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Cell Surface Actin Remodeling Thomas P Cell Science at a Glance 3261 Cell surface actin filament polarity defines the direction The survival and motility, albeit myosin motors move on them (from sometimes abnormal, of cells lacking remodeling the pointed end to the barbed end). ABPs that have powerful effects on actin Thomas P. Stossel1, Gabriel The barbed end is both more in vitro imply that no single mechanism Fenteany2 and John H. Hartwig1 thermodynamically favored for new can explain surface actin remodeling for addition of actin monomer and more all cell types and occasions. This 1Hematology Division, Brigham and Women’s Hospital, Boston, MA, 02115 USA kinetically dynamic (fast exchanging) in complexity is not surprising because the 2Department of Chemistry, University of Illinois, the presence of ATP hydrolysis, which same or similar ABPs in highly motile Chicago, IL, 60607 USA drives conformational changes in the amoeboid cells lacking permanent Authors for correspondence (e-mail: [email protected]; [email protected]; exchanging subunits (Kuhn and Pollard, surface features can hardly be doing the [email protected]) 2005). What makes actin truly interesting, same work that they do in a brush-border however, is the variety of lengths and microvillus (which has a stable Journal of Cell Science 119, 3261-3264 Published by The Company of Biologists 2006 spatial conformations conferred upon it architecture) or within oocytes or yeast doi:10.1242/jcs.02994 by hundreds of actin-binding proteins (which undergo relatively slow (ABPs). These control linear elongation, morphological changes). Indeed it is the Actin filament remodeling at cell surfaces shortening and architectural organization details of actin remodeling that confer so is a fundamental aspect of cellular life. of actin filaments in response to signaling much variety on cell behaviors. Except for minor sequence variations, cascades set in motion by environmental actin proteins are structurally identical. cues. The resulting exquisite variety of The problem of cell surface (cortical) They have similar self-association actin filament lengths and spatial actin remodeling, however, is not properties and ATPase activities that configurations accounts for the diverse hopelessly impenetrable. Four decades accommodate their assembly into morphologies of eukaryotic cells and their of research have revealed findings polarized semi-flexible filaments. The highly specific changes in shape. consistent with a nine-step cycle of Cell Surface Actin Remodeling Thomas P. Stossel, Gabriel Fenteany and John H. Hartwig Branching 4 amplification Arp 2/3 complex Filament 5 crosslinking 9 Monomer sequestration α-Actinins, filamins, Elongation Thymosins and profilins 2 fimbrins, esprins P Y PI3K TESK1 P PAKS LIMKS P ADF/cofilin Journal of Cell Science P Cdc42 Rac cAMP 2+ 14-13-3ζ HS1 Src Rac Rho Ca 2 Barbed-end capping Nck Calmodulin Cortactin P Cronophin 1 Initiation P Toca-1 PIP-5K-1α ROCK Calcineurin PI-4K MLCK Slingshots P WASPs D4 Phosphoinositides cAMP 8b,c Lateral stabilization 3c Polymerization promoters, 3b WIPs P Myosin II Tropomyosins, barbed-end capping inhibitors ADF/cofilin 1a Barbed-end uncapping caldesmons, Profilins, (M)ENA, Drebrin, 1a Filamin tropomodulin VASP, Dia, Formins, cGMP Gelsolin P 3a MLCP Src Vinculin, WASPs, Spir, CARMIL Arp 2/3 1 Uncapping P cAMP P Other FERMs capping CARMIL Aib Myosin II P 8a 4 Capping α-Actinin proteins proteins Motoring and 3b Profilin, Ena/VASP, Fermins etc Stabilizers contraction 6 Actin gelation, 3c Myosins 6 Actin elongation membrane Actin Actin Weak severing 8b 2 3c attachment contraction disassembly 5 7 Accelerated pointed- 6 end depolymerization 8c ADF/Cofillins jcs.biologists.org Membrane attachment 7 Signals leading to actin filament nucleation, branching and elongation Spectrins, Barbed-end capping 3a FERMS, talin, filamins, Signals leading to actin filament cross-linking and membrane attachment Cap(Z)/(G), Adducin, Hsp27/70, Eps8 α-actinins, catenin Signals leading to actin filament disassembly Signals leading to activation of myosin for actin filament contraction Signals leading to myosin inactivation Grey text depicts molecules in more than one pathway Strong filament severing and barbed-end capping 8a Gelsolin family © Journal of Cell Science 2006 (119, pp. 3261-3264) (See poster insert) 3262 Journal of Cell Science 119 (16) functions manifested by ABPs that can leading to focal polyphosphoinositide 2004), the lack of an effect of Arp2/3 on adequately explain many aspects of accumulation and actin filament actin filament network rigidity required cortical actin remodeling, each step assembly and rearrangement (Niggli, for lamellar extension (Nakamura et al., being responsive to signaling cascades. 2005; Yin and Janmey, 2003). 2002) and the results of experiments Here, we briefly summarize the key employing RNAi in fibroblasts (Di features of this cycle and their regulation. Nardo et al., 2005). Notice that the outline of actin Elongation remodeling provided is based on Actin filament barbed-end capping by information obtained from studies with factors that promote or inhibit capping Actin filament crosslinking different cell types but predominantly (see below) regulates the extent of actin Bivalent actin-filament-crosslinking mammalian platelets, leukocytes, filament elongation (see poster, step 2). proteins either abet or repel the inherent fibroblasts, epithelial cells, neuronal parallel alignment of actin filaments cells and tumor cells. promoted by thermodynamic and ionic Termination factors (see poster, step 5). Relatively Degradation of polyphosphoinositides, small globular or rod-like ABPs, such as Initiation activation of the barbed-end-capping fimbrin, scruin, ␣-actinins and espins, Initiation (see poster, step 1) defines activity of CapG by Ca2+ and activation of stabilize actin bundles, whereas larger where and when actin filament Hsp70 or CapZ-interacting protein by ABPs that have inherent spring-like elongation occurs at the cell surface. phosphorylation (During et al., 2005; properties, such as the filamins, instead Cells have several strategies for initiating Eyers et al., 2005) terminate actin promote high-angle (orthogonal) filament new actin polymerization, including de filament elongation (see poster, step 3a). organization (Gardel et al., 2006; Gardel novo nucleation by the Arp2/3 complex, By contrast, the capping protein inhibitors et al., 2004). ␣-Actinins, filamins and formins and Spir (Nicholson-Dykstra et ENA, VASP, profilin, formins and spectrins, a family of membrane- al., 2005; Rafelski and Theriot, 2004). CARMIL promote elongation even in the associated crosslinking proteins, Polymerization of actin from newly presence of active capping proteins (step also function as scaffolds for signaling exposed actin filament barbed ends is 3b) (Barzik et al., 2005; Bubb et al., 2003; intermediates that stimulate actin also a compelling mechanism for Higgs, 2005; Kovar, 2006; Yang et al., elongation; so they are well positioned to initiating new filament assembly. Free 2005). Actin-filament-stabilizing proteins direct the orientation of elongating actin barbed ends elicit diffusion-limited such as tropomyosins, caldesmons, filaments (Broderick and Winder, 2005; polymerization of actin subunits bound calponins, and tropomodulin (which also Feng and Walsh, 2004). to actin-monomer-sequestering proteins, caps pointed ends in the presence of the thymosins and profilins (step 9) tropomyosin) (Fischer and Fowler, 2003) (Yarmola and Bubb, 2004). Barbed-end also promote elongation by retarding Actin filament contraction, cargo exposure can result from uncapping – the subunit depolymerization and inhibiting motoring, and membrane binding Journal of Cell Science removal of numerous barbed-end- actin-depolymerizing ABPs, as described Parallel bundles and orthogonal networks capping proteins (gelsolin family, CapZ, below (step 3c) (Bakin et al., 2004; Eyers represent extremes of the highly complex Hsp70, ankyrins, Eps8) (step 1a) (Allen, et al., 2005; Mirzapoiazova et al., 2005). actin filament arrangements observable at 2003; Barkalow et al., 2003; Disanza et the cell surface by electron microscopy al., 2004) – or from the action of ABPs and other high-resolution techniques. that sever actin filaments without Branching Actin filament configurations are capping them (step 7b) (DesMarais et al., Nucleation and transient 70° branching susceptible to deformation by contractile 2005). One thing that makes these (see poster, step 4) of actin filaments forces generated by bipolar myosin mechanisms attractive is the fact that half mediated by the Arp2/3 complex filaments (predominantly myosin II) of the nearly millimolar actin in most (Pollard and Borisy, 2003; Stradal and (Landsverk and Epstein, 2005), which act eukaryotic non-muscle cells exists as Scita, 2006; Vicente-Manzanares et al., especially on actin networks attached to short filaments, which provide ample 2005) is essential for the intracellular membranes. Unconventional myosins barbed ends for rapid elongatation when movements of certain pathogens primarily move vesicles and other cargoes uncapped and exposed to the large (Listeria monocytogenes, Shigella, along actin filaments (‘motoring’) (see reservoir of sequestered actin monomers Salmonella and Rickettsia species and poster, step 6). Signals contributing to that cannot spontaneously nucleate. This poxviruses) (Gouin et al., 2005), some actin elongation, such as mechanism is linked to signaling vesicles, and for the normal dynamics of polyphosphoinositides, also
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