1993

Expression of alpha 7 integrin cytoplasmic domains during skeletal muscle development: alternate forms, conformational change, and homologies with serine/threonine kinases and tyrosine phosphatases.

We recently reported the cloning and sequencing of the alpha 7 integrin chain and its regulated expression during the development of skeletal muscle (Song et al. (1992) J. Cell Biol. 117, 643-657). The alpha 7 chain is expressed during the development of the myogenic lineage and on adult muscle fibers and this suggests that it participates in multiple and diverse functions at different times during muscle development. One interesting portion of this isoform is its cytoplasmic domain; comprised of 77 amino acids it is the largest in the alpha chains thus reported. In these experiments we begin to study the potential functions of the alpha 7 cytoplasmic domain by analyzing homologies between the rat and human sequences, by immunologic studies using an anti-cytoplasmic domain antiserum, and by identifying two alternate forms. In keeping with the nomenclature used to describe the alpha 3 and alpha 6 alternate cytoplasmic domains, we refer to the originally reported species as alpha 7B and the two additional forms as alpha 7A and alpha 7C. These three cytoplasmic domains likely arise as a consequence of alternate splicing. A splice site at the junctions of the transmembrane and cytoplasmic domains is used to generate the alpha 3, alpha 6 and alpha 7 A and B forms. The alpha 7A form RNA contains an additional 113 nucleotides compared to the B form, and a common coding region in the A and B form RNAs is used in alternate reading frames. Part of the coding region of alpha 7B appears to be used as the 3'-untranslated region of the alpha 7A form. The alpha 7C mRNA is 595 nucleotides smaller than the alpha 7B RNA and part of the 3'-untranslated region of the alpha 7B isoform is used as coding sequence in alpha 7C. There is developmental specificity in expression of these alternate mRNAs: alpha 7A and alpha 7C transcripts are found upon terminal myogenic differentiation whereas alpha 7B is present earlier in replicating cells and diminishes upon differentiation. We suggest this selective expression of the alpha 7 cytoplasmic domains underlies the diversity in function of the alpha 7 beta 1 integrin at different stages of muscle development. Immunochemical analyses indicate that the alpha 7B cytoplasmic domain undergoes a change in conformation in response to binding laminin or upon crosslinking initiated with antibody reactive with the integrin extracellular domain. Crosslinking also promotes association of the integrin with the cell cytoskeleton.(ABSTRACT TRUNCATED AT 400 WORDS)

Alternative Splicing↗
PubMed1996

Distinct alpha 7A beta 1 and alpha 7B beta 1 integrin expression patterns during mouse development: alpha 7A is restricted to skeletal muscle but alpha 7B is expressed in striated muscle, vasculature, and nervous system.

The laminin binding alpha 7 beta 1 integrin has been described as a major integrin in skeletal muscle. The RNA coding for the cytoplasmic domain of alpha 7 integrin undergoes alternative splicing to generate two major forms, denoted alpha 7A and alpha 7B. In the current paper, we have examined the developmental expression patterns of the alpha 7A and alpha 7B splice variants in the mouse. The alpha 7 integrin expression is compared to that of the nonintegrin laminin receptor dystroglycan and to that of laminin-alpha 1 and laminin-alpha 2 chains. Alpha 7A integrin was found by in situ hybridization to be specific to skeletal muscle. Antibodies specific for alpha 7B integrin and in situ hybridization revealed the presence of alpha 7 mRNA and alpha 7B protein in the E10 myotome and later in primary and secondary myotubes. In the heart, alpha 7B integrin was not detectable in the endocardium or myocardium during embryonic and fetal heart development. Northern blot analysis and immunohistochemistry revealed a postnatal induction of alpha 7B in the myocardium. In addition to striated muscle, alpha 7B integrin was localized to previously unreported nonmuscle locations such as a subset of vascular endothelia and restricted sites in the nervous system. Comparison of the alpha 7 integrin expression pattern with that of different laminin isoforms and dystroglycan revealed a coordinated temporal expression of dystroglycan, alpha 7 integrin, and laminin-alpha 2, but not laminin-alpha 1, in the forming skeletal muscle. We conclude that the alpha 7A and alpha 7B integrin variants are expressed in a developmentally regulated, tissue-specific pattern suggesting different functions for the two splice forms.

Animals↗
PubMed1995

Localized distribution of alpha 9 integrin in the cornea and changes in expression during corneal epithelial cell differentiation.

A recently characterized integrin alpha-chain, alpha 9, forms heterodimers with the integrin beta 1-chain and is present in the skin with a distribution similar to that of alpha 2 and alpha 3, other beta 1 integrins. To determine whether alpha 9 is expressed in the stratified squamous epithelium of the cornea, we used immunohistochemical techniques to compare the distribution of alpha 9 in the adult mouse cornea with that of alpha 3. Abundant alpha 9 was expressed in the lateral and basal membranes of the basal cells of the conjunctiva and corneal limbus, but very little alpha 9 was present in the basal cells of the central corneal epithelium. In contrast, alpha 3 was present in the membranes of basal cells of the conjunctiva, limbus, and central cornea. To determine when during postnatal maturation of the corneal epithelium alpha 9 becomes restricted to the limbus, we looked at the distribution of alpha 9 and alpha 3 in the developing mouse eye from birth to eyelid opening. At birth, the basal cells of the cornea and developing limbal region did not express alpha 9, but there was abundant alpha 9 expressed in suprabasal cells between the fused lids and in the basal cells of the skin and conjunctiva. In contrast, alpha 3, integrin was expressed uniformly in the basal cells across the surface of the conjunctiva, limbus, and cornea and was present only in the basal cells of the epithelium between the fused eyelids. In the central cornea, alpha 9 expression increased in basal cells up until Day 10 after birth. After Day 10, alpha 9 expression in the central cornea began to decrease; after the lids were open, alpha 9 expression in the central cornea became restricted to the limbus. In the basal and suprabasal cells between the fused eyelids expression of alpha 9 became increasingly restricted over time to the basal cells. Recent data suggest that alpha 9 beta 1 can interact with tenascin. Our dual labeling confocal microscopy studies indicate that localization of alpha 9 and tenascin are not coordinated in the developing mouse cornea. Many recent studies have shown an important role for beta 1 integrins in mediating epithelial cell differentiation in vitro; in vivo, changes in integrin expression have been found in wound healing, psoriasis, and in basal and squamous cell carcinomas.(ABSTRACT TRUNCATED AT 400 WORDS)

Age Factors↗
PubMed1992

Coevolution of the vertebrate integrin alpha- and beta-chain genes.

The integrin receptors are heterodimers whose alpha and beta subunits are encoded by separate, evolutionarily unrelated multigene families. Phylogenetic analysis of DNA sequences from these two gene families showed that they have not always evolved in a parallel fashion. The integrin alpha chains that can form heterodimers with beta 1 do not constitute a monophyletic group, nor do the beta chains which can form heterodimers with alpha V. On the other hand, the vertebrate alpha chains associating with beta 2 are a monophyletic group. In the metal cation-binding region of the alpha chain, an exon exchange took place between human alpha M and alpha X approximately 40-50 Mya, homogenizing this functionally important region in these two alpha chains. When integrin beta chains of different functional classes are compared, nonsynonymous (amino acid altering) nucleotide substitutions that alter amino acid residue charge in the central region of the molecule occur at a rate significantly higher than that expected under random replacement. By contrast, when closely related beta 1 chains are compared, residue charge is conserved in this region. These results pinpoint the central region as a focus of functional divergence among integrin beta chains, perhaps relating to the ability of each beta integrin class to associate with a specific array of alpha integrins. Furthermore, they imply that positive, directional selection on this region has occurred in the evolution of the integrin beta-chain gene family.

Animals↗
PubMed1991

Cloning and expression of cDNAs for the alpha subunit of the murine lymphocyte-Peyer's patch adhesion molecule.

cDNA clones encoding the alpha chain of the murine lymphocyte-Peyer's patch adhesion molecule (LPAM), which is associated with lymphocyte homing, have been isolated by screening with the human VLA-4 (alpha 4h) probe. Several alpha 4 antigenic determinants were identified on COS-7 cells after transfection. From overlapping clones, approximately 5 kb of contiguous nucleotide sequence have been determined, encoding a protein sequence of 1039 amino acids for the LPAM alpha chain (alpha 4m). LPAM is a member of the integrin family of cell-surface heterodimers, and alpha 4m is the murine homologue of the human alpha 4 h chain. The two proteins have a total sequence similarity of 84%, with an almost perfect conservation (31/32 amino acids) in the cytoplasmic domain. Like alpha 4h, alpha 4m is distinct from other integrin alpha chains because it has neither an I-domain nor a COOH-terminal cleavage site. The positions of the characteristic Cysteine residues are conserved, and a putative protease cleavage site is located near the middle of the protein sequence. The NH2-terminal part of the protein contains seven homologous repeats, and three of them include putative divalent cation-binding sites. These sites are among the most conserved between the alpha 4m sequence and other alpha chains, and may therefore be involved in the binding of integrin alpha and beta chains. An additional cDNA clone was isolated which shares a sequence of perfect homology with the alpha 4m encoding cDNAs, but has a unique 3' poly-A end. This observation correlates with the fact that three discrete murine RNA bands are observed in Northern blot experiments using alpha 4m as a probe, whereas only two human RNA species are described for alpha 4h, indicating a higher complexity for murine than for human sequences.

Amino Acid Sequence↗
PubMed1999

Alteration in alpha 2 integrin immunocytochemical expression on cultured human gingival fibroblasts following nicotine exposure.

BACKGROUND: Clinical epidemiologic studies carried out in smokers versus non smokers support the concept that tobacco-related factor may affect the periodontal tissues and wound healing. METHODS: In this study, the role of nicotine on the integrin alpha 2 chain immunocytochemical expression, in human gingival fibroblasts (HGF) was investigated in vitro. The kinetic induction of this type of integrin on HGF in response to increasing percentage of nicotine was been characterized. A human gingival fibroblast strain, derived from a healthy individual with non-inflamed gingiva, was used in this study. The cells were then grown on acetylated microscope slides and fixed with cold ethanol, samples were then incubated for 16 to 19 hrs at 4 degrees C to anti-human alpha 2 integrin chain monoclonal antibody. RESULTS: In control cultures and in HGF treated with 0.025 microM nicotine the initial higher expression of alpha 2 chain decreased (grade 1 in both culture) while in HGF treated with 0.075 microM increased (grade 3). After 48 hours HGF exposed to 0.075 microM nicotine, increased further their expression of alpha 2 chain. CONCLUSIONS: The results obtained demonstrate a dose-time dependent nicotine influence on immunocytochemical expression of alpha 2 integrin chain. These data suggest that nicotine may promote a collagene breakdown via an increase of alpha 2 integrin chain expression.

Cells, Cultured↗
PubMed1997

Defining extracellular integrin alpha-chain sites that affect cell adhesion and adhesion strengthening without altering soluble ligand binding.

It was previously shown that mutations of integrin alpha4 chain sites, within putative EF-hand-type divalent cation-binding domains, each caused a marked reduction in alpha4beta1-dependent cell adhesion. Some reports have suggested that alpha-chain "EF-hand" sites may interact directly with ligands. However, we show here that mutations of three different alpha4 "EF-hand" sites each had no effect on binding of soluble monovalent or bivalent vascular cell adhesion molecule 1 whether measured indirectly or directly. Furthermore, these mutations had minimal effect on alpha4beta1-dependent cell tethering to vascular cell adhesion molecule 1 under shear. However, EF-hand mutants did show severe impairments in cellular resistance to detachment under shear flow. Thus, mutation of integrin alpha4 "EF-hand-like" sites may impair 1) static cell adhesion and 2) adhesion strengthening under shear flow by a mechanism that does not involve alterations of initial ligand binding.

Amino Acid Sequence↗
PubMed1995

Expression and function of beta 1 and alpha v beta 3 integrins in ovarian cancer.

Ovarian cancer cells disseminate by implanting onto the peritoneal mesothelial cell surface of the abdominal cavity. A common feature of these peritoneal implants is the presence of tumor cell invasion into the submesothelial extracellular matrix (ECM). In view of the important role of integrins in ECM recognition and cell migration, we were interested in defining the pattern of integrin expression and function in ovarian cancer cell lines and primary tissue samples. The beta 1 integrin chain was expressed by CAOV-3, SKOV-3, OVCAR-3, and SW626 ovarian cancer cell lines, associated with expression of alpha 1, -2, -3, -5, and -6 chains. The alpha 4 chain was also expressed by two of the four lines. In addition to beta 1 integrins, the alpha v beta 3 integrin was also expressed, although there was no expression of beta 2, -4, and -7 chains. Immunoprecipitation of surface-labeled CAOV-3 cells with an anti-beta 1 antibody revealed a band at approximately 110-130 kDa consistent with the known molecular mass of the beta 1 chain, as well as several associated bands consistent with noncovalently linked integrin alpha chains. A similar pattern of beta 1 and alpha v beta 3 integrin expression was observed for primary ovarian cancer tissue samples. Ovarian cancer cell lines exhibited significant binding to collagen type I and laminin which was primarily mediated by beta 1 integrins. In contrast, ovarian cancer cell binding to fibronectin was mediated by both alpha 5 beta 1 and alpha v beta 3 integrins. Even though mesothelial cells were observed to express fibronectin mRNA and protein, binding of ovarian cancer cells to peritoneal mesothelium was not blocked by neutralizing antibodies to beta 1 or alpha v beta 3 integrins. These data suggest that functional integrins are commonly expressed by ovarian cancer cells, although they do not appear to mediate ovarian cancer cell implantation onto peritoneal mesothelium. The role that integrins play in the invasion of ovarian cancer cells into the submesothelial ECM deserves further investigation.

Amino Acid Sequence↗
PubMed1997

Extracellular matrix remodeling at the early stages of liver regeneration in the rat.

Previous studies have shown that activity of urokinase-type plasminogen activator (u-PA) increases very rapidly (within 1 minute) after partial hepatectomy. In view of the well-recognized roles of u-PA as one of the major initiators of the matrix proteolysis cascade and as an activator of plasminogen and hepatocyte growth factor (HGF), we studied matrix degradation in liver shortly after partial hepatectomy. The activation of plasminogen to plasmin following partial hepatectomy was examined by Western blot analysis, and a small increase in plasmin at approximately 15 minutes followed by a large elevation at approximately 3 to 6 hours after partial hepatectomy was detected. In addition, we found that fibrinogen, the major substrate for plasmin, begins to be degraded at approximately 15 to 30 minutes following partial hepatectomy. Using immunohistochemical staining, we detected that the distribution of fibrinogen in normal liver is localized to the perisinusoidal space surrounding the periportal region. A decreased distribution of fibrinogen in the periportal region was found by 15 minutes and continued through 24 hours following partial hepatectomy. In addition, the distribution of fibronectin in normal liver was localized to the perisinusoidal space surrounding the periportal and the pericentral regions. A strikingly decreased distribution of fibronectin in the periportal region was found at 5 minutes after partial hepatectomy. Furthermore, we observed that the protein levels of laminin, entactin, and fibronectin in an extracellular matrix (ECM)-enriched preparation decreased shortly after partial hepatectomy, and were restored later. No changes were observed with either vitronectin or the integrin chain alpha(v). In contrast to the protein levels of the ECM components, the messenger RNA (mRNA) levels of fibronectin, integrin chain beta1, and integrin chain alpha(v) gradually increased over 18 hours and then decreased thereafter. Taken together, these results suggest that rapid reorganization of selected ECM components are important for hepatocyte proliferation at the early stages of liver regeneration.

Animals↗
PubMed1995

Expression of vitronectin receptor on human NK cells and its role in protein phosphorylation, cytokine production, and cell proliferation.

In this paper, we provide evidence that the vitronectin receptor (VNR) alpha v beta 3 is expressed on human NK cells. The presence of this VNR on freshly purified NK cells was demonstrated by flow cytometry analysis, as well as biochemically, after 125I-labeled surface lactoperoxidase labeling and immunoprecipitation. mAbs LM142 and LM609 specific for alpha v and alpha v beta 3, respectively, precipitated a heterodimer of alpha- and beta-chains with approximate molecular masses of 155 and 110 kDa under nonreducing conditions. Under reducing conditions, there was an apparent decrease in the molecular mass of the alpha-chain, which is likely to result from the release of a protein of 20 to 30 kDa linked by internal disulfide bond to the alpha v-chain. Integrin alpha v beta 3 expressed on NK cells became functional, i.e., was able to bind its ligand, vitronectin (VN), only after cellular activation or when costimulation with an additional signal was provided. Thus, NK cells adhered to plastic-immobilized VN only after IL-2 activation, and RGD-containing synthetic peptides or mAbs specific for alpha v beta 3 complex inhibited this binding. To assess the role of the VNR in signal transduction, anti-beta 3 mAb was used to cluster the VNR on NK cells and, thereby, mimic the process that occurs during formation of adhesive contacts. Cross-linking of VNR on fresh NK cells stimulated phosphorylation on tyrosine residues of several intracellular proteins. The major increase in tyrosine phosphorylation was observed in proteins of approximate molecular masses of 75 and 120 kDa. Therefore, signal transduction by the VNR on NK cells induced activation of intracellular protein kinases. Ligand engagement of the VNR on NK cells also costimulated cytokine production and proliferation of NK cells. Binding of NK cells to plastic-immobilized VN served as a costimulus with either anti-Fc gamma RIII or IL-2 to produce IFN-gamma, TNF-alpha, and cell proliferation. Our findings suggest that occupancy and subsequent clustering of VNRs play a role in the activation and function of human NK cells.

Amino Acid Sequence↗
PubMed1992

A family of beta 7 integrins on human mucosal lymphocytes.

The heterodimeric protein complex recognized by the human mucosal lymphocyte 1 (HML-1) monoclonal antibody is expressed on 95% of intraepithelial lymphocytes but on only 1-2% of peripheral blood lymphocytes [Cerf-Bensusson, N., Jarry, A., Brousse, N., Lisowska-Grospierre, B., Guy-Grand, D. & Griscelli, C. (1987) Eur. J. Immunol. 17, 1279-1285]. We purified the smaller HML-1 subunit (105 kDa under nonreducing conditions) from hairy-cell leukemia cells and determined the N-terminal amino acid sequence of this chain. The 17 residues determined were identical to the deduced amino acid sequence encoded by an integrin beta 7 cDNA clone [Yuan, Q., Jiang, W.-M., Krissansen, G.W. & Watson, J.D. (1990) Int. Immunol. 2, 1097-1108]. Biochemical analysis of the larger HML-1 subunit (175 kDa under nonreducing conditions) suggested that it was a distinct member of the cleaved group of integrin alpha chains, which we designated alpha E. The beta 7 chain also was associated with the integrin alpha 4 subunit, suggesting that the HML-1 antigen (alpha E beta 7) and alpha 4 beta 7 constitute a beta 7 integrin family on mucosal lymphocytes. Interestingly, regulation of the expression of the HML-1 antigen was reciprocal to that of lymphocyte function-associated molecule 1 in the presence of transforming growth factor beta 1. We suggest that these beta 7 integrins may play a specific role in mucosal localization or adhesion and that the expression of the HML-1 antigen might be regulated by transforming growth factor beta 1 produced at or near epithelial tissues.

Amino Acid Sequence↗
PubMed1995

Integrin regulation of an inflammatory effector gene. Direct induction of the tissue factor promoter by engagement of beta 1 or alpha 4 integrin chains.

Inflammatory genes are regulated in cells of monocyte (Mo) lineage by a variety of cellular encounters, including adhesion mediated by integrins. The role of the beta 1 family of integrins in the direct induction of immediate early gene expression was analyzed by using the tissue factor (TF) gene. Engagement of alpha 4 or beta 1 on Mo, but not members of the beta 2 integrin family, with specific mAbs as surrogate ligands immediately and directly induced high level surface expression of TF, and accumulation of TF mRNA, as well as production of TNF-alpha and HIV-1 virus. The mechanism responsible for induction of TF gene transcription mediated by the engagement of alpha 4 or beta 1 was elucidated by using THP-1 monoblastic leukemia cells. Functional analysis of plasmids containing the TF promoter expressing the luciferase reporter gene identified a cis-acting integrin-responsive element (InRE), which contained two AP-1 sites as well as a single kappa B-like site. Mutation of either the AP-1 sites or kappa B-like site greatly diminished responsiveness to integrin engagement. This InRE also conferred responsiveness to a heterologous promoter in the same reporter plasmid. Binding of mAbs to either alpha 4 or beta 1 led to nuclear translocation of the c-Rel/p65 heterodimer that preferentially bound to the TF kappa B-like site. In contrast, constitutive binding of AP-1 proteins to the two AP-1 sites was not increased by alpha 4 or beta 1 integrin engagement. These studies expand knowledge of integrin regulation of immediate early gene expression in Mo and molecular encounters that are inferred to play an active role in Mo effector functions.

Base Sequence↗
PubMed1995

Expression of a novel beta 1 integrin in the dysplastic progression of the cervical epithelium.

Epithelial cell interactions with matrices and basal membranes are central for tissue organization, and integrins are a family of adhesion molecules that play a major role in these interactions. We have analyzed the expression of a novel integrin alpha chain, alpha 10.1.2, in the squamous epithelium of the portio vaginalis uteri from patients with cervical intraepithelial neoplasia (CIN) and from control samples without apparent cervical abnormalities. The localization of beta 1 and alpha 6 chains was also investigated, together with the distribution of intraepithelial HLA-DR and CD1c-positive Langerhans cells. In the normal cervical epithelium, all of the integrin chains were detected in the basal cell layer, albeit with a different localization in the apical, lateral, and basal cell surfaces. Langerhans cells were evenly distributed in the deep 2/3 of the squamous epithelium. Expression of alpha 10.1.2 was reduced or absent in all of the CIN 1 specimens in which the other integrin chains were either normal or slightly reduced. CIN 2 was characterized by overexpression of integrins, namely of beta 1 and of alpha 10.1.2 chains which were consistently detected also in suprabasal cell layers. None of the integrin chains was found in CIN3 samples in which Langerhans cells were also absent. Thus, modulation and redistribution of integrins occur in the progression of cervical dysplasia, and lack of integrin expression characterizes high-grade lesions. As in other dysplasias and cancers of squamous epithelia, the localization of alpha 10.1.2 chains provides reliable diagnostic and possibly prognostic criteria.

Adult↗
PubMed1998

Altered expression of alpha 6 integrin subunit in oral squamous cell carcinoma and oral potentially malignant lesions.

The expression and distribution of integrin chains alpha 2, alpha 3, alpha 5, alpha 6, beta 1, beta 4, collagen type IV, laminin 1 and laminin 5 in oral squamous cell carcinoma (SCC) and oral keratoses with and without dysplasia (OL) have been studied by immunochemistry and western blotting. Focal interruptions of basement membrane protein staining were detected in SCC indicating a loss of continuity, whereas tumour nests were apparently completely surrounded by laminin 1, type IV collagen and laminin 5; the loss of basement membrane components in OL was found in only one specimen showing severe dysplasia. The localisation of integrins showed altered suprabasal and pericellular expression of the alpha 6 chain in all but one SCC, as well as in many OL samples, whereas the beta 4 subunit showed only a faint pericellular redistribution in SCC. In OL, beta 4 was often seen in a normal basally polarised distribution. Western blotting analysis confirmed that alpha 6 protein levels were abnormally high in cancerous lesions, whereas quantitative recovery of the beta 4 subunit in SCC was only minimal, suggesting a dissociation in the synthetic ratios of the two chains of the alpha 6 beta 4 heterodimer in SCC. Because alterations in the polarised expression of integrin alpha 6 beta 4 have been seen during epithelial tumour progression and wound healing, we suggest that the lack of restricted basal polarisation of alpha 6 could be an early but non-specific marker of oral malignancy, indicating that the generation of abnormal signals from the extracellular matrix may be involved.

Antigens, CD↗
PubMed1991

Cell type-specific integrin variants with alternative alpha chain cytoplasmic domains.

The integrin heterodimers composed of the alpha 6 subunit with the beta 1 or beta 4 subunit (alpha 6 beta 1 and alpha 6 beta 4) are receptors for laminin and basement membrane components, respectively. The alpha 3 beta 1 integrin recognizes laminin, collagen, fibronectin, or epiligrin. We report the identification of structural variants (A and B) of the alpha 6 and alpha 3 subunits, containing distinct cytoplasmic domains. The expression of one cytoplasmic domain or the other, based probably on alternative exon usage, is cell-type dependent. Most transformed cell lines express both alpha 6A and alpha 6B isoforms, as determined by mRNA amplification or antibody immunoprecipitation. In contrast, embryonic fibroblasts express exclusively alpha 6A, and embryonic stem cells express exclusively alpha 6B. In most normal tissues, both alpha 6 isoforms are detectable, but several tissues express either alpha 6A or alpha 6B. The alpha 3B mRNA was amplified from heart and brain, while all other tissues and cell lines tested contained only alpha 3A mRNA. Alternative cytoplasmic domains may provide a means for varying the cellular responses to the ligands of alpha 6 and alpha 3 integrins according to the cell type.

Amino Acid Sequence↗
PubMed1997

Integrated expression of glomerular extracellular matrix proteins and beta 1 integrins in monoclonal light chain-related renal diseases.

Light-chain deposition disease (LCDD) and amyloid light-chain amyloidosis (AL-Am) represent the two classical diseases associated with glomerular alterations in monoclonal light chain-related renal diseases. LCDD is characterized by deposition of extracellular matrix proteins in the mesangium, thus creating the morphologic appearance recognized as nodular glomerulosclerosis. In AL-Am, the mesangial matrix is replaced by polymerized light chains in the form of amyloid fibrils. Integrins are responsible for cell-to-cell and cell-to-matrix communication and, therefore, are expected to play a key role in the alterations encountered in these two diseases. The present article addresses the expression of selected extracellular matrix proteins (collagen IV, laminin, fibronectin, and tenascin) and their respective receptor beta 1 integrins (alpha 2, alpha 3, alpha 5, and alpha 9) in glomeruli with LCDD and AL-Am by immunohistochemical methods. The corresponding integrin (alpha 9 beta 1) co-localized with tenascin in the center of the mesangial nodules in LCDD. In AL-Am, tenascin is found primarily at the periphery of replaced mesangial areas and in the remaining mesangium not replaced by the amyloid. Tenascin co-localized with alpha 9 beta 1 integrin in mesangial areas in the earlier phases of the process. Fibronectin, laminin, and collagen IV, although increased in absolute amounts, are pushed toward the periphery of mesangial areas, in which correlated expression of their corresponding beta 1 integrins (alpha 2, alpha 3, and alpha 5, respectively) is documented in both LCDD and AL-Am. Deposition of tenascin might be at least partially responsible for the perpetuation and irreversibility of the glomerular lesion in LCDD.

Albumins↗