Regulation from within: The cytoskeleton in transmembrane signaling

Department of Systems Biology, Harvard Medical School, Boston, MA, USA.
Trends in cell biology (Impact Factor: 12.01). 08/2012; 22(10):515-26. DOI: 10.1016/j.tcb.2012.07.006
Source: PubMed


There is mounting evidence that the plasma membrane is highly dynamic and organized in a complex manner. The cortical cytoskeleton is proving to be a particularly important regulator of plasmalemmal organization, modulating the mobility of proteins and lipids in the membrane, facilitating their segregation, and influencing their clustering. This organization plays a critical role in receptor-mediated signaling, especially in the case of immunoreceptors, which require lateral clustering for their activation. Based on recent developments, we discuss the structures and mechanisms whereby the cortical cytoskeleton regulates membrane dynamics and organization, and how the nonuniform distribution of immunoreceptors and their self-association may affect activation and signaling.

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    • "These properties have important implications for chemical reactions and hence signaling at the cell surface (Chaudhuri et al., 2011). This is particularly significant since several transmembrane signaling receptors (TCR, Integrin receptors, EGFR) have either direct links with actin, or associate with protein domains (e.g., ERM proteins) that recruit filamentous actin (Doherty and McMahon, 2008; Jaqaman and Grinstein, 2012). Signaling reactions involving these receptors are likely to be buffered from temperature dependent diffusion by engaging with the dynamic cortical actin activity. "
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    ABSTRACT: Molecular diffusion at the surface of living cells is thought to be predominantly driven by thermal kicks. However, there is growing evidence that certain cell surface molecules are driven by the fluctuating dynamics of cortical cytoskeleton. Using fluorescence correlation spectroscopy (FCS) we measure the diffusion coefficient of a variety of cell-surface molecules over a temperature range 24-37°C. Predictably, exogenously incorporated fluorescent lipids with short acyl chains exhibit the expected increase of diffusion coefficient over this temperature range. In contrast, we find that GPI-anchored proteins exhibit temperature independent diffusion over this range, and revert to temperature-dependent diffusion on cell membrane blebs, in cells depleted of cholesterol, and upon acute perturbation of actin dynamics and myosin activity. A model transmembrane protein with a cytosolic actin-binding domain also exhibits the temperature independent behavior, thereby directly implicating the role of cortical actin. We show that diffusion of GPI-anchored proteins also becomes temperature-dependent when the filamentous dynamic actin nucleator, formin, is inhibited. However, changes in cortical actin mesh size or perturbation of branched actin nucleator Arp2/3 do not affect this behavior. Thus, the cell surface diffusion of GPI-anchored proteins and transmembrane protein that associate with actin, are driven by the active fluctuations of dynamic cortical actin filaments in addition to thermal fluctuations, consistent with expectations from an "active actin-membrane composite" cell surface.
    Molecular biology of the cell 09/2015; DOI:10.1091/mbc.E15-06-0397 · 4.47 Impact Factor
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    • "Membrane proteins can be influenced by the cytoskeleton in two distinct ways. The first involves direct or indirect anchoring or tethering to the cytoskeleton (Haggie et al., 2006; Chen et al., 2009; Jaqaman and Grinstein, 2012). The second involves the creation of cytoskeletal barriers, which limit protein diffusion (Kusumi et al., 2005a). "
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    ABSTRACT: CX3CL1 is a unique chemokine that acts both as a transmembrane endothelial adhesion molecule and, upon proteolytic cleavage, a soluble chemoattractant for circulating leukocytes. The constitutive release of soluble CX3CL1 requires the interaction of its transmembrane species with the integral membrane metalloprotease, ADAM10, yet the mechanisms governing this process remain elusive. Using single-particle tracking and sub-diffraction imaging, we studied how ADAM10 interacts with CX3CL1. We observed that the majority of cell surface CX3CL1 diffused within restricted confinement regions structured by the cortical actin cytoskeleton. These confinement regions sequestered CX3CL1 from ADAM10, precluding their association. Disruption of the actin cytoskeleton reduced CX3CL1 confinement and increased CX3CL1-ADAM10 interactions, promoting the release of soluble chemokine. Our results demonstrate a novel role for the cytoskeleton in limiting membrane protein proteolysis thereby regulating both cell surface levels, and the release of soluble ligand.
    Molecular Biology of the Cell 12/2014; 25(24):3884-99. DOI:10.1091/mbc.E13-11-0633 · 4.47 Impact Factor
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    • "If confined by pickets and fences, it is unclear whether FcgR could cluster effectively, particularly during the short window of opportunity presented by the casual contact with particles such as microorganisms, which can be mobile. In addition, it was of interest to establish whether the rearrangement of the cytoskeleton that accompanies phagocytosis can itself alter the mobility of the receptors (Jaqaman and Grinstein, 2012; Jaumouillé and Grinstein, 2011). To address these questions , we analyzed lateral mobility of FcgR at the single-molecule level. "
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    ABSTRACT: Clustering of immunoreceptors upon association with multivalent ligands triggers important responses including phagocytosis, secretion of cytokines, and production of immunoglobulins. We applied single-molecule detection and tracking methods to study the factors that control the mobility and clustering of phagocytic Fcγ receptors (FcγR). While the receptors exist as monomers in resting macrophages, two distinct populations were discernible based on their mobility: some diffuse by apparent free motion, while others are confined within submicron boundaries that reduce the frequency of spontaneous collisions. Src-family and Syk kinases determine the structure of the actin cytoskeleton, which is fenestrated, accounting for the heterogeneous diffusion of the FcγR. Stimulation of these kinases during phagocytosis induces reorganization of the cytoskeleton both locally and distally in a manner that alters receptor mobility and clustering, generating a feedback loop that facilitates engagement of FcγR at the tip of pseudopods, directing the progression of phagocytosis.
    Developmental Cell 06/2014; 29(5):534-546. DOI:10.1016/j.devcel.2014.04.031 · 9.71 Impact Factor
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