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Results for “Integrin alpha6beta1”

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PubMed2003

Expression and prognostic roles of integrins and interleukin-1 receptor type I in patients with ductal adenocarcinoma of the pancreas.

To investigate the prognostic indicator, we examined the expression of alpha6- and alpha5-integrin and interleukin-1 receptor type I (IL-1RI) immunohistochemically, and analyzed the correlation between immunohistochemical findings and clinicopathological factors in pancreatic cancer. In patients with a strongly expressing alpha6-integrin subunit or weakly expressing alpha5beta1-integrin in pancreatic cancer tissues there was a significant association with advanced TNM stage (P = 0.027 and 0.014, respectively), presence of liver metastases (P = 0.032 and 0.002, respectively), and poor prognosis (P = 0.0155 and 0.0056, respectively). In patients with a weakly expressing alpha6 integrin subunit or weakly expressing alpha5beta1-integrin in noncancerous pancreatic tissues there was a significant association with poor prognosis (P = 0.0324 and 0.0396, respectively). Multivariate analysis demonstrated that strong expression of alpha6- and weak expression of alpha5beta1-integrin were found to be independent prognosticators in pancreatic cancer patients. Our present results indicate that alpha6beta1- and alpha5beta1-integrin expression can be a significant prognostic indicator in pancreatic cancer.

Aged↗

PubMed2004

Cross-talk of integrin alpha3beta1 and tissue factor in cell migration.

In cancer and angiogenesis, coagulation-independent roles of tissue factor (TF) in cell migration are incompletely understood. Immobilized anti-TF extracellular domain antibodies induce cell spreading, but this phenomenon is epitope specific and is not induced by anti-TF 5G9. Spreading on anti-TF is beta1 integrin-dependent, indicating functional interactions of the TF extracellular domain 5G9 epitope (a presumed integrin-binding site) and integrins. Recombinant TF extracellular domain supports adhesion of cells expressing alphavbeta3 or certain beta1 integrin heterodimers (alpha3beta1, alpha4beta1, alpha5beta1, alpha6beta1, alpha9beta1) and adhesion is blocked by specific anti-integrin antibodies or mutations in the integrin ligand-binding site. Although several studies have linked TF to cell migration, we here demonstrate that TF specifically regulates alpha3beta1-dependent migration on laminin 5. Expression of TF suppresses alpha3beta1-dependent migration, but only when the TF cytoplasmic domain is not phosphorylated. Suppression of migration can be reversed by 5G9, presumably by disrupting integrin interaction, or by the protease ligand VIIa, known to induce PAR-2-dependent phosphorylation of TF. In both cases, release of alpha3beta1 inhibition is prevented by mutation of critical phosphorylation sites in the TF cytoplasmic domain. Thus, TF influences integrin-mediated migration through cooperative intra- and extracellular interactions and phosphorylation regulates TF's function in cell motility.

Animals↗

PubMed2003

Multiple integrin-ligand interactions synergize in shear-resistant platelet adhesion at sites of arterial injury in vivo.

Damage to the integrity of the vessel wall results in exposure of the subendothelial extracellular matrix (ECM), which triggers integrin-dependent adhesion and aggregation of platelets. The role of platelet beta1 integrins in these processes remains mostly undefined. Here, we demonstrate by intravital fluorescence microscopy that platelet adhesion and thrombus growth on the exposed ECM of the injured carotid artery is not significantly altered in alpha2-null mice and even in mice with a Cre/loxP-mediated loss of all beta1 integrins on their platelets. In contrast, inhibition of alphaIIbbeta3 integrin on platelets in wild-type mice blocked aggregate formation and reduced platelet adhesion by 60.0%. Strikingly, alphaIIbbeta3 inhibition had a comparable effect in alpha2-null mice, demonstrating that other receptors mediate shear-resistant adhesion in the absence of functional alpha2beta1 and alphaIIbbeta3. These were identified to be alpha5beta1 and/or alpha6beta1 as alphaIIbbeta3 inhibition abrogated platelet adhesion in beta1-null mice. We conclude that shear-resistant platelet adhesion on the injured vessel wall in vivo is a highly integrated process involving multiple integrin-ligand interactions, none of which by itself is essential.

Animals↗

PubMed1999

Integrin function in breast carcinoma progression.

The differentiation and function of mammary epithelial cells is dependent upon the combined action of growth factor/hormone receptors and integrin receptors, which act in concert to control the signals required for normal cell function. It is now becoming clear that integrin receptors also contribute to carcinoma cell behavior and that alterations in expression and function during transformation have a large impact on breast carcinoma progression. The focus of this review is to discuss integrin-dependent functions that can be manipulated as targets for the therapeutic intervention of breast cancer. A combination of correlative and mechanistic studies have contributed to the identification of specific integrin receptors, namely alpha2beta1, alpha6beta1, and alpha6beta4, implicated in breast carcinoma progression. Although this field is still emerging and much remains to be learned, potential integrin-dependent signaling targets have been identified.

Animals↗

PubMedDate not supplied

The role of integrins in human embryo implantation.

Integrins are adhesion molecules present in endometrial, decidual, and extravillous cytotrophoblast (EVCT) cells. They participate in cell-cell adhesion as well as in adhesion between cells and components of the extracellular matrix, and they play an important role in the endometrial phenotype change that occurs during the secretory phase, the first stage of implantation. At the beginning of pregnancy, the change in integrin expression is synchronized with the trophoblast attachment (embryo-endometrium interactions with integrins alpha(v)beta3, alpha4beta1, alpha6beta1, and alpha7beta1) and the embryo's invasion of the decidua (integrins alpha6beta4-->alpha5beta1-->alpha1beta1-->alpha4beta1 switch from proliferative to endovascular EVCT). Several diseases, including preeclampsia, intrauterine growth retardation caused by vascular problems and defective luteal phases, may be explained by anomalies in integrin patterns.

Cell Adhesion Molecules↗

PubMed2001

Expression of integrins, degradative enzymes and their inhibitors in uveal melanoma: differences between in vitro and in vivo expression.

Posterior uveal melanoma is the most common intraocular malignancy in adults. Metastasis occurs in approximately 40% of all cases and spread is primarily to the liver. Once secondary hepatic disease has developed the prognosis is poor. Metastasis involves a series of adhesion and de-adhesion events, coupled with regulated tissue degradation to facilitate tumour cell invasion and spread to both local and distant sites. These processes are assisted by the expression of integrins and degradative enzymes by both tumour and host cells. Using a series of 10 uveal melanomas, we investigated the expression of a panel of integrins, degradative enzymes and their inhibitors that have been shown to be associated with metastasis. In addition, we undertook to establish if there might be differential expression in response to growth under artificial conditions. All the tumours expressed matrix metalloproteinases (MMP)-2 and-9, tissue inhibitor of metalloproteases (TIMP)-2, urokinase plasminogen activator (u-PA), plasminogen activator inhibitor (PAI)-1 and PAI-2. Differences in the expression of the integrins alpha1beta1, alpha2beta1 and alpha6beta1 were observed; in particular, these differences appeared to relate to expression as a consequence of growth in culture. In summary, uveal melanoma cells express both degradative enzymes and their respective inhibitors, which are important in metastasis. It would appear that differential expression of integrins is present, probably as a response to in vitro stimulation.

Adult↗

PubMed2000

alpha3beta1 and alpha6beta4 integrin receptors for laminin-5 are not essential for epidermal morphogenesis and homeostasis during skin development.

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

Animals↗

PubMed1996

Triflavin, an Arg-Gly-Asp-containing peptide, inhibits the adhesion of tumor cells to matrix proteins via binding to multiple integrin receptors expressed on human hepatoma cells.

Integrins are a superfamily of cell surface glycoproteins that promote cellular adhesion. The interaction of integrins with extracellular matrices such as fibronectin and vitronectin has been shown to be mediated through an arginine-glycine-aspartic acid (RGD) sequence within adhesive proteins. Triflavin, a 7.5-kDa cysteine-rich polypeptide purified from Trimeresurus flavoviridis snake venom, belongs to a family of RGD-containing peptides, termed disintegrins. Disintegrins have been isolated from the venom of various vipers and have been shown to be potent inhibitors of platelet aggregation. In this study, we found that human hepatoma cell adhesion to immobilized matrix proteins (i.e. fibronectin, collagen, laminin, and vitronectin) was differentially affected by various anti-integrin monoclonal antibodies (mAbs) (i.e., alpha3beta1, alpha5beta1, alpha6beta1, and alpha v beta3) as well as by the peptide GRGDS. Indirect flow cytometric analysis of hepatoma cells with anti-integrin mAbs demonstrated that alpha6beta1 was uniformly expressed at a high density, while alpha3beta1, and alpha5beta1 were moderately expressed and alpha v beta3 was expressed in small amounts on hepatoma cells, consistent with the results obtained from immunofluorescence microscopic analysis. When immobilized on plastic wells, triflavin promoted hepatoma cell attachment; this cell attachment was inhibited by either GRGDS or mAbs against integrins alpha3beta1, alpha5beta1 and alpha v beta3). In addition, the binding of FITC-conjugated triflavin to hepatoma cells was inhibited by GRGDS, anti-alpha3beta1, antialpha5beta1, and anti-alpha v beta3 mAbs. Among these mAbs, anti-alpha5beta1 exerted the most pronounced inhibitory effect (>70%) on the binding of triflavin to hepatoma cells. Taken together, these results suggest that triflavin binds via its RGD sequence to multiple integrin receptors (i.e., alpha5beta1, alpha3beta1, and alpha v beta3) expressed on the surface of hepatoma cells, resulting in inhibition of hepatoma cell adhesion to extracellular matrices (i.e., fibronectin and vitronectin).

Antibodies, Monoclonal↗

PubMed2002

Prostatic tumor cell plasticity involves cooperative interactions of distinct phenotypic subpopulations: role in vasculogenic mimicry.

BACKGROUND: Tumor cell plasticity represents a significant clinical challenge in that the fate and function of tumor cells can be elusive until a tumor mass is evident. A remarkable example of plasticity is tumor cell vasculogenic mimicry, recently described in aggressive uveal and cutaneous melanoma, in addition to ovarian carcinoma, whereby tumor cells express endothelial-associated genes and form de novo vasculogenic-like networks in three-dimensional (3-D) culture. In the current investigation, we examined whether there is evidence for vasculogenic mimicry in heterogeneous prostatic neoplasms. METHODS: Dunning rat and human prostate cancer cell lines (comprised of epithelial- and fibroblastic-like tumor subpopulations) were tested for their ability to express selected endothelial-associated genes, laminin, the alpha6beta1 laminin-binding integrin, and for their potential to form perfusable tubular networks in 3-D culture. Simultaneous morphological analysis of tumor-lined channels in rat and human tumors was also performed. RESULTS: Green fluorescent protein labeling of prostatic clonal subpopulations revealed unique cooperative interactions of epithelial- and fibroblastic-like tumor cells in the formation of perfusable vasculogenic-like networks. Furthermore, while these cell lines were shown to express various vascular markers, prostatic tumor cell-lined channels were also detected in vivo in high grade tumors, and occurred in some cases in close proximity to conventional endothelial-lined vasculature. CONCLUSIONS: A multidisciplinary approach to assess vasculogenic mimicry by prostatic tumor cells has revealed supportive evidence that it occurs in invasive, heterogeneous prostate cancer cell lines, and circumstantially in aggressive rat and human tumors. These results reflect the plasticity of aggressive prostatic tumor cells and may provide new prognostic markers for clinical diagnosis and new therapeutic intervention strategies.

Animals↗

PubMed2005

ADAM-Integrin Interactions: potential integrin regulated ectodomain shedding activity.

ADAMs (a disintegrin and metalloprotease) are a family of cell surface proteins related to the Class III snake venom metalloproteases (SVMP). ADAMs are members of the Metazincin family which includes the matrix matalloproteases and the ADAMTS proteins. Unlike their snake venom relatives, ADAMs are expressed as transmembrane cell surface proteins. The domain structure of ADAMs suggests that these proteins posses both proteolytic and adhesive functions. Several members of the ADAM protein family have been shown to be involved in ectodomain shedding of many important cell surface proteins resulting in the release of biologically active soluble factors. The carboxyl-terminal domains, especially the disintegrin-like domain of ADAMs, have been demonstrated to support cell adhesion. The disintegrin-like domains of many ADAMs are capable of acting as integrin ligands. Integrins known to interact with ADAM disintegrin-like domains include alpha4beta1, alpha4beta7, alpha5beta1, alpha6beta1, alpha9beta1, alphavbeta3, and alphavbeta5. This integrin mediated interaction of the disintegrin-like domains with the cell surface suggests that ADAMs may function as cellular counter receptors. In this review we discuss the individual functions ascribed to members of the ADAM family especially those related to integrin interactions and the potential for integrin mediated regulation of ectodomain shedding.

Animals↗

PubMed2001

Expression of dominant-negative and chimeric subunits reveals an essential role for beta1 integrin during myelination.

Myelination represents a remarkable example of cell specialization and cell-cell interaction in development. During this process, axons are wrapped by concentric layers of cell membrane derived either from central nervous system (CNS) oligodendrocytes or peripheral nervous system Schwann cells. In the CNS, oligodendrocytes elaborate a membranous extension with an area of more than 1000 times that of the cell body. The mechanisms regulating this change in cell shape remain poorly understood. Signaling mechanisms regulated by cell surface adhesion receptors of the integrin family represent likely candidates. Integrins link the extracellular environment of the cell with both intracellular signaling molecules and the cytoskeleton and have been shown to regulate the activity of GTPases implicated in the control of cell shape. Our previous work has established that oligodendrocytes and their precursors express a limited repertoire of integrins. One of these, the alpha6beta1 laminin receptor, can interact with laminin-2 substrates to enhance oligodendrocyte myelin membrane formation in cell culture. However, these experiments do not address the important question of integrin function during myelination in vivo, nor do they define the respective roles of the alpha and beta subunits in the signaling pathways involved. Here, we use a dominant-negative approach to provide, for the first time, evidence that beta1 integrin function is required for myelination in vivo and use chimeric integrins to dissect apart the roles of the extracellular and cytoplasmic domains of the alpha6 subunit in the signaling pathways of myelination.

Animals↗

PubMed1998

N-methylformamide induces changes on adhesive properties and lung-colonizing potential of M14 melanoma cells.

We have studied whether N-methylformamide can affect the expression pattern of adhesion molecules and the attachment behaviour of M14 human melanoma cells. The role of N-methylformamide on experimental and spontaneous pulmonary metastases from M14 cells in nude mice was also investigated. We demonstrate that N-methylformamide in vitro pretreatment of M14 cells, although inducing a significant increase in the expression of alpha2beta1, alpha6beta1 and alpha(v)beta3 integrin receptors, slightly modifies alpha5beta1 heterodimer and beta1 subunit expression. After this modulation, enhancement of cell adhesion to laminin, collagen I, vitronectin and fibrinogen, which is blocked by specific anti-integrin antibodies, also occurs. No changes in binding to fibronectin are observed. In vitro N-methylformamide pretreatment also results in an increased number of experimental nodules and in a decrease in spontaneous metastases. Moreover, in vivo treatment with N-methylformamide significantly reduces the number of spontaneous metastases. Collectively, these data show that N-methylformamide modulates the expression of some adhesion receptors, cell adhesion to laminin, collagen I, vitronectin and fibrinogen as well as the metastatic behaviour of M14 cells. Our data also suggest that the effect of N-methylformamide might be evaluated in combination with antineoplastic agents for the treatment of human melanoma.

Animals↗

PubMed2004

Ultrastructural localization of integrin subunits alpha3 and alpha6 in capillarized sinusoids of the human cirrhotic liver.

Normal liver sinusoids are not lined by a basement membrane (BM). In contrast, in the course of development of liver cirrhosis, a structured BM is formed de novo in the space of Disse. This BM contributes to the inhibition of the metabolic function of the liver but the pathogenic background of the formation of this perisinusoidal BM is still unclear. Integrins of the beta1-class are generally essential for BM stability and some of them (such as alpha2beta1, alpha3beta1 and alpha6beta1) appear de novo in the perisinusoidal space of the cirrhotic liver. Their cellular distribution in capillarized sinusoids as well as the correlation between their cellular distribution and the formation of the microvascular BM in the cirrhotic liver has not been shown at the ultrastructural level. In the present work we aimed to clarify this issue. We focused on integrins alpha3beta1 and alpha6beta1 and localised them ultrastructurally in human cirrhotic liver microvessels using postembedding immunogold which allows the ultrastructural localization of antigens with high resolution in the tissue. The newly formed basement membrane of capillarized sinusoids was visualized by means of fixation with addition of tannic acid, which enables the visualization of structures of the extracellular matrix with the highest resolution. Also, we carried out laminin detection using postembedding immunogold. Our results show that both alpha3beta1 and alpha6beta1 are expressed on the surface of both hepatocytes and endothelial cells, i.e. on both sides of the newly formed basement membrane. This latter shows zones of higher density both in close proximity to the endothelial and to the hepatocytic surfaces which resemble laminae densae. We propose that hepatocytes and endothelial cells may, therefore, by expressing such integrins, contribute to the formation of this pathological BM in the microvessels of the human cirrhotic liver. On stellate cells, which are major producers of BM components, both integrins alpha3beta1 and alpha6beta1 were also localized.

Basement Membrane↗

PubMed2000

The role of extracellular and cytoplasmic splice domains of alpha7-integrin in cell adhesion and migration on laminins.

The major laminin-binding integrin of skeletal, smooth, and heart muscle is alpha7beta1-integrin, which is structurally related to alpha6beta1. It occurs in three cytoplasmic splice variants (alpha7A, -B, and -C) and two extracellular forms (X1 and X2) which are developmentally regulated and differentially expressed in skeletal muscle. Previously, we have shown that ectopic expression of the alpha7beta-integrin splice variant in nonmotile HEK293 cells specifically induced cell locomotion on laminin-1 but not on fibronectin. To investigate the specificity and the mechanism of the alpha7-mediated cell motility, we expressed the three alpha7-chain cytoplasmic splice variants, as well as alpha6A- and alpha6B-integrin subunits in HEK293 cells. Here we show that all three alpha7 splice variants (containing the X2 domain), as well as alpha6A and alpha6B, promote cell attachment and stimulate cell motility on laminin-1 and its E8 fragment. Deletion of the cytoplasmic domain (excluding the GFFKR consensus sequence) from alpha7B resulted in a loss of the motility-enhancing effect. On laminin-2/4 (merosin), the predominant isoform in mature skeletal muscle, only alpha7-expressing cells showed enhanced motility, whereas cells transfected with alpha6A and alpha6B neither attached nor migrated on laminin-2. Adhesion of alpha7-expressing cells to both laminin-1 and laminin-2 was specifically inhibited by a new monoclonal antibody (6A11) specific for alpha7. Expression of the two extracellular splice variants alpha7X1 and alpha7X2 in HEK293 cells conferred different motilities on laminin isoforms: Whereas alpha7X2B promoted cell migration on both laminin-1 and laminin-2, alpha7X1B supported motility only on laminin-2 and not on laminin-1, although both X1 and X2 splice variants revealed similar adhesion rates to laminin-1 and -2. Fluorescence-activated cell sorter analysis revealed a dramatic reduction of surface expression of alpha6-integrin subunits after alpha7A or -B transfection; also, surface expression of alpha1-, alpha3-, and alpha5-integrins was significantly reduced. These results demonstrate selective responses of alpha6- and alpha7-integrins and of the alpha7 splice variants to laminin-1 and -2 and indicate differential roles in laminin-controlled cell adhesion and migration.

Antigens, CD↗

PubMed1998

Specific interaction of the recombinant disintegrin-like domain of MDC-15 (metargidin, ADAM-15) with integrin alphavbeta3.

MDC-15 (ADAM-15, metargidin), a membrane-anchored metalloprotease/disintegrin/cysteine-rich protein, is expressed on the surface of a wide range of cells and has an RGD tripeptide in its disintegrin-like domain. MDC-15 is potentially involved in cell-cell interactions through its interaction with integrins. We expressed a recombinant MDC-15 disintegrin-like domain as a fusion protein with glutathione S-transferase (designated D-15) in bacteria and examined its binding function to integrins using mammalian cells expressing different recombinant integrins. We found that D-15 specifically interacts with alphavbeta3 but not with the other integrins tested (alpha2beta1, alpha3beta1, alpha4beta1, alpha5beta1, alpha6beta1, alpha6beta4, alphavbeta1, alphaIIbbeta3, and alphaLbeta2). Mutation of the tripeptide RGD to SGA totally blocked binding of D-15 to alphavbeta3, suggesting that D-15-alphavbeta3 interaction is RGD-dependent. When the sequence RPTRGD is mutated to NWKRGD, D-15 is recognized by both alphaIIbbeta3 and alphavbeta3, suggesting that the receptor binding specificity is mediated by the sequence flanking the RGD tripeptide, as in snake venom disintegrins. These results indicate that the disintegrin-like domain of MDC-15 functions as an adhesion molecule and may be involved n alphavbeta3-mediated cell-cell interactions.

ADAM Proteins↗

PubMed1997

Altered cell-matrix contact: a prerequisite for breast cancer metastasis?

The integrins are receptors that regulate interaction between epithelial cells and the extracellular matrix. Previous studies have shown that a reduction in the expression of the alpha2beta1, alpha3beta1, alpha6beta1, alpha(v)beta1 and alpha(v)beta5 integrins in primary breast cancer is associated with positive nodal status. In order to assess the functional significance of altered integrin expression, primary breast cancer cells were derived from individual patients with known tumour characteristics using immunomagnetic separation. Purified human fibronectin, vitronectin, laminin and type IV collagen were used to represent the principal extracellular matrix proteins in an in vitro adhesion assay. Primary breast cancer cells from lymph node-positive patients were significantly less adhesive to each of the matrix proteins studied (P<0.001, Mann-Whitney U-test). Matrix adhesion of primary breast cancer cells from node-negative patients was inhibited by appropriate integrin monoclonal antibodies (P<0.001, paired Wilcoxon test). Adhesion to fibronectin, vitronectin and laminin, but not type IV collagen, was influenced by the inhibitor arginine-glycine-aspartate, suggesting that breast cancer cell recognition of collagen IV is mediated through alternative epitopes. Weak matrix adhesion correlated with loss of integrin expression in tissue sections from corresponding patients assessed using immunohistochemistry. This study demonstrates a link between altered integrin expression and function in primary breast cancers predisposed to metastasize.

Adult↗

PubMed2000

Cell-cell adhesion via the ECM: integrin genetics in fly and worm.

Integrins are essential for the development of the two genetically tractable invertebrate model organisms, the nematode worm Caenorhabditis elegans and the fruit fly Drosophila melanogaster. Just two integrins are present in C. elegans: one putative RGD binding integrin alphapat-2betapat-3, corresponding to Drosophila alphaPS2betaPS and vertebrate alpha5beta1, alphaVbeta1 and alpha8beta1, and one putative laminin binding integrin alphaina-1betapat-3, corresponding to Drosophila alphaPS1betaPS and vertebrate alpha3beta1, alpha6beta1 and alpha7beta1. In this review, the function of this minimal set of integrins during the development of these two invertebrates is compared. Despite the differences in bodyplan and developmental strategy, integrin adhesion to the extracellular matrix is required for similar processes: the formation of the link that translates muscle contraction into movement of the exoskeleton, cell migration, and morphogenetic interactions between epithelia. Other integrin functions, such as regulation of gene expression, have not yet been experimentally demonstrated in both organisms. Additional proteins have been characterised in each organism that are essential for integrin function, including extracellular matrix ligands and intracellular interacting proteins, but so far different proteins have been found in the two organisms. This in part represents the fact that the characterisation of the full set of interacting proteins is not complete in either system. However, in other cases different proteins appear to be used for similar functions in the two animals. The continued use of genetic approaches to identify proteins required for integrin function in these two model organisms should lead to the identification of the minimal set of conserved components that form integrin adhesive structures.

Animals↗

PubMed1997

A homozygous mutation in the integrin alpha6 gene in junctional epidermolysis bullosa with pyloric atresia.

The alpha6 integrin subunit participates in the formation of both alpha6beta1 and alpha6beta4 laminin receptors, which have been reported to play an important role in cell adhesion and migration and in morphogenesis. In squamous epithelia, the alpha6beta4 heterodimer is the crucial component for the assembly and stability of hemidesmosomes. These anchoring structures are ultrastructurally abnormal in patients affected with junctional epidermolysis bullosa with pyloric atresia (PA-JEB), a recessively inherited blistering disease of skin and mucosae characterized by an altered immunoreactivity with antibodies specific to integrin alpha6beta4. In this report, we describe the first mutation in the alpha6 integrin gene in a PA-JEB patient presenting with generalized skin blistering, aplasia cutis, and defective expression of integrin alpha6beta4. The mutation (791delC) is a homozygous deletion of a single base (C) leading to a frameshift and a premature termination codon that results in a complete absence of alpha6 polypeptide. We also describe the DNA-based prenatal exclusion of the disease in this family at risk for recurrence of PA-JEB. Our results demonstrate that, despite the widespread distribution of the alpha6 integrin subunit, lack of expression of the alpha6 integrin chain is compatible with fetal development, and results in a phenotype indistinguishable from that caused by mutations in the beta4 chain, which is expressed in a more limited number of tissues.

Antigens, Surface↗