Regulation from within: The cytoskeleton in transmembrane signaling

Department of Systems Biology, Harvard Medical School, Boston, MA, USA.
Trends in cell biology (Impact Factor: 12.31). 08/2012; 22(10):515-26. DOI: 10.1016/j.tcb.2012.07.006
Source: PubMed

ABSTRACT 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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    • "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 · 4.55 Impact Factor
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    • "Its many components and accessory/regulatory proteins provide structural stability and shape, conduits for the transport of vesicles and macromolecules, and scaffolding for receptors and ion channels. It also communicates with multiple signaling pathways within and outside of cells to modulate these activities in response to the ever-changing demands of cells and their environments (Jaqaman and Grinstein, 2012). Mechanosensitive channels provide an important means of crosstalk between chemical and mechanical signaling systems. "
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    ABSTRACT: The roles of pannexin 1 (Panx1) large-pore ion and metabolite channels are becoming recognized in many physiological and pathophysiological scenarios. Recent evidence has tightly linked Panx1 trafficking and function to the cytoskeleton, a multi-component network that provides critical structural support, transportation, and scaffolding functions in all cell types. Here we review early work demonstrating the mechanosensitive activation of Panx1 channels, and expand on more recent evidence directly linking Panx1 to the cytoskeleton. Further, we examine the reciprocal regulation between Panx1 and the cytoskeleton, and discuss the involvement of Panx1 in cytoskeletal-regulated cell behaviors. Finally, we identify important gaps in the current knowledge surrounding this emerging Panx1-cytoskeleton relationship.
    Frontiers in Physiology 01/2014; 5:27. DOI:10.3389/fphys.2014.00027 · 3.50 Impact Factor
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    • "The functional consequence of changes in protein mobility in response to APC contact, and the dependence of these changes on underlying cytoskeletal elements, have become key tenets of immune system physiology. As initially shown in erythrocytes, the role of the underlying cytoskeleton in regulating membrane protein dynamics is now a common theme and has recently been reviewed in detail (Jaqaman & Grinstein, 2012). The potential for future studies to move beyond the standard three-dimensional K d , as measured in solution chemistry, to the more physiologically relevant two-dimensional K d , derived in part from measurements of membrane protein dynamics, has important physiologic and pharmacologic implications. "
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    ABSTRACT: The organization of the plasma membrane is both highly complex and highly dynamic. One manifestation of this dynamic complexity is the lateral mobility of proteins within the plane of the membrane, which is often an important determinant of intermolecular protein-binding interactions, downstream signal transduction, and local membrane mechanics. The mode of membrane protein mobility can range from random Brownian motion to immobility and from confined or restricted motion to actively directed motion. Several methods can be used to distinguish among the various modes of protein mobility, including fluorescence recovery after photobleaching, single-particle tracking, fluorescence correlation spectroscopy, and variations of these techniques. Here, we present both a brief overview of these methods and examples of their use to elucidate the dynamics of membrane proteins in mammalian cells-first in erythrocytes, then in erythroblasts and other cells in the hematopoietic lineage, and finally in non-hematopoietic cells. This multisystem analysis shows that the cytoskeleton frequently governs modes of membrane protein motion by stably anchoring the proteins through direct-binding interactions, by restricting protein diffusion through steric interactions, or by facilitating directed protein motion. Together, these studies have begun to delineate mechanisms by which membrane protein dynamics influence signaling sequelae and membrane mechanical properties, which, in turn, govern cell function.
    Current Topics in Membranes 01/2013; 72C:89-120. DOI:10.1016/B978-0-12-417027-8.00003-9 · 1.77 Impact Factor
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