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Results for “Integrin beta1”

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PubMed1997

Activation of beta1 integrins on CML progenitors reveals cooperation between beta1 integrins and CD44 in the regulation of adhesion and proliferation.

Adhesion of normal colony-forming cells (CFC) to bone marrow (BM) stroma and the extracellular matrix (ECM) component fibronectin (FN) depends at least in part on the alpha4beta1 and alpha5beta1 integrins and the CD44 receptor. Aside from anchoring progenitors in the marrow microenvironment, beta1 integrin-dependent adhesion of normal CFC is associated with inhibition of their proliferation. In contrast to normal CFC, chronic myelogenous leukemia (CML) Ph+ CFC adhere significantly less to either stroma or FN. CML Ph+ CFC proliferation is also not inhibited by coculture with stroma or FN. However, equal numbers of alpha4, alpha5, and beta1 integrins and CD44 are present on CML and normal CD34+ cells. We have previously demonstrated that beta1-dependent adhesion to and subsequent proliferation inhibition by FN can be restored when CML Ph+ CFC are incubated with the beta1 integrin activating antibody, 8A2, and demonstrated a role for the alpha5beta1 integrin in this phenomenon. Since the integrin alpha4beta1 and the proteoglycan form of CD44 may cooperate in establishing normal CFC adhesion to FN, we examined if treatment of CML Ph+ CFC with 8A2 also restores the cooperativity between beta1 integrins and CD44. We demonstrate that 8A2 induces adhesion of CML Ph+ CFC not only to intact FN but also to alpha4beta1, alpha5beta1, and proteoglycan binding fragments of FN. 8A2-induced adhesion to these fragments and peptides also results in a significant inhibition of the proliferation of CML Ph+ CFC. Addition of antibodies to either the alpha5, alpha4, or beta1 integrins, antibodies against the CD44 receptor, or removal of chondroitin sulfate glycosaminoglycans from the surface of CML CD34+ HLA-DR+ cells significantly reduced the 8A2-induced adhesion to and adhesion-mediated inhibition of proliferation by FN. These studies demonstrate that activation of beta1 integrins on CML Ph+ CFC not only results in upregulation of beta1 integrin-dependent adhesion and adhesion-mediated inhibition of proliferation, but also in the restoration of cooperation between beta1 integrins and CD44. These studies suggest that decreased beta1 integrin avidity may also affect the function of the proteoglycan adhesion receptor CD44, both of which may contribute to the abnormal circulation and expansion of malignant progenitors in CML.

Antigens, CD↗

PubMed1996

Mutations in the cytoplasmic domain of the integrin beta1 chain indicate a role for endocytosis factors in bacterial internalization.

Mutations that result in defective beta1-integrin focal adhesion formation were analyzed for effects on bacterial internalization. Mutations in the cytoplasmic domain of the beta1 chain that disrupt the sequence NPIY resulted in integrins deficient in bacterial uptake. Other mutations in the beta1 chain that reduced cytoskeletal association showed enhanced bacterial uptake. Replacement of the NPIY sequence of the beta1 subunit by the endocytosis internalization sequence PPGY resulted in integrin receptors highly proficient in bacterial internalization, yet severely defective in focal contact localization. Electron microscopy indicated that coated structures associated specifically with bacteria-binding beta1-integrins, with an apparent recruitment of coated pits from ventral cell surfaces to apical surfaces corresponding to nascent bacterial phagosomes. Clathrin inhibition studies indicated a role for the adaptor molecule AP2 as well as clathrin in integrin-mediated bacterial internalization. These results indicate that association of beta1-integrins with the cytoskeleton at focal contacts interferes with integrin-mediated bacterial internalization. Also, although actin polymerization is required for bacterial uptake, clathrin is probably involved in bacterial uptake promoted by beta-1-integrins.

Amino Acid Sequence↗

PubMed2001

The linkage between beta1 integrin and the actin cytoskeleton is differentially regulated by tyrosine and serine/threonine phosphorylation of beta1 integrin in normal and cancerous human breast cells.

BACKGROUND: Structural requirements for the beta1 integrin functions in cell adhesion, spreading and signaling have been well documented mainly for fibroblasts. In this study, we examined the reason for the reduced surface expression of beta1 integrin in human breast cancer MCF-7 cells compared to normal human breast epithelial (HBE) cells, both of which adhered to collagen type IV. RESULTS: The beta1 integrin immunoprecipitates from either HBE or MCF-7 cells involved alpha-actinin while actin coprecipitated with beta1 integrin from HBE cells but not from MCF-7 cells. Immunoblotting using the anti-phosphotyrosine (PY) antibody indicated the phosphorylation of beta1 integrin at least at tyrosine in both cells. Dephosphorylation of beta1 integrin from HBE cells by protein tyrosine phosphatase (PTP), but not by protein serine/threonine phosphatase (PP), caused dissociation of actin from beta1 integrin, although dephosphorylation of it from MCF-7 cells by either PTP or PP caused association of the two proteins. In MCF-7 cells beta1 integrin coprecipitated doublet of proteins having the Ca2+/calmodulin-dependent protein kinase (CaMK) II activity that was susceptible to KN-62, a specific inhibitor of CaMKII. CONCLUSION: The results suggest that beta1 integrin is tyrosine phosphorylated and links with actin via alpha-actinin in HBE cells but prevented from linking with actin in MCF-7 cells by phosphorylation at both tyrosine and serine/threonine of beta1 integrin which forms a complex with alpha-actinin and CaMKII. Thus the linkage formation of beta1 integrin with actin may be differentially regulated by its tyrosine and serine/threonine phosphorylation in normal HBE cells and breast cancer MCF-7 cells.

Actin Cytoskeleton↗

PubMedDate not supplied

Adenovirus type 5 uptake by lung adenocarcinoma cells in culture correlates with Ad5 fibre binding is mediated by alpha(v)beta1 integrin and can be modulated by changes in beta1 integrin function.

BACKGROUND: Recombinant adenoviruses (Ad) have been employed as vectors for a wide variety of gene therapy applications, but their use has been hindered by problems relating to efficacy and safety. The efficiency of Ad-mediated gene transfer depends on the interaction of the fibre and penton base proteins with their corresponding cell receptors. Ad infection is initiated by the formation of a high affinity complex between the fibre protein and a host cell protein that for most Ad serotypes is CAR (the coxsackie B virus and Ad receptor). A second molecule, the MHC class I, may also be involved in Ad type 2 and Ad type 5 uptake. Ad internalization results from the interaction of the penton base protein with cell surface integrins alpha(v)beta3 and alpha(v)beta5. In this study, we addressed the interaction between Ad type 5 (Ad5) and its receptors on lung derived adenocarcinoma cells in culture. METHODS: Using flow cytometry, we determined the level of expression of attachment and internalization receptors that are expressed on the cell surface of A549, H322 and H441 lung-derived adenocarcinoma cells in culture. The level of alpha(v)beta1 cell surface integrin was assessed by immunoprecipitation. Measuring the level of luciferase gene expression at different viral titres quantitated Ad5 uptake by these cells. The kinetics of binding of Ad5 fibre knobs to A549, H322 and H441 cells was assessed in direct binding studies using 125I labelling of purified recombinant Ad5 fibre-knob domains. In order to assess the functionality of integrins, adhesion assays were performed in the presence or absence of activators of integrin function. In competition experiments, prior to exposure to the virus, the cells were pre-incubated with purified recombinant Ad5 fibre-knob domains, function blocking anti-integrin antibodies, or integrin activating agents, prior to the introduction of luciferase expressing Ad5. RESULTS: We found that Ad5-mediated gene transfer in A549, H322 and H441 adenocarcinoma cells in culture is highly variable and that this variation correlates with specific binding of Ad5 fibre-knob domain binding to the cell surface. We also found, for the first time, that Ad5 infection is mediated by integrin alpha(v)beta1 and that functional activation of beta1 integrin by means of the specific anti-beta1 monoclonal antibody, TS2/16, induced increased A549 cell adhesion to fibronectin and vitronectin and also enhanced Ad5 uptake by these cells. CONCLUSIONS: Our studies demonstrate that the Ad5 fibre-knob domain interaction with CAR represents a major determinant of Ad5-mediated gene transfer to lung-derived adenocarcinoma cells in culture. The finding that integrin alpha(v)beta1 is involved in Ad5 infection has implications for the use of recombinant Ad5 vectors for cancer gene therapy, since alpha(v)beta1 is expressed at high levels and acts as an alternative vitronectin receptor in many epithelial and some melanoma tumours which express no alpha(v)beta3 and constant low levels of alpha(v)beta5. The fact that the beta1 integrin-activating antibody TS2/16 can enhance alpha(v)beta1-mediated Ad5 infection suggests that the efficacy of Ad5-mediated gene transfer might be influenced not only by the level of cell surface expression of integrins but also by their state of activation.

Adenocarcinoma↗

PubMed1998

Mac-2 binding protein is a cell-adhesive protein of the extracellular matrix which self-assembles into ring-like structures and binds beta1 integrins, collagens and fibronectin.

Human Mac-2 binding protein (M2BP) was prepared in recombinant form from the culture medium of 293 kidney cells and consisted of a 92 kDa subunit. The protein was obtained in a native state as indicated by CD spectroscopy, demonstrating alpha-helical and beta-type structure, and by protease resistance and immunological analysis. It was highly modified by N- and O-glycosylation but not by glycosaminoglycans. Ultracentrifugation showed non-covalent association into oligomers with molar masses of 1000-1500 kDa. Electron microscopy showed ring-like shapes with diameters of 30-40 nm. M2BP bound in solid-phase assays to collagens IV, V and VI, fibronectin and nidogen, but not to fibrillar collagens I and III or other basement membrane proteins. The protein also mediated adhesion of cell lines at comparable strength with laminin. Adhesion to M2BP was inhibited by antibodies to integrin beta1 subunits but not to alpha2 and alpha6 subunits, RGD peptide or lactose. This distinguishes cell adhesion of M2BP from that of laminin and excludes involvement of lactose-binding galectin-3. Immunological assays demonstrated variable secretion by cultured human cells of M2BP, which was detected in the extracellular matrix of several mouse tissues.

Animals↗

PubMed2005

Down-regulation of CD9 in human ovarian carcinoma cell might contribute to peritoneal dissemination: morphologic alteration and reduced expression of beta1 integrin subsets.

Peritoneal dissemination is one of the main causes of death in cancer patients. Pathophysiology of metastasis has been well investigated, but the mechanism of diffuse spread of tumor colonies in the peritoneal cavity is not fully understood. CD9 is a member of tetraspanin and its down-regulation is known to be involved in poor prognosis. To investigate the significance of the down-regulation of CD9, HTOA, an ovarian carcinoma cell line that highly expressed CD9, was transiently transfected with small interfering RNA (siRNA) against CD9, and CD9-negative cells (HTOA(CD9-)) were purified. HTOA(CD9-) showed altered adhesion patterns on Matrigel, collagen, fibronectin, and laminin compared with those of control siRNA-transfected HTOA (control-HTOA). Flow cytometry and fluorescence cytostainings revealed that the expression levels of integrins beta1, alpha2, alpha3beta1, alpha5, and alpha6 were lower in HTOA(CD9-) than those of control-HTOA. HTOA(CD9-) showed altered expression of junctional and cytoskeletal molecules. By time-lapse video microscopy, control-HTOA showed solid adhesion to extracellular matrix and formed cobblestone pattern, whereas HTOA(CD9-) showed weaker adhesion and were distributed as diffuse spots. To examine whether the expression level of CD9 change during tumor dissemination, HTOA-P, a highly disseminative subclone of HTOA, was established. HTOA-P showed distinctive down-regulation of CD9 at mRNA and protein levels, and showed similar morphologic alteration as HTOA(CD9-) did. These findings indicate that the down-regulation of CD9 may be an acquired event in the process of tumor dissemination. Down-regulated CD9 may attenuate the expression of several integrins and rearrange junctional and cytoskeletal molecules that might contribute to dissemination of ovarian carcinomas.

Adenocarcinoma↗

PubMed1998

Beta1 integrin cytoplasmic domain regulates the constitutive conformation detected by MAb 15/7, but not the ligand-induced conformation.

The anti-integrin beta1 MAb 15/7 sometimes may be a reporter of integrin activation or ligand occupancy. However, certain beta1 tail deletions eliminate ligand binding despite inducing maximal constitutive 15/7 expression [Puzon-Mclaughlin et al. (1 996): J Biol Chem 271:16580-16585]. Here we describe beta1 tail mutations (e.g., double point mutations [D759L/F763L, F766L/E769L], or replacement of the beta1 tail by the beta5 tail) that prevent rather than induce constitutive appearance of the 15/7 epitope. Despite variable losses of constitutive 15/7 epitope, these mutants all retained a similar inducible 15/7 epitope component as seen upon incubation with GRGDSP peptide ligand. In addition, constitutive 15/7 expression did not correlate with integrin localization into focal adhesions. In conclusion, we show for the first time for a fully functional integrin that specific mutations within the beta1 tail can down-regulate the constitutive appearance of an extracellular conformation defined by MAb 15/7. Because this regulation occurs away from the ligand binding site and does not correlate with responsiveness to integrin ligand, cell adhesion, or localization into focal adhesions, a novel type of conformational regulation is suggested.

Amino Acid Sequence↗

PubMed2000

Engagement of beta2 integrins induces surface expression of beta1 integrin receptors in human neutrophils.

Induction of beta1 integrin (CD49/CD29) expression in polymorphonuclear leukocytes (PMN) has been shown to be associated with transendothelial migration recently. Yet, beta1 integrin expression is relatively insensitive to cell activation with soluble agonists, such as N-formyl-methionyl-leucyl-phenylalanine (fMLP). We hypothesized that beta2 integrins (CD11/CD18), critically involved in PMN adhesion and extravasation, may play a role in regulating 1 integrin expression in PMN. Antibody cross-linking of CD18, mimicking adhesion-dependent engagement of beta2 integrins, resulted in rapid, tyrosine kinase-dependent upregulation of beta1 integrins. This response was potentiated by simultaneous chemoattractant (fMLP) stimulation of PMN. Moreover, upregulation of beta1 integrins evoked by CD18 cross-linking was found to support adhesion of fMLP-stimulated PMN to matrix proteins and also was critical for the ability of PMN to migrate in collagen gels in response to a gradient of fMLP. Taken together, these data demonstrate that engagement of beta2 integrins in human PMN induces beta1 integrin expression in these cells of significance for their migration in the extravascular tissue. Thus, beta2 integrins may serve the function to regulate PMN locomotion in extravascular tissue via receptor crosstalk with beta1 integrins.

Biological Transport↗

PubMed1999

The engagement of beta1 integrins on promonocytic cells promotes phosphorylation of Syk and formation of a protein complex containing Lyn and beta1 integrin.

The protein-tyrosine kinase Syk participates in signal transduction pathways downstream from multiple immune recognition receptors. Recent evidence indicates that Syk is also functionally coupled to cell surface integrins, which mediate interactions between the actin cytoskeleton and extracellular matrix proteins. The interactions of undifferentiated, promonocytic HL60 or U937 cells with fibronectin or anti-beta1 integrin antibodies leads to an apparent activation and tyrosine phosphorylation of Syk that is independent of tight cellular adhesion and spreading. In response to fibronectin or anti-beta1 integrin antibodies, beta1 integrins become associated with a complex of proteins that include the Lyn protein tyrosine kinase and endogenous kinase substrates of 29 and 75-80 kDa. Lyn becomes transiently activated following integrin engagement and co-localizes with the actin cytoskeleton. These studies suggest a major role for Lyn in coupling beta1 integrins to the activation of Syk.

Actins↗

PubMed2006

Integrin beta1 silencing in osteoblasts alters substrate-dependent responses to 1,25-dihydroxy vitamin D3.

Surface microroughness increases osteoblast differentiation and enhances responses of osteoblasts to 1,25-dihydroxyvitamin D3 [1alpha,25(OH)2D3]. The observations that beta1 integrin expression is increased in osteoblasts grown on Ti substrates with rough microarchitecture, and that it is regulated by 1alpha,25(OH)2D3 in a surface-dependent manner, suggest that beta1 may play a role in mediating osteoblast response. To test this hypothesis, we silenced beta1 expression in MG63 human osteoblast-like cells using small interfering RNA (siRNA) and examined the responses of the beta1-silenced osteoblasts to surface microtopography and 1alpha,25(OH)2D3. To better understand the role of beta1, MG63 cells were also treated with two different monoclonal antibodies to human beta1 to block ligand binding. beta1-silenced MG63 cells grown on a tissue culture plastic had reduced alkaline phosphatase activity and levels of osteocalcin, transforming growth factor beta1, prostaglandin E2, and osteoprotegerin in comparison with control cells. Moreover, beta1-silencing inhibited the effects of surface roughness on these parameters and partially inhibited effects of 1alpha,25(OH)2D3. Anti beta1 antibody AIIB2 had no significant effect on cell number and osteocalcin, but decreased alkaline phosphatase; MAB2253Z caused dose-dependent decreases in cell number and alkaline phosphatase and an increase in osteocalcin. Effects of 1alpha,25(OH)2D3 on cell number and alkaline phosphatase were reduced and effects on osteocalcin were increased. These findings indicate that beta1 plays a major and complex role in osteoblastic differentiation modulated by either surface microarchitecture or 1alpha,25(OH)2D3. The results also show that beta1 mediates, in part, the synergistic effects of surface roughness and 1alpha,25(OH)2D3.

Animals↗

PubMed1997

ICAP-1, a novel beta1 integrin cytoplasmic domain-associated protein, binds to a conserved and functionally important NPXY sequence motif of beta1 integrin.

The cytoplasmic domains of integrins are essential for cell adhesion. We report identification of a novel protein, ICAP-1 (integrin cytoplasmic domain- associated protein-1), which binds to the 1 integrin cytoplasmic domain. The interaction between ICAP-1 and beta1 integrins is highly specific, as demonstrated by the lack of interaction between ICAP-1 and the cytoplasmic domains of other beta integrins, and requires a conserved and functionally important NPXY sequence motif found in the COOH-terminal region of the beta1 integrin cytoplasmic domain. Mutational studies reveal that Asn and Tyr of the NPXY motif and a Val residue located NH2-terminal to this motif are critical for the ICAP-1 binding. Two isoforms of ICAP-1, a 200-amino acid protein (ICAP-1alpha) and a shorter 150-amino acid protein (ICAP-1beta), derived from alternatively spliced mRNA, are expressed in most cells. ICAP-1alpha is a phosphoprotein and the extent of its phosphorylation is regulated by the cell-matrix interaction. First, an enhancement of ICAP-1alpha phosphorylation is observed when cells were plated on fibronectin-coated but not on nonspecific poly-L-lysine-coated surface. Second, the expression of a constitutively activated RhoA protein that disrupts the cell-matrix interaction results in dephosphorylation of ICAP-1alpha. The regulation of ICAP-1alpha phosphorylation by the cell-matrix interaction suggests an important role of ICAP-1 during integrin-dependent cell adhesion.

3T3 Cells↗

PubMed2006

Down-regulation of the expression of beta1,4-galactosyltransferase V promotes integrin beta1 maturation.

In previous study, we have shown that beta1,4-galactosyltransferase V (GalT V) functions as a positive growth regulator in glioma. Here, we reported that down-regulation of the expression of GalT V in SHG44 cells by transfection with antisense cDNA specifically up-regulated the expression of cell surface integrin beta1 without the change of its mRNA, and with integrin beta1 125 kDa mature form increased and 105 kDa precursor form decreased. It is well known that the N-glycans of integrins modulate the location and functions of integrins. The SHG44 cells transfected with antisense cDNA of GalT V demonstrated decreased Golgi localization of integrin beta1, strengthened the interaction between integrin alpha5 and beta1 subunit, and enhanced the adhesion ability to fibronectin and the level of focal adhesion kinase phosphorylation. Our results suggested that the down-regulation of the expression of GalT V could promote the expression of cell surface integrin beta1 and subsequently inhibit glioma malignant phenotype.

Astrocytoma↗

PubMed2000

Laminin binding to beta1-integrins selectively alters beta1- and beta2-adrenoceptor signalling in cat atrial myocytes.

1. Perforated patch recordings were used to determine how plating atrial cells on laminin alters beta-adrenergic receptor (beta-AR) regulation of L-type Ca2+ current (ICa,L). 2. Isoproterenol (isoprenaline; ISO; 0.01 microM), a non-selective beta-AR agonist, elicited a greater stimulation of ICa,L in cells plated on laminin (+79 +/- 16 %; n = 17) than on glass (+33 +/- 5 %; n = 23). Also, desensitization to ISO was greater in cells on laminin (-16 +/- 2 %) than on glass (-3 +/- 1 %). Atenolol (0.1 microM), a selective beta1-AR antagonist, inhibited the effects of ISO in cells on glass but not laminin. Conversely, 0.1 microM ICI 118,551, a selective beta2-AR antagonist, inhibited the effects of ISO in cells on laminin but not glass. With beta2-ARs blocked, ISO-induced stimulation of ICa,L was greater in cells on glass than laminin. 3. Zinterol (0.01-0.1 microM), a selective beta2-AR agonist, elicited a greater stimulation of ICa,L in cells on laminin than on glass. The effects of zinterol were blocked by ICI 118,551. 4. ISO-induced stimulation of ICa,L was greater in cells plated on an alphabeta1-integrin antibody than on glass. Also, addition of 20 microM cytochalasin D to cells on laminin prevented the enhanced effects of ISO typically elicited in cells on laminin alone. 5. We conclude that laminin binding to alphabeta1-integrins, in conjunction with the actin cytoskeleton, reduces beta1-AR and enhances beta2-AR signalling which regulates ICa,L. This novel mechanism may contribute to remodelling of beta-AR signalling in the failing heart.

Actins↗

PubMed1999

Role of abnormal integrin-cytoskeletal interactions in impaired beta1 integrin function in chronic myelogenous leukemia hematopoietic progenitors.

Abnormal circulation and unregulated proliferation of chronic myelogenous leukemia (CML) progenitors is related, at least in part, to BCR/ABL induced abnormalities in beta1 integrin-mediated adhesion and signaling. The BCR/ABL oncogene has several potential interactions with cytoskeletal elements that are important for normal integrin signaling. In the present study, we evaluated whether abnormalities in beta1 integrin-cytoskeletal interactions were present in primary CML progenitors and contributed to defective integrin function. beta1 integrin-cytoskeletal interactions were studied in CML and normal CD34+ primary hematopoietic progenitors as well as BCR/ABL-transfected or mock-transfected M07e cells. In normal CD34+ progenitors, antibody-mediated cross-linking of beta1 integrins resulted in their redistribution into caps via a process requiring receptor-cytoskeletal interactions. CML CD34+ cells demonstrated significantly impaired beta1 integrin capping. This defect was related to the presence of the BCR/ABL gene, because capping also was impaired in BCR/ABL-transfected M07e cells. Defective receptor capping was not seen for non-integrin receptors. In addition, CML CD34- and M07eBCR/ABL cells also demonstrated increased actin polymerization and altered actin cytoskeletal organization. Further studies suggested that impaired beta1 integrin capping and defective integrin-mediated adhesion and proliferation inhibition in CML cells were related to abnormally enhanced integrin-cytoskeletal association and restricted receptor mobility. Finally, interferon alpha, which restores integrin-mediated adhesion and signaling in CML progenitors, also enhanced integrin capping in CD34+ cells. These studies suggest that p210BCR/ABL induces abnormal association of integrin receptors with the cytoskeleton and restricted receptor mobility and provide new insights into mechanisms underlying abnormal integrin function in CML progenitors.

Actins↗

PubMed1998

Beta3-integrins rather than beta1-integrins dominate integrin-matrix interactions involved in postinjury smooth muscle cell migration.

BACKGROUND: Smooth muscle cell (SMC) migration is a vital component in the response of the arterial wall to revascularization injury. Cell surface integrin-extracellular matrix interactions are essential for cell migration. SMCs express both beta1- and beta3-integrins. In this study, we examined the relative functional roles of beta1- and beta3-integrin-matrix interactions in postinjury SMC migration. METHODS AND RESULTS: Flow cytometry and fluorescence microscopy of migrating SMCs immunostained with anti-beta1 and anti-alpha(v)beta3/5 antibodies (Abs) revealed expression of both beta1- and beta3-integrins, with beta1 observed as linear streaks and beta3 found in focal contacts. In a scrape-wound migration assay, anti-beta1 Abs (92.0+/-10.7% of control, P=.1) and 0.5 mmol/L linear RGD (105+/-5% of control, P=.2) did not alter SMC migration at 48 hours after injury. Beta3-blockade, however, via Abs (anti-beta3/5 35.7+/-4.5% of control, anti-beta3 61+/-12% of control, both P<.001) and cyclic RGD (0.5 mmol/L) (12+/-10% of control, P<.001) decreased migration. Neither beta1- nor beta3-inhibition altered postinjury [3H]thymidine incorporation. In the rat carotid injury model, local adventitial polymer-based delivery of radiolabeled linear or cyclic RGD led to uptake and retention of label, for both peptides, over a 72-hour period after injury. Local arterial wall beta1-blockade via polymer-based delivery of linear RGD had no effect on SMC migration at 4.5 days (11.5+/-3.2 versus 12.8 SMCs per x600 field [control], P=.6) or on neointimal thickening at 14 days (I/M area ratio, 0.664+/-0.328 versus 1.179+/-0.324 [control], P=.6) after injury. In contrast, local beta3-blockade via cRGD limited migration (0.8+/-0.8 versus 12.8+/-4.4 SMCs per x600 field [control], P<.01) and thickening (I/M area ratio, 0.004+/-0.008 versus 1.179+/-0.324 [control], P<.01). CONCLUSIONS: In postinjury migrating SMCs, beta3- rather than beta1-integrin-matrix interactions are of greater functional significance in adhesive processes essential for SMC migration in vitro and in vivo. Blockade of dominant SMC integrin (beta3)-matrix interactions may be a valuable approach for limiting injury-induced SMC migration and late arterial renarrowing.

Animals↗

PubMed2005

High glucose and angiotensin II increase beta1 integrin and integrin-linked kinase synthesis in cultured mouse podocytes.

Alterations of integrin alpha3beta1 may play a role in the development of diabetic nephropathy. We have investigated the effects of high glucose and angiotensin II on the expression of integrin alpha3 and beta1, and whether these changes are associated with integrin-linked kinase (ILK) in cultured mouse podocytes. Integrin beta1 and ILK mRNA expression and protein production were rapidly up-regulated in a dose-dependent manner by high glucose and angiotensin II stimulation. ILK mRNA levels in the mouse podocytes exposed to 30 mmol/l glucose were 1.66, 1.89, and 1.28 times higher than those in control cells at 6, 24, and 72 h exposure, respectively. ILK mRNA levels in mouse podocytes exposed to 1 nM, 10 nM, and 100 nM angiotensin II for 6 h were 1.38, 1.55, and 1.93 times higher, respectively, than those in control cells. Angiotensin-II-induced integrin beta1 and ILK mRNA expression was significantly inhibited by treatment with losartan (100 muM). In addition, the up-regulation of ILK synthesis induced by these stimuli was related to beta1 integrin synthesis and increased ILK kinase activity. Cell adhesion assay displayed inhibitory effects when podocytes were exposed to high concentrations of angiotensin II. Interestingly, glucose and angiotensin II stimulation induced shrinkage of the cell body and elongation of the podocyte processes, a phenotype similar to that of immature podocytes. In addition, beta1 integrin showed higher levels of staining on both the cell membranes and the cell-cell contact areas. Thus, high glucose and angiotensin II may affect the regulation of the integrin-ILK system in podocytes; this system may therefore play a role in the pathogenesis of diabetic nephropathy and other renal diseases affecting podocytes.

Angiotensin II↗

PubMed2002

Induction of cell death in T lymphocytes by invasin via beta1-integrin.

Ligand binding to beta1-integrins exerts multiple effects on cells of the immune system including adhesion, spreading, haptotaxis and costimulation of T cells activated by anti-CD3. Here we show that a high-affinity ligand for beta1-integrins, the invasin (Inv) protein of Yersinia pseudotuberculosis, can induce cell death in T lymphocytes via a rapid process. Partially purified native Inv protein and an Inv fusion protein caused apoptotic/necrotic caspase-independent cell death in T lymphocytes as determined by phosphatidylserine exposure on the cell surface, uptake of propidium iodide, labeling of DNA strand breaks and presence of DNA ladder. Inv-induced cell death was mediated via beta1-integrins as indicated by the fact that Inv bound to the beta1-integrin subunit (CD29), that anti-beta(1)-integrin antibodies blocked Inv-induced cell death and that Inv-induced cell death was absent in two beta1-integrin- cell lines produced by different procedures. Killing via beta1-integrins represents a novel pathway for cell death in T lymphocytes.

Adhesins, Bacterial↗

PubMed1998

Knockout of alpha6 beta1-integrin expression reverses the transformed phenotype of hepatocarcinoma cells.

BACKGROUND & AIMS: Hepatocellular carcinoma is a common complication in liver cirrhosis. The integrin alpha6 beta1, a receptor for the laminin family of extracellular matrix proteins, has been found to be overexpressed in hepatocarcinoma. In an effort to further characterize the involvement of alpha6 beta1-integrin in hepatocarcinoma progression and to study alpha6 beta1-mediated functions, a human hepatocarcinoma cell line, HepG2, that express high surface levels of alpha6 beta1 and uses only this integrin to mediate adhesion on laminin was identified. METHODS: To assess the role of alpha6 beta1 in these cells, a cytoplasmic domain deletion mutant of the beta4-integrin subunit by complementary DNA transfection was expressed. The expression of the mutant beta4 subunit in association with endogenous alpha6 showed a dominant-negative effect on alpha6 beta1 expression. RESULTS: Stable transfectants of HepG2 that expressed the mutant beta4 subunit showed a reduced ability to adhere and migrate on laminin matrices and to invade Matrigel. Furthermore, transfected cells showed significantly lower growth rates and reduced anchorage-independent growth compared with mock-transfected cells. CONCLUSIONS: These findings on the expression and function of alpha6 beta1 in hepatocarcinoma cells emphasize the potential contribution of this laminin receptor in the neoplastic transformation of hepatocytes.

Antigens, CD↗