Mechanisms of integrin activation and trafficking.
TL;DR: Endocytosis and recycling play an important role in the regulation of integrin turnover and integrin redistribution in adherent cells, especially during dynamic processes such as cell migration and invasion.
About: This article is published in Current Opinion in Cell Biology.The article was published on 2011-10-01. It has received 322 citations till now. The article focuses on the topics: Integrin, beta 6 & Integrin alpha M.
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TL;DR: The authors in this paper reviewed the interdisciplinary field of biocompatible implant surfaces from the viewpoint of materials science, biochemistry and cell biology, and provided an overview on basic information about bulk and surface properties of implant surfaces.
637 citations
TL;DR: A variety of current approaches for enhancing the delivery of oligonucleotides including molecular scale targeted ligand-oligonucleotide conjugates, lipid- and polymer-based nanoparticles, antibody conjugate and small molecules that improve oligon nucleotide delivery are examined.
Abstract: The oligonucleotide therapeutics field has seen remarkable progress over the last few years with the approval of the first antisense drug and with promising developments in late stage clinical trials using siRNA or splice switching oligonucleotides. However, effective delivery of oligonucleotides to their intracellular sites of action remains a major issue. This review will describe the biological basis of oligonucleotide delivery including the nature of various tissue barriers and the mechanisms of cellular uptake and intracellular trafficking of oligonucleotides. It will then examine a variety of current approaches for enhancing the delivery of oligonucleotides. This includes molecular scale targeted ligand-oligonucleotide conjugates, lipid- and polymer-based nanoparticles, antibody conjugates and small molecules that improve oligonucleotide delivery. The merits and liabilities of these approaches will be discussed in the context of the underlying basic biology.
609 citations
Cites background from "Mechanisms of integrin activation a..."
...Integrins serve both as structural proteins and as components of the signal transduction machinery (86,87)....
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TL;DR: In this paper, the authors used intravital imaging to demonstrate that secretion of exosomes from late endosomes is required for directionally persistent and efficient in vivo movement of cancer cells.
Abstract: Directional cell movement through tissues is critical for multiple biological processes and requires maintenance of polarity in the face of complex environmental cues. Here we use intravital imaging to demonstrate that secretion of exosomes from late endosomes is required for directionally persistent and efficient in vivo movement of cancer cells. Inhibiting exosome secretion or biogenesis leads to defective tumour cell migration associated with increased formation of unstable protrusions and excessive directional switching. In vitro rescue experiments with purified exosomes and matrix coating identify adhesion assembly as a critical exosome function that promotes efficient cell motility. Live-cell imaging reveals that exosome secretion directly precedes and promotes adhesion assembly. Fibronectin is found to be a critical motility-promoting cargo whose sorting into exosomes depends on binding to integrins. We propose that autocrine secretion of exosomes powerfully promotes directionally persistent and effective cell motility by reinforcing otherwise transient polarization states and promoting adhesion assembly.
440 citations
TL;DR: This review summarizes the current understanding of the functions of microtubules in persistent cell migration and of the migration-associated signals that promote microtubule network polarization.
Abstract: Migration is a polarized cellular process that opposes a protrusive front edge to a retracting trailing edge. From the front to the rear, actin-mediated forces sequentially promote cell protrusion, adhesion, contraction, and retraction. Over the past decade, microtubules have revealed their pivotal role in cell migration. Through their roles in cell mechanics, intracellular trafficking, and signaling, microtubules participate in all essential events leading to cell migration. The front-rear polarization of microtubule functions relies on the asymmetric regulation of microtubule dynamics and stability; the asymmetric distribution of microtubule-associated protein complexes; and finally, the orientation of the microtubule network along the axis of migration. Microtubule network polarity controls the establishment and maintenance of the spatial and temporal coordination of migration events and is therefore the key to persistent directed migration. This review summarizes our current understanding of the functions of microtubules in persistent cell migration and of the migration-associated signals that promote microtubule network polarization.
421 citations
Cites background from "Mechanisms of integrin activation a..."
...Integrin endocytosis occurs through both clathrin-dependent and clathrin-independent pathways (Margadant et al. 2011)....
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...However, whether inactivation is required for integrin internalization is still a matter of debate and may depend on cell types and integrin subtypes (Margadant et al. 2011)....
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TL;DR: Evidence is provided that behavioral paradigms and signaling pathways that are involved in longevity also affect neuromuscular junction stability and sarcopenia, suggesting that the mechanisms involved in neuromUScular junction maintenance might be disturbed during aging.
Abstract: The neuromuscular junction is the chemical synapse between motor neurons and skeletal muscle fibers. It is designed to reliably convert the action potential from the presynaptic motor neuron into the contraction of the postsynaptic muscle fiber. Diseases that affect the neuromuscular junction may cause failure of this conversion and result in loss of ambulation and respiration. The loss of motor input also causes muscle wasting as muscle mass is constantly adapted to contractile needs by the balancing of protein synthesis and protein degradation. Finally, neuromuscular activity and muscle mass have a major impact on metabolic properties of the organisms. This review discusses the mechanisms involved in the development and maintenance of the neuromuscular junction, the consequences of and the mechanisms involved in its dysfunction, and its role in maintaining muscle mass during aging. As life expectancy is increasing, loss of muscle mass during aging, called sarcopenia, has emerged as a field of high medical need. Interestingly, aging is also accompanied by structural changes at the neuromuscular junction, suggesting that the mechanisms involved in neuromuscular junction maintenance might be disturbed during aging. In addition, there is now evidence that behavioral paradigms and signaling pathways that are involved in longevity also affect neuromuscular junction stability and sarcopenia.
274 citations
Cites background from "Mechanisms of integrin activation a..."
...These findings show that Dok-7 can also mediate inside-out signaling, a phenomenon that is well documented for integrins, a family of heterodimeric (with one and one subunit) receptors that bind to a wide variety of extracellular matrix proteins (278)....
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References
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TL;DR: This review summarizes recent progress in the structural and molecular functional studies of this important class of adhesion receptor.
Abstract: Integrins are large, membrane-spanning, heterodimeric proteins that are essential for a metazoan existence. All members of the integrin family adopt a shape that resembles a large "head" on two "legs," with the head containing the sites for ligand binding and subunit association. Most of the receptor dimer is extracellular, but both subunits traverse the plasma membrane and terminate in short cytoplasmic domains. These domains initiate the assembly of large signaling complexes and thereby bridge the extracellular matrix to the intracellular cytoskeleton. To allow cells to sample and respond to a dynamic pericellular environment, integrins have evolved a highly responsive receptor activation mechanism that is regulated primarily by changes in tertiary and quaternary structure. This review summarizes recent progress in the structural and molecular functional studies of this important class of adhesion receptor.
976 citations
"Mechanisms of integrin activation a..." refers background in this paper
...Moreover, integrin-ligand interactions induce a plethora of ‘outside-in’ events such as cell spreading and migration, ECM assembly, and the activation of several signal transduction pathways that regulate cell proliferation, survival, and gene expression (1)....
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...containing adhesion complexes: (1) Focal complexes (red arrows) are Rac-induced peripheral adhesions (≤1 μm)...
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TL;DR: This review focuses on the mechanisms whereby two key proteins, talin and the kindlins, regulate integrin activation by binding the tails of integrin-β subunits.
Abstract: Integrins are transmembrane cell-adhesion molecules that carry signals from the outside to the inside of the cell and vice versa. Like other cell surface receptors, integrins signal in response to ligand binding; however, events within the cell can also regulate the affinity of integrins for ligands. This feature is important in physiological situations such as those in blood, in which cells are always in close proximity to their ligands, yet cell-ligand interactions occur only after integrin activation in response to specific external cues. This review focuses on the mechanisms whereby two key proteins, talin and the kindlins, regulate integrin activation by binding the tails of integrin-beta subunits.
762 citations
"Mechanisms of integrin activation a..." refers background in this paper
...Insideout activation also requires kindlin-3, a member of the kindlin family of proteins whose FERM domains bind the membrane-distal (MD)-NxxY motif in β-tails (6)....
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TL;DR: It is shown that α5β1 integrin switches between relaxed and tensioned states in response to myosin II–generated cytoskeletal force, which connects cytoskeleton and extracellular matrix mechanics to adhesion-dependent motility and signaling pathways.
Abstract: The cytoskeleton, integrin-mediated adhesion, and substrate stiffness control a common set of cell functions required for development and homeostasis that are often deranged in cancer. The connection between these mechanical elements and chemical signaling processes is not known. Here, we show that α 5 β 1 integrin switches between relaxed and tensioned states in response to myosin II–generated cytoskeletal force. Force combines with extracellular matrix stiffness to generate tension that triggers the integrin switch. This switch directly controls the α 5 β 1 -fibronectin bond strength through engaging the synergy site in fibronectin and is required to generate signals through phosphorylation of focal adhesion kinase. In the context of tissues, this integrin switch connects cytoskeleton and extracellular matrix mechanics to adhesion-dependent motility and signaling pathways.
689 citations
TL;DR: Kindlin-3 is identified as a novel and essential element for platelet integrin activation in hemostasis and thrombosis because it can directly bind to regions of β-integrin tails distinct from those of Talin and trigger integrinactivation.
Abstract: Integrin-mediated platelet adhesion and aggregation are essential for sealing injured blood vessels and preventing blood loss, and excessive platelet aggregation can initiate arterial thrombosis, causing heart attacks and stroke1. To ensure that platelets aggregate only at injury sites, integrins on circulating platelets exist in a low-affinity state and shift to a high-affinity state (in a process known as integrin activation or priming) after contacting a wounded vessel2. The shift is mediated through binding of the cytoskeletal protein Talin to the β subunit cytoplasmic tail3,4,5. Here we show that platelets lacking the adhesion plaque protein Kindlin-3 cannot activate integrins despite normal Talin expression. As a direct consequence, Kindlin-3 deficiency results in severe bleeding and resistance to arterial thrombosis. Mechanistically, Kindlin-3 can directly bind to regions of β-integrin tails distinct from those of Talin and trigger integrin activation. We have therefore identified Kindlin-3 as a novel and essential element for platelet integrin activation in hemostasis and thrombosis.
681 citations
"Mechanisms of integrin activation a..." refers background in this paper
...First, the effects of kindlins are cell-type-specific, as kindlin-3 overexpression enhances integrin activation in macrophages but not in CHO cells (9)....
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...gation in mice, and kindlin-3-deficient leukocytes fail to adhere to endothelial cells (7-10)....
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TL;DR: Catch bond formation appears to involve force-assisted activation of the headpiece but not integrin extension, and binding of monoclonal antibodies that induce the active conformation of the integrin headpiece shifted catch bonds to a lower force range.
Abstract: Binding of integrins to ligands provides anchorage and signals for the cell, making them prime candidates for mechanosensing molecules. How force regulates integrin–ligand dissociation is unclear. We used atomic force microscopy to measure the force-dependent lifetimes of single bonds between a fibronectin fragment and an integrin α5β1-Fc fusion protein or membrane α5β1. Force prolonged bond lifetimes in the 10–30-pN range, a counterintuitive behavior called catch bonds. Changing cations from Ca2+/Mg2+ to Mg2+/EGTA and to Mn2+ caused longer lifetime in the same 10–30-pN catch bond region. A truncated α5β1 construct containing the headpiece but not the legs formed longer-lived catch bonds that were not affected by cation changes at forces <30 pN. Binding of monoclonal antibodies that induce the active conformation of the integrin headpiece shifted catch bonds to a lower force range. Thus, catch bond formation appears to involve force-assisted activation of the headpiece but not integrin extension.
662 citations
"Mechanisms of integrin activation a..." refers background in this paper
...The lifetime of α5β1-FN bonds is thus increased by tensile force (18)....
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