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PubMed1999

Signaling via beta1 integrins and mitogen-activated protein kinase determines human epidermal stem cell fate in vitro.

Human epidermal stem cells express higher levels of beta1 integrins and are more adhesive than keratinocytes that are destined to differentiate. To investigate whether high beta1 integrin expression and adhesiveness are essential for maintaining keratinocytes in the stem cell compartment, we introduced a dominant-negative beta1 integrin mutant, CD8beta1, into cultured human keratinocytes, thereby interfering with beta1 integrin function. Surface beta1 integrin levels, adhesiveness, and mitogen-activated protein (MAP) kinase activation on fibronectin were reduced, and exit from the stem cell compartment was stimulated. Adhesiveness and proliferative potential were restored by overexpressing wild-type beta1 integrin or by constitutive MAP kinase activation. Conversely, a dominant-negative MAP kinase kinase 1 mutant decreased adhesiveness and stem cell number in the absence of CD8beta1. MAP kinase activation by alpha6beta4-mediated adhesion and mitogens was normal in CD8beta1 cells, and constitutive MAP kinase activation did not affect adhesion and proliferation of control keratinocytes. We conclude that beta1 integrins and MAP kinase cooperate to maintain the epidermal stem cell compartment in vitro.

Calcium-Calmodulin-Dependent Protein Kinases↗
PubMed2001

A functional comparison of mutations in integrin beta cytoplasmic domains: effects on the regulation of tyrosine phosphorylation, cell spreading, cell attachment and beta1 integrin conformation.

Cell adhesion is a multistep process that requires the interaction of integrins with their ligands in cell attachment, the activation of integrin-triggered signals, and cell spreading. Integrin beta subunit cytoplasmic domains (beta tails) participate in regulating each of these steps; however, it is not known whether the same or different regions within beta tails are required. We generated a panel of amino acid substitutions within the beta1 and beta3 cytoplasmic domains to determine whether distinct regions within beta3 tails regulate different steps in adhesion. We expressed these beta cytoplasmic domains in the context of interleukin 2 (IL-2) receptor (tac) chimeras and tested their ability to activate tyrosine phosphorylation, to regulate beta1 integrin conformation and to inhibit beta1 integrin function in cell attachment and spreading. We found that many of the mutant beta3 and beta3 chimeras either had no effect on these parameters or dramatically inhibited the function of the beta tail in most assays. However, one set of analogous Ala substitutions in the beta1 and beta3 tails differentially affected the ability of the tac-beta3 and tac-beta3 chimeras to activate tyrosine phosphorylation. The tac-beta1 mutant containing Ala substitutions for the VTT motif did not signal, whereas the analogous tac-beta3 mutant was able to activate tyrosine phosphorylation, albeit not to wild-type levels. We also identified a few mutations that inhibited beta tail function in only a subset of assays. Ala substitutions for the Val residue in the VTT motif of the beta1 tail or for the conserved Asp and Glu residues in the membrane-proximal region of the beta3 tail greatly diminished the ability of tac-beta1 and tac-beta3 to inhibit cell spreading, but had minimal effects in other assays. Ala substitutions for the Trp and Asp residues in the conserved WDT motif in the beta1 tail had dramatic effects on the ability of tac-beta1 to regulate integrin conformation and function in cell spreading, but had no or intermediate effects in other assays. The identification of mutations in the beta1 and beta3 tails that specifically abrogated the ability of these beta tails to regulate beta1 integrin conformation and function in cell spreading suggests that distinct protein interactions with beta tails regulate beta cytoplasmic domain function in these processes.

Amino Acid Sequence↗
PubMed2005

[The integrin beta1 mRNA changes after orthodontic movement of teeth in periodontitis rats].

OBJECTIVE: To study the integrin beta1 mRNA changes after orthodontic tooth movement in normal teeth and periodontitis teeth of rats. METHODS: The OD of positively stained osteoclasts for integrin beta1 mRNA using in situ hybridzation was detected after orthodontic tooth movement in normal teeth and periodontitis teeth groups. RESULTS: Integrin beta1 mRNA expression were detected on all osteoclasts in tooth movement samples of normal and periodontitis teeth. There were stronger positive signals after given orthodontic force in both of the two groups. But no differences were found after 0.5, 1, 2, 3, 5, 7, 10 days since orthodontic tooth movement. The integrin beta1 mRNA signals in normal tooth movement group were not different from that in periodontitis group. CONCLUSION: The integrin beta1 of osteoclasts may play a role in the stability and remodeling of periodontal ligament in orthodontic tooth movement. There were no difference in the OD of integrin beta1 mRNA staining in orthodontic tooth movement between normal teeth group and periodontitis teeth group.

Animals↗
PubMed2002

Collective cell movement in primary melanoma explants: plasticity of cell-cell interaction, beta1-integrin function, and migration strategies.

Collective cell movement represents an efficient dissemination strategy in neoplastic epithelial and mesenchymal cancer. In primary melanoma explants cultured in three-dimensional collagen lattices, invasive migration of multicellular clusters was dependent on the function of beta1 integrins, as shown by preferential beta1-integrin expression and clustering in a subset of promigratory cells at the leading edge ("guiding cells") and the abrogation of multicellular migration by adhesion-perturbing anti-beta1-integrin antibody. Interference with beta1-integrin function induced complex changes in cluster polarity and cohesion, including development of two or several opposing leading edges, cluster disruption, and the detachment of individual cells followed by beta1-integrin-independent "amoeboid" crawling and dissemination. The conversion from beta1-integrin-dependent collective movement to beta1-integrin-independent single-cell motility suggests efficient cellular and molecular plasticity in tumor cell migration strategies.

Cell Adhesion↗
PubMed2003

Phosphatidylinositol phosphate kinase type 1gamma and beta1-integrin cytoplasmic domain bind to the same region in the talin FERM domain.

Talin is an essential component of focal adhesions that couples beta-integrin cytodomains to F-actin and provides a scaffold for signaling proteins. Recently, the integrin beta3 cytodomain and phosphatidylinositol phosphate (PIP) kinase type 1gamma (a phosphatidylinositol 4,5-bisphosphate-synthesizing enzyme) were shown to bind to the talin FERM domain (subdomain F3). We have characterized the PIP kinase-binding site by NMR using a 15N-labeled talin F2F3 polypeptide. A PIP kinase peptide containing the minimal talin-binding site formed a 1:1 complex with F2F3, causing a substantial number of chemical shift changes. In particular, two of the three Arg residues (Arg339 and Arg358), four of eight Ile residues, and one of seven Val residues in F3 were affected. Although a R339A mutation did not affect the exchange kinetics, R358A or R358K mutations markedly weakened binding. The Kd for the interaction determined by Trp fluorescence was 6 microm, and the R358A mutation increased the Kd to 35 microm. Comparison of these results with those of the crystal structure of a beta3-integrin cytodomain talin F2F3 chimera shows that both PIP kinase and integrins bind to the same surface of the talin F3 subdomain. Indeed, binding of talin present in rat brain extracts to a glutathione S-transferase integrin beta1-cytodomain polypeptide was inhibited by the PIP kinase peptide. The results suggest that ternary complex formation with a single talin FERM domain is unlikely, although both integrins and PIP kinase may bind simultaneously to the talin anti-parallel dimer.

Amino Acid Sequence↗
PubMedDate not supplied

Increased expression of integrin beta1 is a poor prognostic factor in small-cell lung cancer.

The purpose of this study was to investigate the possible association between the expression of integrin beta1 and response to chemotherapy and survival in patients with small cell lung cancer (SCLC). One-hundred and four patients with SCLC, who had received an initial course of chemotherapy between February 1989 and July 1999, were entered into the study. There were 91 males and 13 females, with a median age of 65 years (range 40-85 years). The clinical stage of the tumors was recorded as limited disease in 43 patients and extensive disease in 61. Each patient received a full-dose of combination chemotherapy. Transbroncheal biopsy specimens of tumors obtained before chemotherapy were subjected to immunostaining for integrin beta1. Twenty-nine patients could not be evaluated for integrin beta1 immunostaining, because the tissue samples had been crushed during the biopsy procedure. Fifty-three patients had tumors with < or = 25% integrin beta1-positive cells and 22 patients had tumor with > 25% integrin beta1-positive cells. Among 75 patients whose biopsy specimens were evaluable for integrin beta1, the overall response rate to chemotherapy was 87%. When the relationship between integrin beta1 expression and tumor response to chemotherapy was considered, 17 out of 22 patients with high expression of integrin beta1 and 48 out of 53 patients with low expression of integrin beta1 showed tumor response, although the resistance rate in patients with high expression of integrin beta1 was over twice that of patients with low expression of integrin beta1 (23% vs. 9%, respectively). By comparison, the overall survival of patients with high expression of integrin beta1 (n = 22) was significantly worse than that of individuals whose tumors had low expression of integrin beta1 (n = 53; log-rank test, p=0.043; Wilcoxon test, p=0.049). The association between survival and prognostic factors was examined by multivariate regression analysis; clinical stage and integrin beta1 were found to be independent factors (p = 0.018 andp = 0.041, respectively). In conclusion, the high expression of integrin beta1 in tumor cells is a poorprognostic factor in patients with SCLC.

Adult↗
PubMedDate not supplied

The beta1 integrin subunit is not a specific component of the costamere domain in human myocardial cells.

Studies on altered integrin receptor expression during cardiac hypertrophy and heart failure requires accurate knowledge of the distributional pattern of integrins in myocardial cells. At present the general consensus is that in cardiac muscle the beta1 integrin receptor is mainly localized to the same sarcolemmal domain as vinculin at Z-band levels ('costamere'). Since most previous studies have been focusing on myocardial integrin distribution in lower mammals, the myocardial localization of the beta1 integrin subunit was investigated in biopsies collected from the auricle of patients undergoing a coronary bypass operation. Non-invasive serial optical sectioning was carried out by immuno-laser scanning confocal microscopy. Double-labelling for vinculin/alpha-actinin, and the cytoplasmic domain for the beta1 integrin subunit, showed that beta1 integrin is deposited throughout both the vinculin/alpha-actinin domains and the non-vinculin/alpha-actinin domains. These results were supported by a semi-quantitative analysis in extended focus images of the latter preparations. Higher magnification views at the electron microscopical levels of the large, extracellular domain of the beta1 integrin subunit disclosed a pronounced labelling in the form of a dense, irregular punctuate pattern that was distributed at Z-disc domains as well as along the entire sarcolemmal area between Z-discs. Our findings show that in human, myocardial cells, the beta1 integrin receptor does not only localize to the surface membrane at the Z-disc level ('costamere' in cardiac muscle), but has a widespread distribution along the sarcolemma.

Antibodies, Monoclonal↗
PubMed2002

Cardiac myocyte-specific excision of the beta1 integrin gene results in myocardial fibrosis and cardiac failure.

Integrins link the extracellular matrix to the cellular cytoskeleton and serve important roles in cell growth, differentiation, migration, and survival. Ablation of beta1 integrin in all murine tissues results in peri-implantation embryonic lethality. To investigate the role of beta1 integrin in the myocardium, we used Cre-LoxP technology to inactivate the beta1 integrin gene exclusively in ventricular cardiac myocytes. Animals with homozygous ventricular myocyte beta1 integrin gene excision were born in appropriate numbers and grew into adulthood. These animals had 18% of control levels of beta1D integrin protein in the heart and displayed myocardial fibrosis. High-fidelity micromanometer-tipped catheterization of the intact 5-week-old beta1 integrin knockout mice showed depressed left ventricular basal and dobutamine-stimulated contractility and relaxation (LV dP/dt(max) and LV dP/dt(min)) as compared with control groups (n=8 to 10 of each, P<0.01). Hemodynamic loading imposed by 7 days of transverse aortic constriction showed that the beta1 integrin knockout mice were intolerant of this stress as they had 53% survival versus 88% in controls (n=15 each). By 6 months of age, mice with depressed ventricular expression of beta1 integrin developed a dilated cardiomyopathy that was not evident in any control animals and had patchy decrease in glucose metabolism as determined by positron emission tomography. Myocyte membrane integrity as determined via Evan's blue dye staining was disrupted in the beta1 integrin knockout mice. This model provides strong evidence for the importance of beta1 integrin in cardiac form and function and indicates that integrins can be linked to development of cardiomyopathies.

Animals↗
PubMed2004

Beta1-integrins and glomerular injury.

The renal glomerulus is composed of three types of glomerular cells (mesangial cell (MC), endothelial cell and podocyte) and extracellular matrix (ECM) consisting of the glomerular basement membrane (GBM) and mesangial matrix. It constitutes a highly specialized microcirculation in which the permeability characteristics of the capillary wall allow its unique filtration function. The proliferation of MCs, an increase of mesangial ECM and detachment podocyte from GBM are key biological features of progressive glomerulonephritis (GN), leading to glomerular scarring and dysfunction. Thus, the study of the molecular and cellular mechanisms responsible for pathological glomerular alterations may help to elucidate the pathogenesis of progressive glomerular diseases. A growing body of evidence indicates that beta1 integrin family (beta1 integrins), that mainly mediates cell adhesion to ECM, controls cell behaviors such as cell migration, proliferation, apoptosis and ECM assembly. In addition, a correlation between glomerular expression of beta1 integrins and their ligand ECM components is observed in various human and experimental GN, suggesting that altered beta1 integrins-mediated cell behaviors may contribute to the progression of GN. It is now becoming apparent that the expression of glomerular beta1 integrins is not only critical for maintaining the glomerular capillary permeability but it modulates cell signaling pathways regulating the cell phenotypes involved in the progression of glomerular diseases.

Animals↗
PubMed2001

Assembly of laminin polymers is dependent on beta1-integrins.

Recent reports suggest that laminin deposition is controlled by the cell via specific receptors, one of which is dystroglycan. In this study, the involvement of beta1-integrins in this process was investigated by comparing beta1-integrin-deficient cells of different phenotypes with their normal counterparts. Normal embryonic stem (ES) cells and embryoid bodies (EBs) derived from them were found to deposit cell-associated laminin into fibrillar networks, and in the EBs a basement membrane was assembled under the primitive endoderm. beta1-deficient ES cells and their EBs formed only small amounts of dot-like laminin deposits. Skeletal myotubes formed after prolonged differentiation in EBs were found to be surrounded by laminin, nidogen, and perlecan by immunofluorescent staining irrespective of the presence of beta1-integrins on the myotubes. However, at the electron microscope level only very thin sheet-like structures were detected close to the beta1-deficient myotubes, while the wt myotubes formed thick basement membranes. An epithelial cell line, GE11, derived from the beta1-integrin-deficient ES cells was also unable to assemble laminin on the cell surface, while transfection of the cells with the integrin beta1 subunit resulted in formation of a dense laminin network. Taken together, these results suggest that dystroglycan and beta1-integrins can both contribute to the recruitment of laminin to cell surfaces and that integrins are required at a subsequent step in the formation of basement membranes.

Animals↗
PubMed2003

Vipera lebetina venom contains two disintegrins inhibiting laminin-binding beta1 integrins.

To explain the myotoxic effects of snake venoms, we searched for inhibitors of alpha7beta1 integrin, the major laminin-binding integrin in skeletal muscle. We discovered two inhibitors in the venom of Vipera lebetina. One of them, lebein-1 (known as lebein), has already been proposed to be a disintegrin because of its RGD-containing primary sequence. The other, lebein-2, is a novel protein that also interacts firmly with alpha3beta1, alpha6beta1, and alpha7beta1 integrins, but not with the collagen-binding alpha1beta1 and alpha2beta1 integrins. Ligand binding of laminin-recognizing beta1 integrins was efficiently blocked by both lebein-1 and lebein-2. In cell attachment assays, lebein-1 and lebein-2 inhibited myoblast attachment not only to laminin, but also to fibronectin. However, neither lebein-1 nor lebein-2 interacted with alpha7beta1 integrin in an RGD-dependent manner, similar to the interaction of the laminin with alpha7beta1 integrin. Identical divalent cation dependence of integrin binding to laminin and to either of the two inhibitors and their mutually exclusive binding suggest that both lebein-1 and lebein-2 interact with the ligand-binding site of laminin-binding beta1 integrins by mimicking the yet unknown integrin-binding structure of laminins. Like lebein-1, lebein-2 is a soluble heterodimeric disintegrin of low molecular mass. Together with membrane-bound ADAM-2 and ADAM-9, the two inhibitors seem to form a small group of disintegrins that can bind to laminin-binding beta1 integrins. Because of their inhibitory capability both in vitro and in vivo, lebein-1 and lebein-2 may be valuable tools in influencing laminin-induced, integrin-mediated cell functions such as cell anchorage, migration, and mechanical force transduction on laminin-rich basement membranes.

Animals↗
PubMed2005

Chemokine receptor CXCR4-beta1 integrin axis mediates tumorigenesis of osteosarcoma HOS cells.

It is known that beta1 integrins mediate the migratory response of cells to chemokine stimulation. Also, both beta1 integrins and chemokines have roles in tumor development. In the present study, the beta1 integrin-chemokine axis is assessed using human osteosarcoma (HOS) transfectant cells expressing the CXCR4 receptor for chemokine SDF-1 (CXCL12). We first identified in vitro the specific beta1 integrins that mediated the migratory response to SDF-1 stimulation. Results showed that on collagen type I and laminin, the chemotactic response to SDF-1 was predominantly mediated by alpha2beta1 integrin. On fibronectin, SDF-1-stimulated chemotaxis involved both alpha4beta1 and alpha5beta1 integrins. A comparison of the transfectant clones expressing CXCR4 at low, intermediate, and high levels and the control transfectant revealed that the transfectant clones migratory response in vitro and their ability to form tumors in vivo was related to their levels of CXCR4 expression. In addition, treatment by injection with mAbs to CXCR4, integrin alpha2beta1, or integrin alpha5beta1 effectively inhibited the growth of HOS-CXCR4 transfectant cells in vivo. Therefore, our results show that the beta1 integrins that mediated the migratory response were also functionally linked to the enhanced tumor growth of CXCR4-expressing HOS transfectant cells.

Animals↗
PubMed2005

Transcriptional regulation of beta1 integrin expression in the physio/pathological states of human endometrial tissues.

beta1C integrin is a spliced variant of the human beta1 integrin family that inhibits cell proliferation, at variance with beta1A that stimulates it. During the transition from normal to neoplastic endometrium, both variants are down-regulated at the mRNA level, but only beta1C at the protein level, suggesting a key role of the regulation of beta1C integrin expression in the pathogenesis of endometrial cancer. In this study we show for the first time that, besides beta1A and beta1C, the beta1B spliced variant is expressed in human endometrium, and is up-regulated in hyperplastic and neoplastic endometria in comparison with normal proliferative endometria. To investigate the mechanisms of regulation of beta1 integrin expression during endometrial cancer progression we compared the transcriptional activity of the beta1 integrin gene in normal and diseased endometria by nuclear run-on analysis and we found it significantly reduced in endometrial adenocarcinoma. On the contrary, hyperplastic endometria showed a 2-fold increase in the beta1 transcription rate that directly correlated with the increase in beta1B, beta1C and beta1A steady-state mRNA levels. Finally, we compared the activity of the distal and proximal promoters of the beta1 gene integrin gene in normal and diseased endometria and we found the activity of the proximal promoter decreased in neoplastic endometria and increased in hyperplastic tissues, whereas the activity of the distal promoter did not change in different endometrial physio/pathological conditions. These findings suggest a complex pattern for regulation of the expression of beta1 integrin variants during endometrial malignant transformation.

Adenocarcinoma↗
PubMed2005

Protein kinase C epsilon mediates angiotensin II-induced activation of beta1-integrins in cardiac fibroblasts.

OBJECTIVE: Angiotensin II (AII) promotes cardiac fibrosis by increased extracellular matrix production and enhanced interaction of matrix proteins with their cellular receptors, including integrins. AII and other growth factors augment beta(1)-integrin-dependent adhesion and spreading by "inside-out signaling" without affecting the total number of integrin receptors. "Inside-out signaling" involves specific signaling pathways, including protein kinase C (PKC), leading to activation of beta1-integrins. In the present study we investigated the mechanisms involved in AII-increased adhesion of adult rat cardiac fibroblasts (CFBs), obtained from Sprague-Dawley rats, to collagen I mediated by beta1-integrin. METHODS AND RESULTS: Treatment of CFBs with AII induced a concentration-dependent increase in adhesion to collagen I (2.2-fold, p<0.01) within 3-6 h of treatment. This effect was mediated by beta1-integrin via the angiotensin AT1 receptor and was significantly reduced by protein kinase C inhibition. AII significantly induced phosphorylation of PKC epsilon (PKCepsilon), which is involved in beta1-integrin-dependent adhesion and motility, and phosphorylation of the cytoplasmatic tail of beta1-integrin at threonine 788/789, required for adhesion. Phosphorylation of beta1-integrin and an increase in adhesion was also induced by l-alpha-phosphatidylinositol-3,4,5-triphosphate (l-alpha-PIP3), an activator of endogenous PKCepsilon. AII failed to increase adhesion in myofibroblasts obtained from PKCepsilon (-/-) mice, but not in cells obtained from control mice. Co-immunoprecipitation and double immunofluorescence demonstrated that AII induced a close association of PKCepsilon with beta1-integrin in CFBs. CONCLUSION: The present study demonstrates that AII increased beta1-integrin-dependent adhesion to collagen I in cardiac fibroblasts by inside-out signaling via PKCepsilon and phosphorylation of the cytoplasmatic tail of the beta1-integrin.

Angiotensin II↗
PubMed1997

CD9, but not other tetraspans, associates with the beta1 integrin precursor.

The molecules of the tetraspan superfamily have two unequal extracellular domains separated by four transmembrane (TM) domains. These molecules are associated on the cell surface with each other and with other partner molecules, in particular beta1 integrins. We now show that CD9 associates with the precursor of the beta1 integrin (pre beta1). This association is detected as early as 15 min after metabolic labeling, and the use of Brefeldin A demonstrates that it does not require Golgi modifications of either CD9 or integrin beta1. The specificity of this interaction is demonstrated by the fact that other tetraspans, CD63, CD81, and CD82, do not associate with pre beta1, and CD9 does not associate with immature human histocompatibility leukocyte antigen class I. In order to localize the region of CD9 responsible for the association with the beta1 integrin, we have generated two reciprocal chimeric CD9/CD82 molecules with the junction localized just after the third TM region. The large extracellular loop of CD9 or the fourth TM domain, or both, appear to be sufficient to mediate an association with the mature integrin with a high efficiency, compared to CD82. By contrast, association with pre beta1 requires at least two regions of the molecule. Mutation of CD9 at the consensus site of the tetraspan superfamily, localized between the second and the third TM domain, did not impair the co-precipitation of pre beta1. Finally, because pre beta1 associates with calnexin, we have investigated a possible association of CD9 with this chaperone molecule. CD9 associates with calnexin independently of its association with the beta1 integrin, suggesting that calnexin could be involved in the processing of CD9.

Animals↗
PubMed2003

Lamellipodial motility in wounded endothelial cells exposed to physiologic flow is associated with different patterns of beta1-integrin and vinculin localization.

Integrins- and cytoskeletal-associated focal adhesion proteins may participate in the process of endothelial wound closure, but their relationship in these wounds and in the presence of shear forces has not been defined. The goal in this study was to test the hypotheses that (1) modulation of beta(1)-integrin in human coronary artery endothelial cells (HCAEC) would alter endothelial wound closure under shear stress, and (2) beta(1)-integrin association with vinculin would be necessary for mediating this closure. HCAEC monolayers were pre-conditioned to attain alignment by shearing at 12 dynes/cm(2) for 18 h in a parallel-plate flow chamber. Subsequently, they were divided into three groups: (a) control, (b) treated with anti-beta(1)-integrin adhesion blocking antibody, or (c) treated with anti-beta(1)-integrin adhesion promoting antibody. Next, the monolayers were wounded with a metal spatula, and re-sheared at 20 dynes/cm(2) or left static. Time-lapse imaging and deconvolution microscopy were then performed for 3 h. Immunocytochemistry for beta(1)-integrin expression and vinculin was performed on all wounded monolayers. Under shear stress, vinculin localized to the ends of stress fibers, while beta(1)-integrin took on an intracellular macroaggregate appearance. Treatment with anti-beta(1)-integrin adhesion blocking antibody enhanced wound closure, left the vinculin staining at the lamellipodial tips unchanged, but was associated with beta(1)-integrin staining at the lateral cell edges. Treatment with the anti-beta(1)-integrin adhesion promoting antibody retarded wound closure, increased vinculin staining at cell-cell junctions, and was associated with a fibrillar pattern of beta(1)-integrin staining. Modulation of beta(1)-integrin and changes in beta(1)-integrin and vinculin localization may further our understanding of laminar shear stress-induced endothelial repair in the coronary circulation.

Antibodies, Monoclonal↗
PubMed2002

Pertubation of beta1 integrin function using anti-sense or function-blocking antibodies on corneal cells grown on fibronectin and tenascin.

During corneal development, neural crest derivatives from the periocular mesenchyme migrate into the cornea and differentiate into corneal fibroblasts. During this time, these cells interact with a variety of extracellular matrices for proper orientation and development. In the present studies, we have examined the interaction of beta(1) integrins on periocular mesenchyme cells (POM) and corneal fibroblasts (CF) with fibronectin and tenascin by perturbing the function of this integrin. POM and CF attached and spread to a much greater extent on fibronectin than on tenascin. An antibody against beta(1) integrin, CSAT, decreased spreading and attachment, and resulted in a lack of immuno-detectable beta(1) integrin in focal adhesions on fibronectin; few beta(1) positive focal adhesions were observed in cells grown on tenascin. An anti-sense retroviral construct decreased endogenous levels of beta(1) integrin protein, and caused decreased attachment and spreading as well as sparse, disorganized focal adhesions. These data indicate that in vitro, both POM and CF have beta(1) integrins that interact with fibronectin and allow them to attach and spread, while tenascin is anti-adhesive. Further studies using both of these experimental paradigms will clarify whether these interactions also occur in vivo.

Animals↗
PubMed2005

Sphingosine-1-phosphate induces a PDGFR-dependent cell detachment via inhibiting beta1 integrin in HEK293 cells.

Several different types of interactions between sphingosine-1-phosphate (S1P) receptors and platelet-derived growth factor receptor (PDGFR) have been revealed recently. In this work, we used HEK293 cells to further investigate the potential crosstalk. Interestingly, we observed that S1P specifically induced a PDGFR-dependent cell detachment in HEK293 cells, which could be inhibited by AG1296, a specific inhibitor for PDGFR. EGFR on the other hand, did not have any effect on cell detachment. The detachment was extracellular matrix (ECM) protein specific, suggesting the involvement of specific integrin molecules. When beta(1) integrin was engaged into an active state, S1P-induced cell detachment was blocked, suggesting that S1P induced an inside-out inhibitory effect on beta(1) integrin. G(i) protein and ERK activation were required for the cell detachment induced by S1P, suggesting an endogenous receptor for S1P is likely to be involved.

Blotting, Western↗