Journal articles on the topic 'Integrins'
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1
Díaz-González, F., J. Forsyth, B. Steiner, and M. H. Ginsberg. "Trans-dominant inhibition of integrin function." Molecular Biology of the Cell 7, no. 12 (December 1996): 1939–51. http://dx.doi.org/10.1091/mbc.7.12.1939.
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Occupancy of integrin adhesion receptors can alter the functions of other integrins and cause partition of the ligand-occupied integrin into focal adhesions. Ligand binding also changes the conformation of integrin extracellular domains. To explore the relationship between ligand-induced conformational change and integrin signaling, we examined the effect of ligands specific for integrin alpha IIb beta 3 on the functions of target integrins alpha 5 beta 1 and alpha 2 beta 1. We report that binding of integrin-specific ligands to a suppressive integrin can inhibit the function of other target integrins (trans-dominant inhibition). Trans-dominant inhibition is due to a blockade of integrin signaling. Furthermore, this inhibition involves both a conformational change in the extracellular domain and the presence of the beta cytoplasmic tail in the suppressive integrin. Similarly, ligand-induced recruitment of alpha IIb beta 3 to focal adhesions also involves a conformational rearrangement of its extracellular domain. These findings imply that the ligand-induced conformational changes can propagate from an integrin's extracellular to its intracellular face. Trans-dominant inhibition by integrin ligands may coordinate integrin signaling and can lead to unexpected biological effects of integrin-specific inhibitors.
2
Wei, Ying, and Harold Chapman. "Protease Crosstalk with Integrins: the Urokinase Receptor Paradigm." Thrombosis and Haemostasis 86, no. 07 (2001): 124–29. http://dx.doi.org/10.1055/s-0037-1616208.
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SummaryMigratory cells use both adhesion receptors and proteolytic enzymes to regulate their interaction with and response to extracellular matrices. Cooperation between integrins and proteases operates at several levels: integrin signaling induces proteases, proteases co-localize with integrins, and proteases regulate the interface between integrins and the intracellular cytoskeleton. One protease system intimately connected to integrins is the urokinase/urokinase receptor(uPAR)/plasmin system. Recent studies indicate urokinase promotes the ligand-like binding of its receptor to a set of β1 and β2 integrins, this binding in turn affecting integrin signaling and cell migration. The glycolipid anchor of uPAR associates with cholesterol-rich membrane rafts. Binding of uPAR to integrins may enrich integrin clusters with signaling molecules such as src-family kinases that localize to rafts and are important to integrin function. Signals derived from integrin/uPAR complexes promote the function of other integrins. Thus the urokinase/plasmin system coordinates with integrins to regulate cell: matrix interactions.
3
Triantafilou, Kathy, Martha Triantafilou, Yoshikazu Takada, and Nelson Fernandez. "Human Parechovirus 1 Utilizes Integrins αvβ3 and αvβ1 as Receptors." Journal of Virology 74, no. 13 (July 1, 2000): 5856–62. http://dx.doi.org/10.1128/jvi.74.13.5856-5862.2000.
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ABSTRACT Human parechovirus 1 (HPEV1) displays an arginine-glycine-aspartic acid (RGD) motif in the VP1 capsid protein, suggesting integrins as candidate receptors for HPEV1. A panel of monoclonal antibodies (MAbs) specific for integrins αvβ3, αvβ1, and αvβ5, which have the ability to recognize the RGD motif, and also a MAb specific for integrin α2β1, an integrin that does not recognize the RGD motif, were tested on A549 cells. Our results showed that integrin αv-specific MAb reduced infectivity by 85%. To specify which αv integrins the virus utilizes, we tested MAbs specific to integrins αvβ3 and αvβ1 which reduced infectivity significantly, while a MAb specific for integrin αvβ5, as well as the MAb specific for α2β1, showed no reduction. When a combination of MAbs specific for integrins αvβ3 and αvβ1 were used, virus infectivity was almost completely inhibited; this shows that integrins αvβ3 and αvβ1 are utilized by the virus. We therefore proceeded to test whether αv integrins' natural ligands fibronectin and vitronectin had an effect on HPEV1 infectivity. We found that vitronectin reduced significantly HPEV1 infectivity, whereas a combination of vitronectin and fibronectin abolished infection. To verify the use of integrins αvβ3 and αvβ1 as HPEV1 receptors, CHO cells transfected and expressing either integrin αvβ3 or integrin αvβ1 were used. It was shown that the virus could successfully infect these cells. However, in immunoprecipitation experiments using HPEV1 virions and allowing the virus to bind to solubilized A549 cell extract, we isolated and confirmed by Western blotting the αvβ3 heterodimer. In conclusion, we found that HPEV1 utilises both integrin αvβ3 and αvβ1 as receptors; however, in cells that express both integrins, HPEV1 may preferentially bind integrin αvβ3.
4
Spiess, Matthias, Pablo Hernandez-Varas, Anna Oddone, Helene Olofsson, Hans Blom, Dominic Waithe, John G. Lock, Melike Lakadamyali, and Staffan Strömblad. "Active and inactive β1 integrins segregate into distinct nanoclusters in focal adhesions." Journal of Cell Biology 217, no. 6 (April 9, 2018): 1929–40. http://dx.doi.org/10.1083/jcb.201707075.
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Integrins are the core constituents of cell–matrix adhesion complexes such as focal adhesions (FAs) and play key roles in physiology and disease. Integrins fluctuate between active and inactive conformations, yet whether the activity state influences the spatial organization of integrins within FAs has remained unclear. In this study, we address this question and also ask whether integrin activity may be regulated either independently for each integrin molecule or through locally coordinated mechanisms. We used two distinct superresolution microscopy techniques, stochastic optical reconstruction microscopy (STORM) and stimulated emission depletion microscopy (STED), to visualize active versus inactive β1 integrins. We first reveal a spatial hierarchy of integrin organization with integrin molecules arranged in nanoclusters, which align to form linear substructures that in turn build FAs. Remarkably, within FAs, active and inactive β1 integrins segregate into distinct nanoclusters, with active integrin nanoclusters being more organized. This unexpected segregation indicates synchronization of integrin activities within nanoclusters, implying the existence of a coordinate mechanism of integrin activity regulation.
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Kawakami, Keisuke, Hitoshi Tatsumi, and Masahiro Sokabe. "Dynamics of integrin clustering at focal contacts of endothelial cells studied by multimode imaging microscopy." Journal of Cell Science 114, no. 17 (September 1, 2001): 3125–35. http://dx.doi.org/10.1242/jcs.114.17.3125.
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Human umbilical vein endothelial cells were stained with FITC-labeled anti-β1 integrin antibody and plated on a glass cover slip to elucidate the mechanism of integrin clustering during focal contact formation. The process of integrin clustering was observed by time-lapse total-internal-reflection fluorescence microscopy, which can selectively visualize the labeled integrins at the basal surface of living cells. The clustering of integrins at focal contacts started at 1 hour after plating and individual clusters kept growing for ∼6 hours. Most integrin clusters (∼80%) elongated towards the cell center or along the cell margin at a rate of 0.29±0.24 μm minute−1. Photobleaching and recovery experiments with evanescent illumination revealed that the integrins at the extending tip of the clusters were supplied from the intracellular space. Simultaneous time-lapse imaging of exocytosis of integrin-containing vesicles and elongating focal contacts showed that most exocytosis occurred at or near the focal contacts followed by their elongation. Double staining of F-actins and integrins demonstrated that stress fibers were located near the integrin clusters and that intracellular punctate integrins were associated with these stress fibers. These results suggest that the clustering of integrins is mediated by actin-fiber-dependent translocation of integrins to the extending tip of focal contacts.
6
Fasoulakis, Zacharias, Michaela-Zoi Psarommati, Angeliki Papapanagiotou, Vasilios Pergialiotis, Antonios Koutras, Athanasios Douligeris, Anastasia Mortaki, et al. "MicroRNAs Can Influence Ovarian Cancer Progression by Dysregulating Integrin Activity." Cancers 15, no. 18 (September 8, 2023): 4449. http://dx.doi.org/10.3390/cancers15184449.
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Ovarian cancer is a deadly disease that affects thousands of women worldwide. Integrins, transmembrane receptors that mediate cell adhesion and signaling, play important roles in ovarian cancer progression, metastasis, and drug resistance. Dysregulated expression of integrins is implicated in various cellular processes, such as cell migration, invasion, and proliferation. Emerging evidence suggests that microRNAs (miRNAs) can regulate integrin expression and function, thus affecting various physiological and pathological processes, including ovarian cancer. In this article, we review the current understanding of integrin-mediated cellular processes in ovarian cancer and the roles of miRNAs in regulating integrins. We also discuss the therapeutic potential of targeting miRNAs that regulate integrins for the treatment of ovarian cancer. Targeting miRNAs that regulate integrins or downstream signaling pathways of integrins may provide novel therapeutic strategies for inhibiting integrin-mediated ovarian cancer progression.
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Shimoda, Michiko, Yoko Takada, Emanual Maverakis, Brunhilde Felding, and Yoshikazu Takada. "CD40L acts as an allosteric activator of integrins for signal transduction independent of inside-out signaling." Journal of Immunology 206, no. 1_Supplement (May 1, 2021): 24.04. http://dx.doi.org/10.4049/jimmunol.206.supp.24.04.
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Abstract CD40L plays a major role in immune response and is a target for inflammatory disease therapy. Besides CD40, CD40L binds to several integrins but their role in signaling is unclear. We showed that integrins αvβ3 and α5β1 bind to the CD40L trimeric interface through classical ligand binding site of integrins (site 1). Several CD40L mutants from HIGM1 (hyper-IgM syndrome type 1) patients were clustered in trimeric interface and defective in integrin binding, and in NF-κB and B cell activation, but still bound CD40 and acted as antagonists of CD40L signaling. Thus, integrins play a critical role in CD40L signaling. Previous studies showed that CX3CL1 and sPLA2-IIA can activate integrins by binding to a recently identified allosteric site (site 2) of integrins. Using cell-free assays, we found that soluble (s)-CD40L activated soluble integrins, α4β1, αvβ3 and α5β1, and induced their binding to known specific ligands independent of inside-out signaling. Also, sCD40L activated cell-surface integrins in CHO cells lacking CD40. Finally, sCD40L bound to a cyclic peptide derived from site 2. These findings indicate that CD40L acts as an allosteric activator of integrins by binding to site 2. Docking simulation predicted that the integrin site 2-binding site of CD40L is located outside of CD40L trimer. Importantly, four HIGM1 mutations are clustered in the predicted site 2-binding site of CD40L. The K143T and G144E mutants were the most defective in integrin activation, indicating that integrin binding occurs around these residues of the predicted site 2-binding site. We propose that allosteric integrin activation by CD40L plays a role in CD40L signaling and that defective integrin site 2-binding may be causal for defective CD40L signaling in HIGM1.
8
Takada, Yoko K., Scott I. Simon, and Yoshikazu Takada. "The C-type lectin domain of CD62P (P-selectin) functions as an integrin ligand." Life Science Alliance 6, no. 7 (April 25, 2023): e202201747. http://dx.doi.org/10.26508/lsa.202201747.
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Recognition of integrins by CD62P has not been reported and this motivated a docking simulation using integrin αvβ3 as a target. We predicted that the C-type lectin domain of CD62P functions as a potential integrin ligand and observed that it specifically bound to soluble β3 and β1 integrins. Known inhibitors of the interaction between CD62P–PSGL-1 did not suppress the binding, whereas the disintegrin domain of ADAM-15, a known integrin ligand, suppressed recognition by the lectin domain. Furthermore, an R16E/K17E mutation in the predicted integrin-binding interface located outside of the glycan-binding site within the lectin domain, strongly inhibited CD62P binding to integrins. In contrast, the E88D mutation that strongly disrupts glycan binding only slightly affected CD62P-integrin recognition, indicating that the glycan and integrin-binding sites are distinct. Notably, the lectin domain allosterically activated integrins by binding to the allosteric site 2. We conclude that CD62P-integrin binding may function to promote a diverse set of cell–cell adhesive interactions given that β3 and β1 integrins are more widely expressed than PSGL-1 that is limited to leukocytes.
9
Grande-García, A., A. Echarri, and M. A. Del Pozo. "Integrin regulation of membrane domain trafficking and Rac targeting." Biochemical Society Transactions 33, no. 4 (August 1, 2005): 609–13. http://dx.doi.org/10.1042/bst0330609.
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Integrins are crucial regulators of essential cellular processes such as gene expression, cell proliferation and migration. Alteration of these processes is central to tumourigenesis. Integrin signals mediate anchorage dependence of cell growth, while growth of cancer cells is anchorage-independent. Integrins critically regulate Rho family GTPases, that are also involved in cell-cycle progression and oncogenesis. In addition to their effect on GTP loading, integrins independently control the translocation of GTP-bound Rac to the plasma membrane. This step is essential for Rac binding to effectors. Integrins increase membrane affinity for Rac, leading to RhoGDI dissociation and effector coupling locally, in the vicinity of activated/bound integrins. Integrin-regulated Rac binding sites are within CEMMs (cholesterol-enriched membrane microdomains). Integrins control Rac signalling by preventing the internalization of its binding sites in CEMMs. Integrin regulation of signalling pathways initiated in CEMMs may be important for the spatial control of cell migration and anchorage dependence of cell growth.
10
Miyamoto, S., H. Teramoto, J. S. Gutkind, and K. M. Yamada. "Integrins can collaborate with growth factors for phosphorylation of receptor tyrosine kinases and MAP kinase activation: roles of integrin aggregation and occupancy of receptors." Journal of Cell Biology 135, no. 6 (December 15, 1996): 1633–42. http://dx.doi.org/10.1083/jcb.135.6.1633.
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Integrins mediate cell adhesion, migration, and a variety of signal transduction events. These integrin actions can overlap or even synergize with those of growth factors. We examined for mechanisms of collaboration or synergy between integrins and growth factors involving MAP kinases, which regulate many cellular functions. In cooperation with integrins, the growth factors EGF, PDGF-BB, and basic FGF each produced a marked, transient activation of the ERK (extracellular signal-regulated kinase) class of MAP kinase, but only if the integrins were both aggregated and occupied by ligand. Transmembrane accumulation of total tyrosine-phosphorylated proteins, as well as nonsynergistic MAP kinase activation, could be induced by simple integrin aggregation, whereas enhanced transient accumulation of the EGF-receptor substrate eps8 required integrin aggregation and occupancy, as well as EGF treatment. Each type of growth factor receptor was itself induced to aggregate transiently by integrin ligand-coated beads in a process requiring both aggregation and occupancy of integrin receptors, but not the presence of growth factor ligand. Synergism was also observed between integrins and growth factors for triggering tyrosine phosphorylation of EGF, PDGF, and FGF receptors. This collaborative response also required both integrin aggregation and occupancy. These studies identify mechanisms in the signal transduction response to integrins and growth factors that require various combinations of integrin aggregation and ligands for integrin or growth factor receptors, providing opportunities for collaboration between these major regulatory systems.
11
Martel, V., L. Vignoud, S. Dupe, P. Frachet, M. R. Block, and C. Albiges-Rizo. "Talin controls the exit of the integrin alpha 5 beta 1 from an early compartment of the secretory pathway." Journal of Cell Science 113, no. 11 (June 1, 2000): 1951–61. http://dx.doi.org/10.1242/jcs.113.11.1951.
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Talin is a major cytosolic protein that links the intracellular domains of beta1 and beta3 integrins to the cytoskeleton. It is required for focal adhesion assembly. However, its downregulation not only slows down cell spreading and organization of focal adhesions but also impairs the maturation of some beta1 integrins, including the fibronectin receptor alpha5beta1. To investigate this, we characterized the beta1 integrin synthesized in cells expressing talin anti-sense RNA (AT22 cells). We identified a large intracellular pool of beta1 integrins that is abnormally accumulated in an earlier compartment of the secretory pathway. In this report, we show that in talin-deficient AT22 cells, the aberrant glycosylation of integrin receptors is accompanied by a delay in the export of the integrin alpha5beta1. In normal cells, talin was found associated with beta1 integrins in an enriched membrane fraction containing Golgi and endoplasmic reticulum. Finally, microinjection of anti-talin antibodies resulted in accumulation of the integrins within the cells. These data strongly suggest that talin plays a specific role in the export of newly synthesized integrins. We propose that talin binding to the integrin may disclose a diphenylalanine export signal, which is present in the membrane-proximal GFFKR motif conserved in all integrin alpha chains.
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Yago, Tadayuki, Brian G. Petrich, Nan Zhang, Zhenghui Liu, Bojing Shao, Mark H. Ginsberg, and Rodger P. McEver. "Blocking neutrophil integrin activation prevents ischemia–reperfusion injury." Journal of Experimental Medicine 212, no. 8 (July 13, 2015): 1267–81. http://dx.doi.org/10.1084/jem.20142358.
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Neutrophil recruitment, mediated by β2 integrins, combats pyogenic infections but also plays a key role in ischemia–reperfusion injury and other inflammatory disorders. Talin induces allosteric rearrangements in integrins that increase affinity for ligands (activation). Talin also links integrins to actin and other proteins that enable formation of adhesions. Structural studies have identified a talin1 mutant (L325R) that perturbs activation without impairing talin’s capacity to link integrins to actin and other proteins. Here, we found that mice engineered to express only talin1(L325R) in myeloid cells were protected from renal ischemia–reperfusion injury. Dissection of neutrophil function in vitro and in vivo revealed that talin1(L325R) neutrophils had markedly impaired chemokine-induced, β2 integrin–mediated arrest, spreading, and migration. Surprisingly, talin1(L325R) neutrophils exhibited normal selectin-induced, β2 integrin–mediated slow rolling, in sharp contrast to the defective slow rolling of neutrophils lacking talin1 or expressing a talin1 mutant (W359A) that blocks talin interaction with integrins. These studies reveal the importance of talin-mediated activation of integrins for renal ischemia–reperfusion injury. They further show that neutrophil arrest requires talin recruitment to and activation of integrins. However, although neutrophil slow rolling requires talin recruitment to integrins, talin-mediated integrin activation is dispensable.
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Gahmberg, Carl G., Mikaela Grönholm, and Sudarrshan Madhavan. "Regulation of Dynamic Cell Adhesion by Integrin-Integrin Crosstalk." Cells 11, no. 10 (May 19, 2022): 1685. http://dx.doi.org/10.3390/cells11101685.
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Most cells express several integrins. The integrins are able to respond to various cellular functions and needs by modifying their own activation state, but in addition by their ability to regulate each other by activation or inhibition. This crosstalk or transdominant regulation is strictly controlled. The mechanisms resulting in integrin crosstalk are incompletely understood, but they often involve intracellular signalling routes also used by other cell surface receptors. Several studies show that the integrin cytoplasmic tails bind to a number of cytoskeletal and adaptor molecules in a regulated manner. Recent work has shown that phosphorylations of integrins and key intracellular molecules are of pivotal importance in integrin-cytoplasmic interactions, and these in turn affect integrin activity and crosstalk. The integrin β-chains play a central role in regulating crosstalk. In addition to Integrin-integrin crosstalk, crosstalk may also occur between integrins and related receptors, including other adhesion receptors, growth factor and SARS-CoV-2 receptors.
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Brakebusch, C., E. Hirsch, A. Potocnik, and R. Fassler. "Genetic analysis of beta1 integrin function: confirmed, new and revised roles for a crucial family of cell adhesion molecules." Journal of Cell Science 110, no. 23 (December 1, 1997): 2895–904. http://dx.doi.org/10.1242/jcs.110.23.2895.
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Integrins are heterodimeric cell adhesion proteins connecting the extracellular matrix to the cytoskeleton and transmitting signals in both directions. These integrins are suggested to be involved in many different biological processes such as growth, differentiation, migration, and cell death. Of more than 20 known integrins, 10 contain the nearly ubiquitously expressed beta1 integrin subunit. Disruption of the beta1 integrin gene by homologous recombination allows us to assess the supposed functions of beta1 containing integrins in vivo in a new way. This review will present and discuss recent findings derived from such studies concerning the biological roles of beta1 integrins in early development, differentiation and migration, hematopoiesis, tumorigenesis, and supramolecular assembly of extracellular matrix proteins. While several former results were confirmed, others were contradicted and new functions found, significantly changing the previous view of beta1 integrin function in vivo.
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Harston, Rebecca K., and Dhandapani Kuppuswamy. "Integrins Are the Necessary Links to Hypertrophic Growth in Cardiomyocytes." Journal of Signal Transduction 2011 (February 21, 2011): 1–8. http://dx.doi.org/10.1155/2011/521742.
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To compensate for hemodynamic overload of the heart, an event which stretches the myocardium, growth and survival signaling are activated in cardiac muscle cells (cardiomyocytes). Integrins serve as the signaling receptors of cardiomyocytes responsible for mechanotransduction toward intracellular signaling. The main integrin heterodimers on the cardiomyocyte surface are α5β1 and αvβ3, and elimination of either β1 or β3 integrins impedes pressure-induced hypertrophic signaling and leads to increased mortality. The growth signaling pathways downstream of β1 and β3 integrins are well characterized. However, new integrin pathways responsible for inhibiting apoptosis induced by hemodynamic overload are emerging. β1 and β3 integrins activate differential survival signaling, yet both integrins initiate survival signaling downstream of ubiquitination and the kinase pathway including phosphoinositol-3-kinase (PI3K)/Akt. Further characterization of these integrin-signaling mechanisms may lead to drug targets to prevent decompensation to heart failure.
16
Regen, C. M., and A. F. Horwitz. "Dynamics of beta 1 integrin-mediated adhesive contacts in motile fibroblasts." Journal of Cell Biology 119, no. 5 (December 1, 1992): 1347–59. http://dx.doi.org/10.1083/jcb.119.5.1347.
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Motile chick skeletal fibroblasts adhere to a laminin substrate by means of clustered beta 1 integrins. These integrin "macroaggregates" are similar to classic focal contacts but do not appear dark under interference-reflection microscopy. They contain alpha 5 integrin and are associated with extracellular fibronectin. To study their behavior during cell movement, time-lapse, low-light video microscopy was used to image integrins on living cells tagged with a fluorescent anti-beta 1 integrin antibody. Integrin macroaggregates remain fixed with respect to the substratum, despite the fact that they fluctuate in size, density, and shape over a period of minutes. Upon detachment of the cell rear, as much as 85% of the beta 1 integrin density of a macroaggregate remains behind on the substrate, along with both alpha 5 integrin and fibronectin. Release of the cell rear does not involve cleavage of the beta 1 integrin cytoplasmic domain from the remainder of the protein. These results indicate that cell motility does not require regulated detachment of integrin receptors from the substrate. On the other hand, cytoskeletal components and a variable fraction of the integrins are carried forward with the cell during detachment, suggesting that some type of cortical disassembly process does occur. Integrin macroaggregate structures are not recycled intact after detachment of the cell rear from the substrate. They do not persist on the cell surface, nor can they be seen to be engulfed by vesicles; yet, some of the individual integrins that make up these macroaggregates are eventually transported forward by both vesicular and cell-surface routes. Antibody-tagged integrins accumulate in dense patches at the lateral edges and dorsal surface of the cell, and move forward on the cell surface. The tagged integrins also enter cytoplasmic vesicles, which move forward within the cytoplasm. Macroaggregates generally form and grow at the cell front; however, application of fluorescent antibody causes integrins to disappear from the leading edge. Therefore, it has not been possible to directly visualize the recycling of the forward moving tagged integrins into new macroaggregates at the cell front. Surprisingly, under these conditions cells move normally despite the absence of any delivery of tagged integrin to the leading edge, indicating that recycling of integrins to the lamella is not required for apparently normal motility.
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Niland, Stephan, and Johannes A. Eble. "Integrin-Mediated Cell-Matrix Interaction in Physiological and Pathological Blood Vessel Formation." Journal of Oncology 2012 (2012): 1–25. http://dx.doi.org/10.1155/2012/125278.
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Physiological as well as pathological blood vessel formation are fundamentally dependent on cell-matrix interaction. Integrins, a family of major cell adhesion receptors, play a pivotal role in development, maintenance, and remodeling of the vasculature. Cell migration, invasion, and remodeling of the extracellular matrix (ECM) are integrin-regulated processes, and the expression of certain integrins also correlates with tumor progression. Recent advances in the understanding of how integrins are involved in the regulation of blood vessel formation and remodeling during tumor progression are highlighted. The increasing knowledge of integrin function at the molecular level, together with the growing repertoire of integrin inhibitors which allow their selective pharmacological manipulation, makes integrins suited as potential diagnostic markers and therapeutic targets.
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Conrad, ME, JN Umbreit, RD Peterson, EG Moore, and KP Harper. "Function of integrin in duodenal mucosal uptake of iron." Blood 81, no. 2 (January 15, 1993): 517–21. http://dx.doi.org/10.1182/blood.v81.2.517.517.
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Abstract A mechanism for the absorption of inorganic iron in the small intestine is described in which integrins appear to play an important role in the passage of iron across microvillous membranes. Biochemical isolates from microvillous preparations of duodenum from rats dosed with radioiron showed radioactivity concentrated in integrins. The presence of integrins on mucosal surfaces of duodenal cells was confirmed by immunofluorescent microscopy using anti-integrin monoclonal antibodies. Immunoprecipitation methods were used to show that microvillous radioiron was precipitated with anti-integrin antibodies and that mobilferrin, a 56-Kd cytosol iron-binding protein, coprecipitated with integrins. We postulate from these data that the mucosal uptake of iron from the gut lumen is mediated via an integrin-mobilferrin pathway.
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Conrad, ME, JN Umbreit, RD Peterson, EG Moore, and KP Harper. "Function of integrin in duodenal mucosal uptake of iron." Blood 81, no. 2 (January 15, 1993): 517–21. http://dx.doi.org/10.1182/blood.v81.2.517.bloodjournal812517.
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A mechanism for the absorption of inorganic iron in the small intestine is described in which integrins appear to play an important role in the passage of iron across microvillous membranes. Biochemical isolates from microvillous preparations of duodenum from rats dosed with radioiron showed radioactivity concentrated in integrins. The presence of integrins on mucosal surfaces of duodenal cells was confirmed by immunofluorescent microscopy using anti-integrin monoclonal antibodies. Immunoprecipitation methods were used to show that microvillous radioiron was precipitated with anti-integrin antibodies and that mobilferrin, a 56-Kd cytosol iron-binding protein, coprecipitated with integrins. We postulate from these data that the mucosal uptake of iron from the gut lumen is mediated via an integrin-mobilferrin pathway.
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Zhang, Qingfang, Shuo Zhang, Jianrui Chen, and Zhenzhen Xie. "The Interplay between Integrins and Immune Cells as a Regulator in Cancer Immunology." International Journal of Molecular Sciences 24, no. 7 (March 24, 2023): 6170. http://dx.doi.org/10.3390/ijms24076170.
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Integrins are a group of heterodimers consisting of α and β subunits that mediate a variety of physiological activities of immune cells, including cell migration, adhesion, proliferation, survival, and immunotolerance. Multiple types of integrins act differently on the same immune cells, while the same integrin may exert various effects on different immune cells. In the development of cancer, integrins are involved in the regulation of cancer cell proliferation, invasion, migration, and angiogenesis; conversely, integrins promote immune cell aggregation to mediate the elimination of tumors. The important roles of integrins in cancer progression have provided valuable clues for the diagnosis and targeted treatment of cancer. Furthermore, many integrin inhibitors have been investigated in clinical trials to explore effective regimens and reduce side effects. Due to the complexity of the mechanism of integrin-mediated cancer progression, challenges remain in the research and development of cancer immunotherapies (CITs). This review enumerates the effects of integrins on four types of immune cells and the potential mechanisms involved in the progression of cancer, which will provide ideas for more optimal CIT in the future.
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Matthys, Valery S., Elena E. Gorbunova, Irina N. Gavrilovskaya, and Erich R. Mackow. "Andes Virus Recognition of Human and Syrian Hamster β3 Integrins Is Determined by an L33P Substitution in the PSI Domain." Journal of Virology 84, no. 1 (October 21, 2009): 352–60. http://dx.doi.org/10.1128/jvi.01013-09.
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ABSTRACT Andes virus (ANDV) causes a fatal hantavirus pulmonary syndrome (HPS) in humans and Syrian hamsters. Human αvβ3 integrins are receptors for several pathogenic hantaviruses, and the function of αvβ3 integrins on endothelial cells suggests a role for αvβ3 in hantavirus directed vascular permeability. We determined here that ANDV infection of human endothelial cells or Syrian hamster-derived BHK-21 cells was selectively inhibited by the high-affinity αvβ3 integrin ligand vitronectin and by antibodies to αvβ3 integrins. Further, antibodies to the β3 integrin PSI domain, as well as PSI domain polypeptides derived from human and Syrian hamster β3 subunits, but not murine or bovine β3, inhibited ANDV infection of both BHK-21 and human endothelial cells. These findings suggest that ANDV interacts with β3 subunits through PSI domain residues conserved in both Syrian hamster and human β3 integrins. Sequencing the Syrian hamster β3 integrin PSI domain revealed eight differences between Syrian hamster and human β3 integrins. Analysis of residues within the PSI domains of human, Syrian hamster, murine, and bovine β3 integrins identified unique proline substitutions at residues 32 and 33 of murine and bovine PSI domains that could determine ANDV recognition. Mutagenizing the human β3 PSI domain to contain the L33P substitution present in bovine β3 integrin abolished the ability of the PSI domain to inhibit ANDV infectivity. Conversely, mutagenizing either the bovine PSI domain, P33L, or the murine PSI domain, S32P, to the residue present human β3 permitted PSI mutants to inhibit ANDV infection. Similarly, CHO cells transfected with the full-length bovine β3 integrin containing the P33L mutation permitted infection by ANDV. These findings indicate that human and Syrian hamster αvβ3 integrins are key receptors for ANDV and that specific residues within the β3 integrin PSI domain are required for ANDV infection. Since L33P is a naturally occurring human β3 polymorphism, these findings further suggest the importance of specific β3 integrin residues in hantavirus infection. These findings rationalize determining the role of β3 integrins in hantavirus pathogenesis in the Syrian hamster model.
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Shin, Sejeong, Laura Wolgamott, and Sang-Oh Yoon. "Integrin Trafficking and Tumor Progression." International Journal of Cell Biology 2012 (2012): 1–7. http://dx.doi.org/10.1155/2012/516789.
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Integrins are major mediators of cancer cell adhesion to extracellular matrix. Through this interaction, integrins play critical roles in cell migration, invasion, metastasis, and resistance to apoptosis during tumor progression. Recent studies highlight the importance of integrin trafficking, endocytosis and recycling, for the functions of integrins in cancer cells. Understanding the molecular mechanisms of integrin trafficking is pivotal for understanding tumor progression and for the development of anticancer drugs.
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Miura, Kohei, Shashi Uniyal, Mircea Leabu, Tamas Oravecz, Subrata Chakrabarti, Vincent L. Morris, and Bosco M. C. Chan. "Chemokine receptor CXCR4-β1 integrin axis mediates tumorigenesis of osteosarcoma HOS cells." Biochemistry and Cell Biology 83, no. 1 (February 1, 2005): 36–48. http://dx.doi.org/10.1139/o04-106.
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It is known that β1 integrins mediate the migratory response of cells to chemokine stimulation. Also, both β1 integrins and chemokines have roles in tumor development. In the present study, the β1 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 β1 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 α2β1 integrin. On fibronectin, SDF-1-stimulated chemotaxis involved both α4β1 and α5β1 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 α2β1, or integrin α5β1 effectively inhibited the growth of HOS-CXCR4 transfectant cells in vivo. Therefore, our results show that the β1 integrins that mediated the migratory response were also functionally linked to the enhanced tumor growth of CXCR4-expressing HOS transfectant cells.Key words: integrins, chemokines, chemotaxis, osteosarcoma, tumorigenesis.
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Martinez-Lemus, Luis A., Tracy Crow, Michael J. Davis, and Gerald A. Meininger. "αvβ3- and α5β1-integrin blockade inhibits myogenic constriction of skeletal muscle resistance arterioles." American Journal of Physiology-Heart and Circulatory Physiology 289, no. 1 (July 2005): H322—H329. http://dx.doi.org/10.1152/ajpheart.00923.2003.
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In isolated resistance arterioles with spontaneous tone, ligation of α4β1- and α5β1-integrins induces vasoconstriction whereas ligation of αvβ3-integrin induces vasodilation. However, whether integrins directly participate in myogenic constriction to pressure elevation is not known. To answer this question, isolated rat skeletal muscle arterioles were exposed to step increments in pressure in the absence or presence of peptides and function-blocking antibodies known to bind α4β1-, α5β1-, or αvβ3-integrins while vessel diameter was continually monitored. Myogenic constriction, as assessed by the ability of isolated arterioles to reduce their diameter in response to two consecutive increments in intraluminal pressure (90–110 and 110–130 cmH2O), was not affected by treatment with any of the control peptides (RAD, LEV), a control antibody (anti-rat major histocompatibility complex), an α4β1-integrin-binding peptide (LDV), or an anti-α4-integrin antibody. In contrast, α5β1-integrin blockade with either anti-α5- or anti-β1-integrin antibody caused a significant inhibition of myogenic constriction. Also, both RGD peptide and anti-β3-integrin antibody inhibited myogenic constriction. These results indicate that α5β1- and αvβ3-integrins are necessary for myogenic constriction and further suggest that integrins are part of the mechanosensory apparatus responsible for the ability of vascular smooth muscle cells to detect and/or respond to changes in intraluminal pressure.
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Lu, Xinjie, Dong Lu, Mike Scully, and Vijay Kakkar. "The Role of Integrins in Cancer and the Development of Anti-Integrin Therapeutic Agents for Cancer Therapy." Perspectives in Medicinal Chemistry 2 (January 2008): 1177391X0800200. http://dx.doi.org/10.1177/1177391x0800200003.
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Integrins have been reported to mediate cell survival, proliferation, differentiation, and migration programs. For this reason, the past few years have seen an increased interest in the implications of integrin receptors in cancer biology and tumor cell aggression. This review considers the potential role of integrins in cancer and also addresses why integrins are present attractive targets for drug design. It discusses of the several properties of the integrin-based chemotherapeutic agents currently under consideration clinically and provides an insight into cancer drug development using integrin as a target.
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Lee, Tae-Hee, Hava Karsenty Avraham, Huchun Li, Stephen J. Kennel, and Shalom Avraham. "Regulation of Integrin Expression and Activation by VEGF in Human Brain Microvascular Endothelial Cells: Implication of α6 Integrin in Angiogenesis." Blood 104, no. 11 (November 16, 2004): 2609. http://dx.doi.org/10.1182/blood.v104.11.2609.2609.
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Abstract The precise role of vascular endothelial growth factor (VEGF) in the regulation of integrins is not well elucidated due to their high redundancy. Here, we examined the effects of VEGF on the expression and activation of integrins in human brain microvascular endothelial cells (HBMECs). Using human cDNA arrays and Ribonuclease (RNase) protection assays which cover most of the known integrins, we observed that VEGF significantly upregulated the mRNA expression of α1, α2, and α6 integrins in HBMECs. While VEGF was reported to induce α1 and α2 integrins, the observation of α6 integrin induction by VEGF is novel. Using small interfering RNA (siRNA) oligonucleotides for α6 integrin, we observed downregulation of the cell surface expression of α6 integrin in HBMECs. This downregulation resulted in inhibition of both HBMEC capillary morphogenesis and of the VEGF-induced adhesion and migration of the cells. VEGF also induced the activation of α6 integrin in the HBMECs. Functional blocking of α6 integrin by its specific antibody led to inhibition of VEGF-induced adhesion and migration as well as of in vivo angiogenesis, and significantly suppressed tumor angiogenesis and breast carcinoma cell growth in vivo. These results indicate that VEGF can modulate the in vitro angiogenesis of HBMECs via increased expression and activation of the α6 integrin, and that this integrin participates in VEGF-driven angiogenesis in vivo.
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Paule, S. G., and G. Nie. "164. INTEGRIN CLEAVAGE IS MEDIATED BY PROPROTEIN CONVERTASE 6 IN HUMAN ENDOMETRIAL EPITHELIAL CELLS FOR ENDOMETRIAL RECEPTIVITY AND IMPLANTATION." Reproduction, Fertility and Development 22, no. 9 (2010): 82. http://dx.doi.org/10.1071/srb10abs164.
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Integrins are transmembrane glycoproteins composed of non-covalently associated α and β chains. Integrins participates in cell–cell interaction and binding to components of the extracellular matrix. Integrin expression changes during the establishment of receptivity for implantation. Integrins α1β1, α4β1 and αvβ3 are expressed in the endometrium during the window of implantation [1, 2] and deficiency in integrin αvβ3 is associated with idiopathic infertility and delayed endometrial maturation [1, 3, 4]. Proprotein convertases (PCs) cleave proproteins at the basic amino acids consensus motif (K/R)-(X)n-(K/R)↓ (where n = 0, 2, 4 or 6 and X is any aa) for activation. Integrins require post-translational cleavage for activation and are known to be cleaved by PCs. PC6 plays a critical role in the establishment of endometrial receptivity. We hypothesized that PC6 cleaves integrins for its activation in the endometrial epithelium for implantation. The aim of this study was to investigate the functional importance of PC6 in integrin cleavage, using a stable PC6-knockdown in HEC1A cells (HEC1A-HP) by siRNA technology.Cells transfected with a scrambled siRNA sequence (HEC1A-control) were used as the control. To determine the amount of functional integrins on the cell surface, HEC1A-PC6 and HEC1A-control were subjected to an integrin monoclonal antibody array. The amount of functional integrins α1, α3, α5, αv, αvβ3, β1, β3, β4 and α5β1 on the cell surfacewas much less in HEC1A-HP than HEC1A-control cells. Western blot analysis confirmed that cleavage of pro-integrin α5 into disulfide-linked heavy chain (110kDa) and light chain (35kDa) was greater in HEC1A-control compared to HEC1A-HP cells, suggesting that knockdown of PC6 affects integrin cleavage. Our studies imply that integrin cleavage is mediated by PC6 in endometrial epithelial cells for the establishment of receptivity for embryo implantation. (1) Lessey BA, et al., Integrin adhesion molecules in the human endometrium. Correlation with the normal and abnormal menstrual cycle. J Clin Invest, 1992. 90(1): 188–95.(2) Tabibzadeh S, Patterns of expression of integrin molecules in human endometrium throughout the menstrual cycle. Hum Reprod, 1992. 7(6): 876–82.(3) Lessey BA, et al., Further characterization of endometrial integrins during the menstrual cycle and in pregnancy. Fertil Steril, 1994. 62(3): 497–506.(4) Lessey BA, et al., Aberrant integrin expression in the endometrium of women with endometriosis. J Clin Endocrinol Metab, 1994. 79(2): 643–9.
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Thinn, Aye Myat Myat, and Jieqing Zhu. "Structure and Sequence Diversity of the Membrane Distal Region of α-Cytoplasmic Tail in Integrin Activation." Blood 126, no. 23 (December 3, 2015): 3453. http://dx.doi.org/10.1182/blood.v126.23.3453.3453.
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Abstract Integrins are α/β heterodimeric cell adhesion receptors with each subunit comprising of a large extracellular domain, a single-spanning transmembrane domain, and usually a short cytoplasmic tail. Different combinations of 18 α and 8 β subunits make up 24 integrin members that recognize diverse extracellular ligands important in numerous biological functions such as immune responses, maintenance of hemostasis, and development. Abnormal activation of integrin is associated with many pathological conditions including thrombosis, inflammatory diseases, as well as tumor-driven cell growth, metastasis, and angiogenesis. Therefore, tight regulation is crucial in integrin activation. Recent structural and functional studies have shown that integrin activation is regulated by the cytoplasmic tails. Studies on the mechanism of integrin activation from inside the cell (namely inside-out activation) have been focused on the β cytoplasmic tail that is relatively conserved and bears binding sites for the common intracellular activators such as talin and kindlin. However, the role of α cytoplasmic tail in integrin activation remains elusive. The integrin α cytoplasmic tails share a conserved GFFKR motif at the membrane-proximal region that forms a specific interface with the membrane-proximal region of the β cytoplasmic tail. In contrast, the membrane-distal (MD) regions following the GFFKR motif are diverse significantly both in length, sequence and structure when reported, and their roles in integrin activation have not been well characterized. Our recent studies demonstrated that the α-MD region is required for talin and kindlin-induced activation of αIIb, αV, and αL integrins and suggest that the sequence diversity of the α-MD region might play a role in the regulation of integrin activation. In this study, we further examined the role of α-MD regions in integrin inside-out activation using αIIb, αL, and α5 integrins as platforms. Each MD region of αIIb, αL, and α5 was replaced with those of other α subunits that heterodimerize with β3, β2, and β1 integrins, respectively. β3 subunit forms heterodimers with αIIb and αV integrins. β2 subunit forms heterodimers with αL, αM, αD, and αX integrins. β1 subunit forms heterodimers with α1, α2, α3, α4, α5, α6, α7, α8, α9, α10, α11, and αV integrins. Thus, using these integrin α-chimeras, we were able to systemically study the role of 17 α-MD regions in integrin inside-out activation while retaining the native association of α and β subunits at the cytoplasmic domains. Ligand-mimetic mAb PAC-1, intercellular adhesion molecule-1 (ICAM-1), and human fibronectin were used to measure the talin-head-induced activation of αIIb, αL, and α5 chimeras co-expressed in HEK293FT cells with β3, β2, and β1 integrins, respectively. Conformation-specific monoclonal antibodies were used to report integrin conformational activation. The endogenous α5β1 integrin of HEK293FT cells were knocked out by the CRISPR/Cas9 technology. Our data showed that the chimeric α integrins had different levels of inside-out activation when compared with their corresponding wild-type integrins. Some chimeras such as αIIb-αV, αL-αX, αL-αD, αL-αM, α5-α2, α5-α4, and α5-α9 showed lower integrin activation than the wild types, while other chimeras such as α5-α7 and α5-α10 rendered α5β1 integrin more active than wild type. As a control, the αIIb-α1 and αIIb-αL chimeras all showed higher inside-out activation than wild-type αIIb. Our results suggest that specific amino acids of the α-MD region that immediately follow the GFFKR motif might contribute to integrin inside-out activation, probably through regulating the conformational change of the integrin α transmembrane and cytoplasmic domains. Our study demonstrates an important role of the α-MD region in integrin activation and indicates that structure and sequence diversity of the α-MD region might contribute to the diverse functions of integrins, which are determined by different integrin α subunits. Disclosures No relevant conflicts of interest to declare.
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De Mets, Richard, Irene Wang, Martial Balland, Christiane Oddou, Philippe Moreau, Bertrand Fourcade, Corinne Albiges-Rizo, Antoine Delon, and Olivier Destaing. "Cellular tension encodes local Src-dependent differential β1 and β3 integrin mobility." Molecular Biology of the Cell 30, no. 2 (January 15, 2019): 181–90. http://dx.doi.org/10.1091/mbc.e18-04-0253.
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Integrins are transmembrane receptors that have a pivotal role in mechanotransduction processes by connecting the extracellular matrix to the cytoskeleton. Although it is well established that integrin activation/inhibition cycles are due to highly dynamic interactions, whether integrin mobility depends on local tension and cytoskeletal organization remains surprisingly unclear. Using an original approach combining micropatterning on glass substrates to induce standardized local mechanical constraints within a single cell with temporal image correlation spectroscopy, we measured the mechanosensitive response of integrin mobility at the whole cell level and in adhesion sites under different mechanical constraints. Contrary to β1 integrins, high tension increases β3 integrin residence time in adhesive regions. Chimeric integrins and structure–function studies revealed that the ability of β3 integrins to specifically sense local tensional organization is mostly encoded by its cytoplasmic domain and is regulated by tuning the affinity of its NPXY domains through phosphorylation by Src family kinases.
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Park, Si-Hyoung, Chan-wool Lee, Ji-Hyun Lee, Jin Young Park, Mobina Roshandell, Catherine A. Brennan, and Kwang-Min Choe. "Requirement for and polarized localization of integrin proteins during Drosophila wound closure." Molecular Biology of the Cell 29, no. 18 (September 2018): 2137–47. http://dx.doi.org/10.1091/mbc.e17-11-0635.
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Wound reepithelialization is an evolutionarily conserved process in which skin cells migrate as sheets to heal the breach and is critical to prevent infection but impaired in chronic wounds. Integrin heterodimers mediate attachment between epithelia and underlying extracellular matrix and also act in large signaling complexes. The complexity of the mammalian wound environment and evident redundancy among integrins has impeded determination of their specific contributions to reepithelialization. Taking advantage of the genetic tools and smaller number of integrins in Drosophila, we undertook a systematic in vivo analysis of integrin requirements in the reepithelialization of skin wounds in the larva. We identify αPS2-βPS and αPS3-βPS as the crucial integrin dimers and talin as the only integrin adhesion component required for reepithelialization. The integrins rapidly accumulate in a JNK-dependent manner in a few rows of cells surrounding a wound. Intriguingly, the integrins localize to the distal margin in these cells, instead of the frontal or lamellipodial distribution expected for proteins providing traction and recruit nonmuscle myosin II to the same location. These findings indicate that signaling roles of integrins may be important for epithelial polarization around wounds and lay the groundwork for using Drosophila to better understand integrin contributions to reepithelialization.
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Rust, William L., Stephen W. Carper, and George E. Plopper. "The Promise of Integrins as Effective Targets for Anticancer Agents." Journal of Biomedicine and Biotechnology 2, no. 3 (2002): 124–30. http://dx.doi.org/10.1155/s1110724302204015.
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This review will briefly describe integrin function, address why integrins are attractive targets for chemotherapeutic drug design, and discuss some ongoing studies aimed at inhibiting integrin activity. Integrins are cell surface heterodimeric receptors. They modulate many cellular processes including: growth, death (apoptosis), adhesion, migration, and invasion by activating several signaling pathways. Many potential chemotherapeutic agents target integrins directly (eg, polypeptides, monoclonal antibodies, adenovirus vectors). These agents may be clinically useful in controlling the metastatic spread of cancer.
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Fan, Zhichao, Lai Wen, Yi-Ting Yeh, William B. Kiosses, Edgar Gutierrez, Alex Groisman, Joshua Francois, et al. "Kindlin-3 organizes a ring of clustered high affinity β2 integrins during human neutrophil spreading under flow." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 220.1. http://dx.doi.org/10.4049/jimmunol.204.supp.220.1.
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Abstract Neutrophils are vital for inflammation and immune defense. Dependent on β2 integrins, spherical neutrophils spread on vascular endothelium after arrest, which is critical for their recruitment from circulation to resist high shear flow and to initiate intravascular crawling. Here, we use high-resolution quantitative dynamic footprinting microscopy to monitor neutrophil spreading on a substrate of recombinant ICAM-1 and P-selectin under flow. A homogenous binding assay using the conformation-reporter antibodies mAb24 (reporting high-affinity β2, H+) and KIM127 (reporting extended β2, E+) showed three conformations of activated β2 integrins. E−H+ β2 integrins increased before E+H− and E+H+ conformations at the beginning of neutrophil spreading. Integrin extension depended on Syk-mediated integrin outside-in signaling. The ring of E−H+ and E+H+, but not E+H− β2 integrins was fully formed during late neutrophil spreading just before migration. Using kindlin-3-GFP fusion proteins, a ring of kindlin-3 was observed before the ring of H+ integrins appeared. These findings show spatially coordinated integrin activation during spreading. The previously unrecognized E−H+ conformation is the pioneer integrin for neutrophil spreading and appears to be organized by kindlin-3.
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Weerasinghe, Dheepika, Kevin P. McHugh, Frederick P. Ross, Eric J. Brown, Roland H. Gisler, and Beat A. Imhof. "A Role for the αvβ3 Integrin in the Transmigration of Monocytes." Journal of Cell Biology 142, no. 2 (July 27, 1998): 595–607. http://dx.doi.org/10.1083/jcb.142.2.595.
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The β2 integrins and intercellular adhesion molecule-1 (ICAM-1) are important for monocyte migration through inflammatory endothelium. Here we demonstrate that the integrin αvβ3 is also a key player in this process. In an in vitro transendothelial migration assay, monocytes lacking β3 integrins revealed weak migratory ability, whereas monocytes expressing β3 integrins engaged in stronger migration. This migration could be partially blocked by antibodies against the integrin chains αL, β2, αv, or IAP, a protein functionally associated with αvβ3 integrin. Transfection of β3 integrin chain cDNA into monocytes lacking β3 integrins resulted in expression of the αvβ3 integrin and conferred on these cells an enhanced ability to transmigrate through cell monolayers expressing ICAM-1. These monocytes also engaged in αLβ2-dependent locomotion on recombinant ICAM-1 which was enhanced by αvβ3 integrin occupancy. Antibodies against IAP were able to revert this αvβ3 integrin-dependent cell locomotion to control levels. Finally, adhesion assays revealed that occupancy of αvβ3 integrin could decrease monocyte binding to ICAM-1. In conclusion, we show that αvβ3 integrin modulates αLβ2 integrin-dependent monocyte adhesion to and migration on ICAM-1. This could represent a novel mechanism to promote monocyte motility on vascular ICAM-1 and initiate subsequent transendothelial migration.
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Kucik, Dennis F., Timothy E. O'Toole, Alexander Zheleznyak, Denise K. Busettini, and Eric J. Brown. "Activation-enhanced αIIbβ3-Integrin–Cytoskeleton Interactions Outside of Focal Contacts Require the α-Subunit." Molecular Biology of the Cell 12, no. 5 (May 2001): 1509–18. http://dx.doi.org/10.1091/mbc.12.5.1509.
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Integrins link the cell's cytoskeleton to the extracellular matrix, as well as to receptors on other cells. These links occur not only at focal contacts but also at smaller integrin-containing protein complexes outside of focal contacts. We previously demonstrated the importance of focal contact-independent integrin–cytoskeleton interactions of β2 integrins: activation of adhesion resulted from a release of integrins from cytoskeletal constraints. To determine whether changes in integrin–cytoskeleton interactions were related to activation of the integrin, we used single particle tracking to examine focal contact-independent cytoskeletal associations of αIIbβ3-integrin, in which activation results in a large conformational change. Direct activation of αIIbβ3 by mutation did not mimic activation of lymphocytes with phorbol ester, because it enhanced integrin–cytoskeleton interactions, whereas activation of lymphocytes decreased them. Using additional integrin mutants, we found that both α- and β-cytoplasmic domains were required for these links. This suggests that 1) both β2- and β3-integrins interact with the cytoskeleton outside of focal contacts; 2) activation of a cell and activation of an integrin are distinct processes, and both can affect integrin–cytoskeleton interactions; and 3) the role of the α-subunit in integrin–cytoskeleton interactions in at least some circumstances is more direct than generally supposed.
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Danen, Erik H. J. "Integrin Signaling as a Cancer Drug Target." ISRN Cell Biology 2013 (July 24, 2013): 1–14. http://dx.doi.org/10.1155/2013/135164.
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Integrins are transmembrane receptors that mediate cell adhesion to neighboring cells and to the extracellular matrix. Here, the various modes in which integrin-mediated adhesion regulates intracellular signaling pathways impinging on cell survival, proliferation, and differentiation are considered. Subsequently, evidence that integrins also control crucial signaling cascades in cancer cells is discussed. Lastly, the important role of integrin signaling in tumor cells as well as in stromal cells that support cancer growth, metastasis, and therapy resistance indicates that integrin signaling may be an attractive target for (combined) cancer therapy strategies. Current approaches to target integrins in this context are reviewed.
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Juratli, Mazen A., He Zhou, Elsie Oppermann, Wolf O. Bechstein, Andreas Pascher, Felix K. H. Chun, Eva Juengel, Jochen Rutz, and Roman A. Blaheta. "Integrin α2 and β1 Cross-Communication with mTOR/AKT and the CDK-Cyclin Axis in Hepatocellular Carcinoma Cells." Cancers 14, no. 10 (May 14, 2022): 2430. http://dx.doi.org/10.3390/cancers14102430.
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Integrin receptors contribute to hepatocellular carcinoma (HCC) invasion, while AKT-mTOR signaling controls mitosis. The present study was designed to explore the links between integrins and the AKT-mTOR pathway and the CDK-Cyclin axis. HCC cell lines (HepG2, Huh7, Hep3B) were stimulated with soluble collagen or Matrigel to activate integrins, or with insulin-like growth factor 1 (IGF1) to activate AKT-mTOR. HCC growth, proliferation, adhesion, and chemotaxis were evaluated. AKT/mTOR-related proteins, proteins of the CDK-Cyclin axis, focal adhesion kinase (FAK), and integrin-linked kinase (ILK) were determined following IGF1-stimulation or integrin knockdown. Stimulation with collagen or Matrigel increased tumor cell growth and proliferation. This was associated with significant alteration of the integrins α2, αV, and β1. Blockade of these integrins led to cell cycle arrest in G2/M and diminished the number of tumor cell clones. Knocking down the integrins α2 or β1 suppressed ILK, reduced FAK-phosphorylation and diminished AKT/mTOR, as well as the proteins of the CDK-Cyclin axis. Activating the cells with IGF1 enhanced the expression of the integrins α2, αV, β1, activated FAK, and increased tumor cell adhesion and chemotaxis. Blocking the AKT pathway canceled the enhancing effect of IGF on the integrins α2 and β1. These findings reveal that HCC growth, proliferation, and invasion are controlled by a fine-tuned network between α2/β1-FAK signaling, the AKT-mTOR pathway, and the CDK–Cyclin axis. Concerted blockade of the integrin α2/β1 complex along with AKT-mTOR signaling could, therefore, provide an option to prevent progressive dissemination of HCC.
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Yokosaki, Yasuyuki, and Norihisa Nishimichi. "New Therapeutic Targets for Hepatic Fibrosis in the Integrin Family, α8β1 and α11β1, Induced Specifically on Activated Stellate Cells." International Journal of Molecular Sciences 22, no. 23 (November 26, 2021): 12794. http://dx.doi.org/10.3390/ijms222312794.
Full textAbstract:
A huge effort has been devoted to developing drugs targeting integrins over 30 years, because of the primary roles of integrins in the cell-matrix milieu. Five αv-containing integrins, in the 24 family members, have been a central target of fibrosis. Currently, a small molecule against αvβ1 is undergoing a clinical trial for NASH-associated fibrosis as a rare agent aiming at fibrogenesis. Latent TGFβ activation, a distinct talent of αv-integrins, has been intriguing as a therapeutic target. None of the αv-integrin inhibitors, however, has been in the clinical market. αv-integrins commonly recognize an Arg-Gly-Asp (RGD) sequence, and thus the pharmacophore of inhibitors for the 5-integrins is based on the same RGD structure. The RGD preference of the integrins, at the same time, dilutes ligand specificity, as the 5-integrins share ligands containing RGD sequence such as fibronectin. With the inherent little specificity in both drugs and targets, “disease specificity” has become less important for the inhibitors than blocking as many αv-integrins. In fact, an almighty inhibitor for αv-integrins, pan-αv, was in a clinical trial. On the contrary, approved integrin inhibitors are all specific to target integrins, which are expressed in a cell-type specific manner: αIIbβ3 on platelets, α4β1, α4β7 and αLβ2 on leukocytes. Herein, “disease specific” integrins would serve as attractive targets. α8β1 and α11β1 are selectively expressed in hepatic stellate cells (HSCs) and distinctively induced upon culture activation. The exceptional specificity to activated HSCs reflects a rather “pathology specific” nature of these new integrins. The monoclonal antibodies against α8β1 and α11β1 in preclinical examinations may illuminate the road to the first medical agents.
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Takada, Yoshikazu, Masaaki Fujita, and Yoko K. Takada. "Virtual Screening of Protein Data Bank via Docking Simulation Identified the Role of Integrins in Growth Factor Signaling, the Allosteric Activation of Integrins, and P-Selectin as a New Integrin Ligand." Cells 12, no. 18 (September 13, 2023): 2265. http://dx.doi.org/10.3390/cells12182265.
Full textAbstract:
Integrins were originally identified as receptors for extracellular matrix (ECM) and cell-surface molecules (e.g., VCAM-1 and ICAM-1). Later, we discovered that many soluble growth factors/cytokines bind to integrins and play a critical role in growth factor/cytokine signaling (growth factor–integrin crosstalk). We performed a virtual screening of protein data bank (PDB) using docking simulations with the integrin headpiece as a target. We showed that several growth factors (e.g., FGF1 and IGF1) induce a integrin-growth factor-cognate receptor ternary complex on the surface. Growth factor/cytokine mutants defective in integrin binding were defective in signaling functions and act as antagonists of growth factor signaling. Unexpectedly, several growth factor/cytokines activated integrins by binding to the allosteric site (site 2) in the integrin headpiece, which is distinct from the classical ligand (RGD)-binding site (site 1). Since 25-hydroxycholesterol, a major inflammatory mediator, binds to site 2, activates integrins, and induces inflammatory signaling (e.g., IL-6 and TNFα secretion), it has been proposed that site 2 is involved in inflammatory signaling. We showed that several inflammatory factors (CX3CL1, CXCL12, CCL5, sPLA2-IIA, and P-selectin) bind to site 2 and activate integrins. We propose that site 2 is involved in the pro-inflammatory action of these proteins and a potential therapeutic target. It has been well-established that platelet integrin αIIbβ3 is activated by signals from the inside of platelets induced by platelet agonists (inside-out signaling). In addition to the canonical inside-out signaling, we showed that αIIbβ3 can be allosterically activated by inflammatory cytokines/chemokines that are stored in platelet granules (e.g., CCL5, CXCL12) in the absence of inside-out signaling (e.g., soluble integrins in cell-free conditions). Thus, the allosteric activation may be involved in αIIbβ3 activation, platelet aggregation, and thrombosis. Inhibitory chemokine PF4 (CXCL4) binds to site 2 but did not activate integrins, Unexpectedly, we found that PF4/anti-PF4 complex was able to activate integrins, indicating that the anti-PF4 antibody changed the phenotype of PF4 from inhibitory to inflammatory. Since autoantibodies to PF4 are detected in vaccine-induced thrombocytopenic thrombosis (VIPP) and autoimmune diseases (e.g., SLE, and rheumatoid arthritis), we propose that this phenomenon is related to the pathogenesis of these diseases. P-selectin is known to bind exclusively to glycans (e.g., sLex) and involved in cell–cell interaction by binding to PSGL-1 (CD62P glycoprotein ligand-1). Unexpectedly, through docking simulation, we discovered that the P-selectin C-type lectin domain functions as an integrin ligand. It is interesting that no one has studied whether P-selectin binds to integrins in the last few decades. The integrin-binding site and glycan-binding site were close but distinct. Also, P-selectin lectin domain bound to site 2 and allosterically activated integrins.
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Haling, Jacob R., Susan J. Monkley, David R. Critchley, and Brian G. Petrich. "Talin-dependent integrin activation is required for fibrin clot retraction by platelets." Blood 117, no. 5 (February 3, 2011): 1719–22. http://dx.doi.org/10.1182/blood-2010-09-305433.
Full textAbstract:
Abstract Talin functions both as a regulator of integrin affinity and as an important mechanical link between integrins and the cytoskeleton. Using genetic deletion of talin, we show for the first time that the capacity of talin to activate integrins is required for fibrin clot retraction by platelets. To further dissect which talin functions are required for this process, we tested clot retraction in platelets expressing a talin1(L325R) mutant that binds to integrins, but exhibits impaired integrin activation ascribable to disruption of the interaction between talin and the membrane-proximal region (MPR) in the β-integrin cytoplasmic domain. Talin-deficient and talin1(L325R) platelets were defective in retracting fibrin clots. However, the defect in clot retraction in talin1(L325R) platelets, but not talin-deficient platelets, was rescued by extrinsically activating integrins with manganese, thereby proving that integrin activation is required and showing that talin1(L325R) can form functional links to the actin cytoskeleton.
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Teckchandani, Anjali, Natalie Toida, Jake Goodchild, Christine Henderson, Julian Watts, Bernd Wollscheid, and Jonathan A. Cooper. "Quantitative proteomics identifies a Dab2/integrin module regulating cell migration." Journal of Cell Biology 186, no. 1 (July 6, 2009): 99–111. http://dx.doi.org/10.1083/jcb.200812160.
Full textAbstract:
Clathrin-associated endocytic adapters recruit cargoes to coated pits as a first step in endocytosis. We developed an unbiased quantitative proteomics approach to identify and quantify glycoprotein cargoes for an endocytic adapter, Dab2. Surface levels of integrins β1, α1, α2, and α3 but not α5 or αv chains were specifically increased on Dab2-deficient HeLa cells. Dab2 colocalizes with integrin β1 in coated pits that are dispersed over the cell surface, suggesting that it regulates bulk endocytosis of inactive integrins. Depletion of Dab2 inhibits cell migration and polarized movement of integrin β1 and vinculin to the leading edge. By manipulating intracellular and surface integrin β1 levels, we show that migration speed correlates with the intracellular integrin pool but not the surface level. Together, these results suggest that Dab2 internalizes integrins freely diffusing on the cell surface and that Dab2 regulates migration, perhaps by maintaining an internal pool of integrins that can be recycled to create new adhesions at the leading edge.
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Kaneko, Yui, Laura Lecce, Margot L. Day, and Christopher R. Murphy. "β1 and β3 integrins disassemble from basal focal adhesions and β3 integrin is later localised to the apical plasma membrane of rat uterine luminal epithelial cells at the time of implantation." Reproduction, Fertility and Development 23, no. 3 (2011): 481. http://dx.doi.org/10.1071/rd10211.
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The present study investigated the expression of integrin subunits that are known to be associated with focal adhesions, namely β1 and β3 integrins in rat uterine luminal epithelial cells during early pregnancy. The β1 and β3 integrins were concentrated along the basal cell surface and were colocalised and structurally interacted with talin, a principal focal adhesion protein, on Day 1 of pregnancy. At the time of implantation, β1 and β3 integrins disassembled from the site of focal adhesions, facilitating the removal of uterine luminal epithelial cells for embryo invasion. Also at this time, β3 integrin markedly increased along the apical membrane, suggesting a role in embryo attachment. This distributional change in β1 and β3 integrins seen at the time of implantation was predominantly under the influence of progesterone. Taken together, β1 and β3 integrin disassembly from focal adhesions and the increase in β3 integrin apically are key components of hormonally regulated endometrial receptivity.
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Alon, Ronen, Memet Aker, Sara Feigelson, Maya Sokolovsky-Eisenberg, Donald E. Staunton, Guy Cinamon, Valentin Grabovsky, Revital Shamri, and Amos Etzioni. "A novel genetic leukocyte adhesion deficiency in subsecond triggering of integrin avidity by endothelial chemokines results in impaired leukocyte arrest on vascular endothelium under shear flow." Blood 101, no. 11 (June 1, 2003): 4437–45. http://dx.doi.org/10.1182/blood-2002-11-3427.
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Abstract Leukocyte arrest on vascular endothelium under disruptive shear flow is a multistep process that requires in situ integrin activation on the leukocyte surface by endothelium-displayed chemoattractants, primarily chemokines. A genetic deficiency of leukocyte adhesion to endothelium associated with defective β2 integrin expression or function (LAD-1) has been described. We now report a novel severe genetic disorder in this multistep process associated with functional defects in multiple leukocyte integrins, reflected in recurrent infections, profound leukocytosis, and a bleeding tendency. This syndrome is associated with an impaired ability of neutrophil and lymphocyte β1 and β2 integrins to generate high avidity to their endothelial ligands and arrest cells on vascular endothelium in response to endothelial chemoattractant signals. Patient leukocytes roll normally on endothelial selectins, express intact integrins and G protein–coupled chemokine receptors (GPCR), spread on integrin ligands, and migrate normally along a chemotactic gradient. Activation of β2 integrins in response to GPCR signals and intrinsic soluble ligand binding properties of the very late activation antigen-4 (VLA-4) integrin are also retained in patient leukocytes. Nevertheless, all integrins fail to generate firm adhesion to immobilized ligands in response to in situ GPCR-mediated activation by chemokines or chemoattractants, a result of a primary defect in integrin rearrangement at ligand-bearing contacts. This syndrome is the first example of a human integrin-activation deficiency associated with defective GPCR stimulation of integrin avidity at subsecond contacts, a key step in leukocyte arrest on vascular endothelium under shear flow.
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Agle, Kimberle A., Rebecca A. Vongsa, and Michael B. Dwinell. "Chemokine stimulation promotes enterocyte migration through laminin-specific integrins." American Journal of Physiology-Gastrointestinal and Liver Physiology 301, no. 6 (December 2011): G968—G980. http://dx.doi.org/10.1152/ajpgi.00208.2011.
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Intestinal homeostasis is regulated in part by the single cell layer of the mucosal epithelium. This physical barrier is a prominent part of the innate immune system and possesses an intrinsic ability to heal damage and limit infection. The restitutive epithelial migration phase of healing requires dynamic integrin adhesion to the extracellular matrix. Previously, we have shown that the homeostatic chemokine CXCL12 utilizes intracellular calcium to increase enterocyte migration on laminin. The aim of these studies was to investigate integrin specificity and, in turn, functional responses elicited by CXCL12 stimulation. Analysis of cellular adhesion and spreading revealed CXCL12 preferentially activated laminin-specific integrins compared with collagen IV-binding integrins. Laminin-specific cell adhesion and spreading elicited by CXCL12 was dependent on intracellular calcium. CXCL12 increased activated β1-integrins on the surface of epithelial cells compared with untreated cells. RT-PCR confirmed expression of the laminin-binding integrins-α3β1, -α6β1, and -α6β4. Interestingly, shRNA-mediated depletion of laminin-specific α3- or α6-integrin subunits revealed differential functions. α3-Integrin knockdown reduced basal as well as inducible restitution. Depletion of α6-integrin specifically abolished CXCL12-stimulated, but not TGF-β1 or basal, migration. Depletion with either shα3-integrin or shα6-integrin prevented CXCL12-evoked cell spreading. Our data indicate that CXCL12 stimulates the inside-out activation of laminin-specific integrins to promote cell migratory functions. Together, our findings support the notion that extracellular mediators within the gastrointestinal mucosa coordinate cell-matrix interactions during epithelial restitution.
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Pinon, Perrine, Jenita Pärssinen, Patricia Vazquez, Michael Bachmann, Rolle Rahikainen, Marie-Claude Jacquier, Latifeh Azizi, et al. "Talin-bound NPLY motif recruits integrin-signaling adapters to regulate cell spreading and mechanosensing." Journal of Cell Biology 205, no. 2 (April 28, 2014): 265–81. http://dx.doi.org/10.1083/jcb.201308136.
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Integrin-dependent cell adhesion and spreading are critical for morphogenesis, tissue regeneration, and immune defense but also tumor growth. However, the mechanisms that induce integrin-mediated cell spreading and provide mechanosensing on different extracellular matrix conditions are not fully understood. By expressing β3-GFP-integrins with enhanced talin-binding affinity, we experimentally uncoupled integrin activation, clustering, and substrate binding from its function in cell spreading. Mutational analysis revealed Tyr747, located in the first cytoplasmic NPLY747 motif, to induce spreading and paxillin adapter recruitment to substrate- and talin-bound integrins. In addition, integrin-mediated spreading, but not focal adhesion localization, was affected by mutating adjacent sequence motifs known to be involved in kindlin binding. On soft, spreading-repellent fibronectin substrates, high-affinity talin-binding integrins formed adhesions, but normal spreading was only possible with integrins competent to recruit the signaling adapter protein paxillin. This proposes that integrin-dependent cell–matrix adhesion and cell spreading are independently controlled, offering new therapeutic strategies to modify cell behavior in normal and pathological conditions.
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Klaus, Tanja, Christoph Hieber, Matthias Bros, and Stephan Grabbe. "Integrins in Health and Disease—Suitable Targets for Treatment?" Cells 13, no. 3 (January 23, 2024): 212. http://dx.doi.org/10.3390/cells13030212.
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Integrin receptors are heterodimeric surface receptors that play multiple roles regarding cell–cell communication, signaling, and migration. The four members of the β2 integrin subfamily are composed of an alternative α (CD11a–d) subunit, which determines the specific receptor properties, and a constant β (CD18) subunit. This review aims to present insight into the multiple immunological roles of integrin receptors, with a focus on β2 integrins that are specifically expressed by leukocytes. The pathophysiological role of β2 integrins is confirmed by the drastic phenotype of patients suffering from leukocyte adhesion deficiencies, most often resulting in severe recurrent infections and, at the same time, a predisposition for autoimmune diseases. So far, studies on the role of β2 integrins in vivo employed mice with a constitutive knockout of all β2 integrins or either family member, respectively, which complicated the differentiation between the direct and indirect effects of β2 integrin deficiency for distinct cell types. The recent generation and characterization of transgenic mice with a cell-type-specific knockdown of β2 integrins by our group has enabled the dissection of cell-specific roles of β2 integrins. Further, integrin receptors have been recognized as target receptors for the treatment of inflammatory diseases as well as tumor therapy. However, whereas both agonistic and antagonistic agents yielded beneficial effects in animal models, the success of clinical trials was limited in most cases and was associated with unwanted side effects. This unfavorable outcome is most probably related to the systemic effects of the used compounds on all leukocytes, thereby emphasizing the need to develop formulations that target distinct types of leukocytes to modulate β2 integrin activity for therapeutic applications.
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Boyd, Nikhat D., Bosco M. C. Chan, and Nils O. Petersen. "β1 integrins are distributed in adhesion structures with fibronectin and caveolin and in coated pits." Biochemistry and Cell Biology 81, no. 5 (October 1, 2003): 335–48. http://dx.doi.org/10.1139/o03-063.
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Integrins are found in adhesion structures, which link the extracelullar matrix to cytoskeletal proteins. Here, we attempt to further define the distribution of β1 integrins in the context of their association with matrix proteins and other cell surface molecules relevant to the endocytic process. We find that β1 integrins colocalize with fibronectin in fibrillar adhesion structures. A fraction of caveolin is also organized along these adhesion structures. The extracellular matrix protein laminin is not concentrated in these structures. The α4β1 integrin exhibits a distinct distribution from other β1 integrins after cells have adhered for 1 h to extracellular matrix proteins but is localized in adhesion structures after 24 h of adhesion. There are differences between the fibronectin receptors: α5β1 integrins colocalize with adaptor protein-2 in coated pits, while α4β1 integrins do not. This parallels our earlier observation that of the two laminin receptors, α1β1 and α6β1, only αaβ1 integrins colocalize with adaptor protein-2 in coated pits. Calcium chelation or inhibition of mitogen-activated protein kinase kinase, protein kinase C, or src did not affect localization of α1β1 and α5β1 integrins in coated pits. Likewise, the integrity of coated-pit structures or adhesion structures is not required for integrin and adaptor protein-2 colocalization. This suggests a robust and possibly constitutive interaction between these integrins and coated pits.Key words: adhesion, endocytosis, extracellular matrix, microscopy, confocal, signalling.
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Tozer, Eileen Collins, Paul E. Hughes, and Joseph C. Loftus. "Ligand binding and affinity modulation of integrins." Biochemistry and Cell Biology 74, no. 6 (December 1, 1996): 785–98. http://dx.doi.org/10.1139/o96-085.
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Integrins are cell adhesion receptors that mediate cell–cell and cell–extracellular matrix interactions. The extracellular domains of these receptors possess binding sites for a diverse range of protein ligands. Ligand binding is divalent cation dependent and involves well-defined motifs in the ligand. Integrins can dynamically regulate their affinity for ligands (inside-out signaling). This ability to rapidly modulate their affinity state is key to their involvement in such processes as cell migration and platelet aggregation. This review will focus on two aspects of integrin function: first, on the molecular basis of ligand–integrin interactions and, second, on the underlying mechanisms controlling the affinity state of integrins for their ligands.Key words: integrins, ligand binding, affinity modulation.
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Lochter, André, Marc Navre, Zena Werb, and Mina J. Bissell. "α1 and α2 Integrins Mediate Invasive Activity of Mouse Mammary Carcinoma Cells through Regulation of Stromelysin-1 Expression." Molecular Biology of the Cell 10, no. 2 (February 1999): 271–82. http://dx.doi.org/10.1091/mbc.10.2.271.
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Tumor cell invasion relies on cell migration and extracellular matrix proteolysis. We investigated the contribution of different integrins to the invasive activity of mouse mammary carcinoma cells. Antibodies against integrin subunits α6 and β1, but not against α1 and α2, inhibited cell locomotion on a reconstituted basement membrane in two-dimensional cell migration assays, whereas antibodies against β1, but not against α6 or α2, interfered with cell adhesion to basement membrane constituents. Blocking antibodies against α1 integrins impaired only cell adhesion to type IV collagen. Antibodies against α1, α2, α6, and β1, but not α5, integrin subunits reduced invasion of a reconstituted basement membrane. Integrins α1 and α2, which contributed only marginally to motility and adhesion, regulated proteinase production. Antibodies against α1 and α2, but not α6 and β1, integrin subunits inhibited both transcription and protein expression of the matrix metalloproteinase stromelysin-1. Inhibition of tumor cell invasion by antibodies against α1 and α2 was reversed by addition of recombinant stromelysin-1. In contrast, stromelysin-1 could not rescue invasion inhibited by anti-α6 antibodies. Our data indicate that α1 and α2 integrins confer invasive behavior by regulating stromelysin-1 expression, whereas α6 integrins regulate cell motility. These results provide new insights into the specific functions of integrins during tumor cell invasion.
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Wei, Ying, Daniel Simon, David Waltz, and Harold Chapman. "Role of Urokinase Receptor and Caveolin in Regulation of Integrin Signaling." Thrombosis and Haemostasis 82, no. 08 (1999): 291–97. http://dx.doi.org/10.1055/s-0037-1615845.
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Introduction: Integrin-Associated ProteinsIntegrins are a group of heterodimeric adhesion receptors that mediate attachment of cells to extracellular matrices and other cells. These receptors serve as a major site of information flow from the immediate pericellular environment to the cellular interior and, in reverse, as effectors of the cellular responses to such information in biological processes as diverse as inflammation, tissue remodeling, growth, and tumorigenesis.1-3 The binding specificities of integrin receptors are determined by interactions of ligands with both the α and β chains that comprise integrins. Diversity of ligand binding is promoted by the fact that a single α chain may partner with numerous distinct β chains, and cells may express more than one and, sometimes, many α and β chains. Thus, as a family, integrins have the capacity to interact with a large set of cellular and extracellular matrix ligands. The structural features of integrin heterodimers that underlie their interactive potential and ligand specificity have been the subject of several recent reviews and will not be discussed here.4,5 A fundamental feature of integrins is that their function is determined not simply by their expression on the cell surface but by their dynamic regulation through activating events that amplify, sometimes only transiently, the adhesive capacity of integrins for their counter-ligands and the signals that follow.1-3,6,7 These dynamic aspects of integrin function are dependent on integrin interactions with its neighbors in the cell membrane and inside the cell, a structural consequence of the fact that integrins contain only short cytoplasmic tails without intrinsic signaling capacity. Three major sites of dynamic regulation of integrin function, indicated schematically in Figure 1, are as follows: ligand binding, association of cytoplasmic signaling elements with integrin cytoplasmic tails, and regulation of integrin binding and signaling by association with non-integrin “membrane adaptors.” Ligand binding by integrins is a function of their conformational state (Fig. 1a). Recent molecular modeling suggests that integrin α and β chains may exist in a relatively weak binding or “inactive state,” in which α and β chains extensively overlap and the β chain obscures binding sites on the α chain.5,8 In this model “activation” of integrins results from an altered conformation in which there is less overlap and more extensive availability of binding sites for ligand engagement. Such changes in conformational state may occur as a consequence of integrin clustering (following initially weak ligand binding).The capacity of integrins to cluster and connect with the cytoskeleton (Fig. 1b) in a manner promoting adhesion and migration is also regulated by complex interactions of kinases, phosphatases, and various structural proteins that bind to and assemble around integrin cytoplasmic tails. Signals derived from G-protein-coupled chemotactic receptors or generated by engagement of integrin extracellular ligand domains and clustering promote the activation of Src-family kinases, generation of lipid mediators, and in some cases, Ca2+ transients. These membrane proximate signals initiate and then propagate the accumulation of kinases and structural proteins surrounding a cluster of integrins. These events may also, in effect, be “insideout signals” affecting the conformational state of integrin extracellular domains1 (Fig. 1a). The assembly of cytoplasmic signaling elements on or near integrin cytoplasmic tails appears fundamental to the capacity of integrins to mediate adhesion and to impart, by signaling to the cellular interior, the nature of the immediate extracellular milieu.More recently, evidence has emerged that integrin function is also regulated by non-integrin membrane proteins that associate with integrins outside or within the plasma membrane (Fig. 1c). These include the tetraspan family of membrane proteins (CD9, CD63, CD81, CD82, and others), integrin-associated protein (CD47), and CD98.9-11 In addition, we and others have previously reported that β1 integrin function is regulated by its association with the glycosylphosphatidyl-inositol (GPI)-linked non-integrin receptor, the urokinase receptor (u-PAR, CD87), and a cholesterol-binding membrane protein called caveolin.12,13 As with ligand binding, structural features of the integrin heterodimers appear to dictate their association with these different membrane adaptors. For example, CD47 is reported to specifically interact with and promote the signaling function of αv/β3.10 The tetraspan family of proteins predominantly interacts with β1 integrins, but reportedly, only with certain α chain/β1 pairs.9 The functional effects of tetraspan proteins on integrin function is uncertain, though it is remarkable that at least two of these proteins (CD81 and 82) have been reported to inhibit tumor cell motility and act as tumor suppressors.14, 15 Caveolin and u-PAR also exhibit preferences for integrin interactions. Wary et al reported α-chain specificity for the association of β1 integrins with caveolin-1.12 The u-PAR receptor physically binds to the purified β2 integrin Mac-1 (CD11b/CD18), though no binding is observed in similar experiments with the β2 integrin CD11a/CD18 (LFA-1).16 Thus, like extracellular ligand interactions and intracellular cytoplasmic interactions, the capacity of integrins to interact with non-integrin membrane adaptors appears to be determined by amino acid sequences within the integrin heterodimers. The exact molecular basis for these interactions remains uncertain and is being actively investigated. This brief review will focus on the functional consequences of interaction of β1integrins with two of these membrane adaptors, u-PAR and caveolin.
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Jia, Wei, Hong Li, and You-Wen He. "The extracellular matrix protein mindin serves as an integrin ligand and is critical for inflammatory cell recruitment." Blood 106, no. 12 (December 1, 2005): 3854–59. http://dx.doi.org/10.1182/blood-2005-04-1658.
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Leukocyte recruitment to inflammation sites depends on interactions between integrins and extracellular matrix (ECM). In this report we show that mice lacking the ECM protein mindin exhibit severely impaired recruitment of neutrophils and macrophages in 4 different inflammation models. Furthermore, neutrophils directly bind to immobilized mindin, and mindin matrix mediates neutrophil migration in vitro. The adhesion of neutrophils to mindin is blocked by anti–integrin α4, anti–integrin αM, and anti–integrin β2 antibodies. We also show that HEK-293 cells transfected with cDNA encoding these integrins exhibit enhanced binding to immobilized mindin matrix and the increased binding can be blocked by anti-integrin antibodies. Our results suggest that mindin serves as a novel ligand for integrins and mindin-integrin interactions are critical for inflammatory cell recruitment in vivo.