|
|
|
|
|
|
|
|
|||||
| Home Help Feedback Subscriptions Archive Search Table of Contents | |||||
First published online August 9, 2006
doi: 10.1242/10.1242/jcs.02994
Cell Science at a Glance |
1 Hematology Division, Brigham and Women's Hospital, Boston, MA, 02115 USA
2 Department of Chemistry, University of Illinois, Chicago, IL, 60607 USA
Authors for correspondence (e-mail: tstossel{at}rics.bwh.harvard.edu; fenteany{at}uic.edu; hartwig{at}rics.bwh.harvard.edu)
 |
Introduction |
|---|
 Top Introduction InitiationElongationTerminationBranchingActin filament crosslinkingActin filament contraction,...Actin filament disassemblyMonomer sequestrationReferences |
|---|
). What makes actin truly interesting, however, is the variety of lengths and spatial conformations conferred upon it by hundreds of actin-binding proteins (ABPs). These control linear elongation, shortening and architectural organization of actin filaments in response to signaling cascades set in motion by environmental cues. The resulting exquisite variety of actin filament lengths and spatial configurations accounts for the diverse morphologies of eukaryotic cells and their highly specific changes in shape. The survival and motility, albeit sometimes abnormal, of cells lacking ABPs that have powerful effects on actin in vitro imply that no single mechanism can explain surface actin remodeling for all cell types and occasions. This complexity is not surprising because the same or similar ABPs in highly motile amoeboid cells lacking permanent surface features can hardly be doing the same work that they do in a brush-border microvillus (which has a stable architecture) or within oocytes or yeast (which undergo relatively slow morphological changes). Indeed it is the details of actin remodeling that confer so much variety on cell behaviors.
The problem of cell surface (cortical) actin remodeling, however, is not hopelessly impenetrable. Four decades of research have revealed findings consistent with a nine-step cycle of functions manifested by ABPs that can adequately explain many aspects of cortical actin remodeling, each step being responsive to signaling cascades. Here, we briefly summarize the key features of this cycle and their regulation. Notice that the outline of actin remodeling provided is based on information obtained from studies with different cell types but predominantly mammalian platelets, leukocytes, fibroblasts, epithelial cells, neuronal cells and tumor cells.
|
|
Initiation |
|---|
|
TopIntroductionInitiationElongationTerminationBranchingActin filament crosslinkingActin filament contraction,...Actin filament disassemblyMonomer sequestrationReferences |
|---|
; Rafelski and Theriot, 2004). Polymerization of actin from newly exposed actin filament barbed ends is also a compelling mechanism for initiating new filament assembly. Free barbed ends elicit diffusion-limited polymerization of actin subunits bound to actin-monomer-sequestering proteins, the thymosins and profilins (step 9) (Yarmola and Bubb, 2004). Barbed-end exposure can result from uncapping - the removal of numerous barbed-end-capping proteins (gelsolin family, CapZ, Hsp70, ankyrins, Eps8) (step 1a) (Allen, 2003; Barkalow et al., 2003; Disanza et al., 2004) - or from the action of ABPs that sever actin filaments without capping them (step 7b) (DesMarais et al., 2005). One thing that makes these mechanisms attractive is the fact that half of the nearly millimolar actin in most eukaryotic non-muscle cells exists as short filaments, which provide ample barbed ends for rapid elongatation when uncapped and exposed to the large reservoir of sequestered actin monomers that cannot spontaneously nucleate. This mechanism is linked to signaling cascades that regulate ABPs to promote new polymerization from pre-existing barbed ends. Key participants in these are polyphosphoinositides, which remove all known capping proteins from barbed ends. Agonists that promote cortical actin assembly generally do so through activation of the small GTPases Rac, Rho and Cdc42 (Jaffe and Hall, 2005), that in turn stimulate enzymes leading to focal polyphosphoinositide accumulation and actin filament assembly and rearrangement (Niggli, 2005; Yin and Janmey, 2003). |
Elongation |
|---|
|
TopIntroductionInitiationElongationTerminationBranchingActin filament crosslinkingActin filament contraction,...Actin filament disassemblyMonomer sequestrationReferences |
|---|
|
Termination |
|---|
|
TopIntroductionInitiationElongationTerminationBranchingActin filament crosslinkingActin filament contraction,...Actin filament disassemblyMonomer sequestrationReferences |
|---|
; Eyers et al., 2005) terminate actin filament elongation (see poster, step 3a). By contrast, the capping protein inhibitors ENA, VASP, profilin, formins and CARMIL promote elongation even in the presence of active capping proteins (step 3b) (Barzik et al., 2005; Bubb et al., 2003; Higgs, 2005; Kovar, 2006; Yang et al., 2005). Actin-filament-stabilizing proteins such as tropomyosins, caldesmons, calponins, and tropomodulin (which also caps pointed ends in the presence of tropomyosin) (Fischer and Fowler, 2003) also promote elongation by retarding subunit depolymerization and inhibiting actin-depolymerizing ABPs, as described below (step 3c) (Bakin et al., 2004; Eyers et al., 2005; Mirzapoiazova et al., 2005). |
Branching |
|---|
|
TopIntroductionInitiationElongationTerminationBranchingActin filament crosslinkingActin filament contraction,...Actin filament disassemblyMonomer sequestrationReferences |
|---|
; Stradal and Scita, 2006; Vicente-Manzanares et al., 2005) is essential for the intracellular movements of certain pathogens (Listeria monocytogenes, Shigella, Salmonella and Rickettsia species and poxviruses) (Gouin et al., 2005), some vesicles, and for the normal dynamics of adhesive podosomes and related structures (Linder and Kopp, 2005). A role for Arp2/3-mediated actin filament branching in leading-edge actin elongation is less certain, given high-resolution images preserving three-dimensionality (Medalia et al., 2002; Small et al., 2002), the absence of Arp2/3 from the leading edges of certain cells (Gupton et al., 2005; Strasser et al., 2004), the lack of an effect of Arp2/3 on actin filament network rigidity required for lamellar extension (Nakamura et al., 2002) and the results of experiments employing RNAi in fibroblasts (Di Nardo et al., 2005). |
Actin filament crosslinking |
|---|
|
TopIntroductionInitiationElongationTerminationBranchingActin filament crosslinkingActin filament contraction,...Actin filament disassemblyMonomer sequestrationReferences |
|---|
-actinins and espins, stabilize actin bundles, whereas larger ABPs that have inherent spring-like properties, such as the filamins, instead promote high-angle (orthogonal) filament organization (Gardel et al., 2006; Gardel et al., 2004). -Actinins, filamins and spectrins, a family of membrane-associated crosslinking proteins, also function as scaffolds for signaling intermediates that stimulate actin elongation; so they are well positioned to direct the orientation of elongating actin filaments (Broderick and Winder, 2005; Feng and Walsh, 2004). |
Actin filament contraction, cargo motoring, and membrane binding |
|---|
|
TopIntroductionInitiationElongationTerminationBranchingActin filament crosslinkingActin filament contraction,...Actin filament disassemblyMonomer sequestrationReferences |
|---|
), which act especially on actin networks attached to membranes. Unconventional myosins primarily move vesicles and other cargoes along actin filaments (`motoring') (see poster, step 6). Signals contributing to actin elongation, such as polyphosphoinositides, also increase binding of actin filaments and intermediary ABPs, including talin, vinculin, filamins, catenins, -actinins, and zyxin to certain receptors, including integrins (Ginsberg et al., 2005), cadherins (Drees et al., 2005), and proteins of the FERM family (Cho and Stahelin, 2005) (step 7). This brings actin filament barbed ends close to the same signals that promote their elongation, potentially amplifying the mass of elongating actin at the surface. The linkage between actin filaments and membranes is important for mechanical traction against substrates and retraction of membranes for shape changes and locomotion in response to contractile forces. This linkage is also essential for localizing signaling factors to initiate the formation of cell-substratum and cell-cell adhesions, as well as other cellular processes.
|
Actin filament disassembly |
|---|
|
TopIntroductionInitiationElongationTerminationBranchingActin filament crosslinkingActin filament contraction,...Actin filament disassemblyMonomer sequestrationReferences |
|---|
) (see poster, step 8a). Ca2+ can also interfere with binding of crosslinking ABPs and thus destabilize actin networks. Ca2+ works with calmodulin to inhibit binding of filamin to actin (Nakamura et al., 2005) and directly inhibits the binding of some -actinins (Broderick and Winder, 2005).
The second major actin-filament-severing ABPs are proteins of the actin-depolymerizing factor (ADF)/cofilin family, which weakly sever but do not cap the barbed ends of actin filaments (step 8b) (Fass et al., 2004). Barbed ends generated by cofilin either serve as initiation sites for new elongation or become capped (step 3a), depending upon the signals present. A cofilin-binding protein, Aip1, enhances cofilin activity (Okada et al., 2002), as do two families of phosphatases, the slingshots and cronophin. The adaptor protein 14-3-3
antagonizes this effect. Phosphorylation of cofilin by LIM kinase, downstream of Rac activation, inactivates cofilin (Huang et al., 2005; Nishita et al., 2005). Actin-filament-stabilizing proteins, particularly tropomyosins, also inhibit severing of actin filaments by cofilin but are less effective against gelsolin family members, and different tropomyosin isoforms generated by alternative mRNA splicing confer subtlety on this inhibition (Gunning et al., 2005). Polyphosphoinositides strongly inhibit actin filament severing by both protein families, which is consistent with their general propensity to promote actin filament assembly.
Although efficient at breaking down actin networks and providing more filament ends, actin filament severing does not directly contribute to maintenance of an actin monomer pool required for new filament assembly. However, the cofilin proteins, by accelerating subunit dissociation from pointed ends (`nibbling') (step 8c) are the major drivers for this (Carlier et al., 1999).
|
Monomer sequestration |
|---|
|
TopIntroductionInitiationElongationTerminationBranchingActin filament crosslinkingActin filament contraction,...Actin filament disassemblyMonomer sequestrationReferences |
|---|
|
References |
|---|
|
TopIntroductionInitiationElongationTerminationBranchingActin filament crosslinkingActin filament contraction,...Actin filament disassemblyMonomer sequestrationReferences |
|---|
Allen, P. (2003). Actin filament uncapping localizes to ruffling lamellae and rocketing vesicles. Nat. Cell Biol. 5, 972-979.[CrossRef][Medline]
Bakin, A., Safina, A., Rinehart, C., Daroqui, C., Darbary, H. and Helfman, D. (2004). A critical role of tropomyosins in TGF-beta regulation of the actin cytoskeleton and cell motility in epithelial cells. Mol. Biol. Cell 15, 4682-4694.
Barkalow, K., Italiano, J., Jr, Chou, D., Matsuoka, Y., Bennett, V. and Hartwig, J. (2003). a-Adducin dissociates from F-actin and spectrin during platelet activation. J. Cell Biol. 161, 557-570.
Barzik, M., Kotova, T., Higgs, H., Hazelwood, L., Hanein, D., Gertler, F. and Shafer, D. (2005). Ena/VASP proteins enhance actin polymerization in the presence of barbed end capping proteins. J. Biol. Chem. 280, 28653-28662.
Broderick, M. and Winder, S. (2005). Spectrin, alpha-actinin, and dystrophin. Adv. Protein Chem. 70, 203-246.[CrossRef][Medline]
Bubb, M., Yarmola, E., Gibson, B. and Southwick, F. (2003). Depolymerization of actin filaments by profilin. Effects of profilin on capping protein function. J. Biol. Chem. 278, 24629-24635.
Carlier, M.-F., Ressad, F. and Pantaloni, D. (1999). Control of actin dynamics in cell motility. Role of ADF/Cofilin. J. Biol. Chem. 274, 33827-33830.
Cho, W. and Stahelin, R. (2005). Membrane-protein interactions in cell signaling and membrane trafficking. Annu. Rev. Biophys. Biomol. Struct. 34, 119-151.[CrossRef][Medline]
DesMarais, V., Ghosh, M., Eddy, R. and Condeelis, J. (2005). Cofilin takes the lead. J. Cell Sci. 118, 19-26.
Di Nardo, A., Cicchetti, G., Falet, H., Hartwig, J., Stossel, T. and Kwiatkowski, D. (2005). Arp2/3 complex-deficient mouse fibroblasts are viable and have normal leading-edge structure and function. Proc. Natl. Acad. Sci. USA 102, 16263-16268.
Disanza, A., Carlier, M.-F., Stradal, T., Didry, D., Frittoli, E., Confalonieri, S., Croce, A., Wehland, J., DiFiore, P. and Scita, G. (2004). Eps8 controls actin-based motility by capping the barbed ends of actin filaments. Nat. Cell Biol. 6, 1180-1188.[CrossRef][Medline]
Drees, F., Pokutta, S., Yamada, S., Nelson, S. and Weis, W. (2005). a-Catenin is a molecular switch that binds E-cadherin-ß-catenin and regulates actin-filament assembly. Cell 123, 903-915.[CrossRef][Medline]
During, R., Li, W., Hao, B., Koenig, J., Stephens, D., Quinn, C. and Southwick, F. (2005). Anthrax lethal toxin paralyzes neutrophil actin-based motility. J. Infect. Dis. 192, 837-845.[CrossRef][Medline]
Eyers, C., McNeill, H., Knebel, A., Morrice, N., Arthur, S., Cuenda, A. and Cohen, P. (2005). The phosphorylation of CapZ-interacting protein (CapZIP) by stress-activated protein kinases triggers its dissociation from CapZ. Biochem. J. 389, 127-135.[CrossRef][Medline]
Fass, J., Gehler, S., Sarmiere, P., Letourneau, P. and Bamburg, J. (2004). Regulating filopodial dynamics through actin-depolymerizing factor/cofilin. Anat. Sci. Int. 79, 173-183.[CrossRef][Medline]
Feng, Y. and Walsh, C. (2004). The many faces of filamin: a versatile molecular scaffold for cell motility and signalling. Nat. Cell Biol. 6, 1034-1038.[CrossRef][Medline]
Fischer, R. and Fowler, V. (2003). Tropomodulins: life at the slow end. Trends Cell Biol. 13, 593-601.[CrossRef][Medline]
Gardel, M., Shin, J., MacKintosh, F., Madhadevan, L., Matsudaira, P. and Weitz, D. (2004). Elastic behavior of cross-linked and bundled actin networks. Science 304, 1301-1305.
Gardel, M., Nakamura, F., Hartwig, J., Crocker, J., Stossel, T. and Weitz, D. (2006). Pre-stressed F-actin networks cross-linked by hinged filamins replicate mechanical properties of cells. Proc. Natl. Acad. Sci. USA 103, 1762-1767.
Ginsberg, M., Partridge, A. and Shattil, S. (2005). Integrin regulation. Curr. Opin. Cell Biol. 17, 509-516.[CrossRef][Medline]
Gouin, E., Welch, M. and Cossart, P. (2005). Actin-based motility of intracellular pathogens. Curr. Opin. Microbiol. 8, 35-45.[CrossRef][Medline]
Gunning, P., Schevzov, G., Kee, A. and Hardeman, E. (2005). Tropomyosin isoforms: divining rods for actin cytoskeleton function. Trends Cell Biol. 15, 333-341.[CrossRef][Medline]
Gupton, S., Anderson, K., Kole, T., Fischer, R., Ponti, A., Hitchcock-DeGregori, S., Danuser, G., Fowler, V., Wirtz, D., Hanein, D. et al. (2005). Cell migration without a lamellipodium: translation of actin dynamics into cell movement mediated by tropomyosin. J. Cell Biol. 168, 619-631.
Higgs, H. (2005). Formin proteins: a domain-based approach. Trends Biochem. Sci. 30, 342-352.[CrossRef][Medline]
Huang, T., Dermardirossian, C. and Bokoch, G. (2005). Cofilin phosphatases and regulation of actin dynamics. Curr. Opin. Cell Biol. 18, 26-31.[Medline]
Jaffe, A. and Hall, A. (2005). Rho GTPases: biochemistry and biology. Annu. Rev. Cell Dev. Biol. 21, 247-269.[CrossRef][Medline]
Kovar, D. (2006). Molecular details of formin-mediated actin assembly. Curr. Opin. Cell Biol. 18, 11-17.[CrossRef][Medline]
Kuhn, J. and Pollard, T. (2005). Real-time measurements of actin filament polymerization by total internal reflection fluorescence microscopy. Biophys. J. 88, 1387-1402.[CrossRef][Medline]
Kumar, N., Tomar, A., Parrill, A. and Khurana, S. (2004). Functional dissection and molecular characterization of calcium-sensitive actin-capping and actin-depolymerizing sites in villin. J. Biol. Chem. 279, 45036-45046.
Landsverk, M. and Epstein, H. (2005). Genetic analysis of myosin II assembly and organization in model organisms. Cell. Mol. Life Sci. 62, 2270-2282.[CrossRef][Medline]
Linder, S. and Kopp, P. (2005). Podosomes at a glance. J. Cell Sci. 118, 2079-2082.
Medalia, O., Weber, I., Frangakis, A., Nicastro, D., Gerisch, G. and Baumeister, W. (2002). Macromolecular architecture in eukaryotic cells visualized by cryoelectron tomography. Science 298, 1209-1213.
Mirzapoiazova, T., Kolosova, I., Romer, L., Garcia, J. and Verin, A. (2005). The role of caldesmon in the regulation of endothelial cytoskeleton and migration. J. Cell Physiol. 203, 520-528.[CrossRef][Medline]
Nakamura, F., Osborn, E., Janmey, P. and Stossel, T. (2002). Comparison of filamin A-induced cross-linking and Arp2/3 complex-mediated branching on the mechanics of actin filaments. J. Biol. Chem. 277, 9148-9154.
Nakamura, F., Hartwig, J., Stossel, T. and Syzmanski, P. (2005). Ca2+ and calmodulin regulate binding of filamin A to actin filaments. J. Biol. Chem. 280, 32426-32433.
Nicholson-Dykstra, S., Higgs, H. N. and Harris, E. S. (2005). Actin dynamics: growth from dendritic branches. Curr. Biol. 15, R346-R357.[CrossRef][Medline]
Niggli, V. (2005). Regulation of protein activities by phosphoprotein phosphates. Annu. Rev. Cell Dev. Biol. 21, 57-80.[CrossRef][Medline]
Nishita, M., Tomizawa, C., Yamamoto, M., Horita, Y., Ohashi, K. and Mizuno, K. (2005). Spatial and temporal regulation of cofilin activity by LIM kinase and Slingshot is critical for directional cell migration. J. Cell Biol. 171, 349-359.
Okada, K., Blanchoin, L., Abe, H., Chen, H., Pollard, T. and Bamburg, J. (2002). Xenopus actin-interacting protein 1 (XAip1) enhances cofilin fragmentation of filaments by capping filament ends. J. Biol. Chem. 277, 43011-43016.
Pollard, T. and Borisy, G. (2003). Cellular motility driven by assembly and disassembly of actin filaments. Cell 112, 453-465.[CrossRef][Medline]
Rafelski, S. and Theriot, J. (2004). Crawling toward a unified model of cell motiility: spatial and temporal regulation of actin dynamics. Annu. Rev. Biochem. 73, 209-239.[CrossRef][Medline]
Small, J., Stradal, T., Vignal, E. and Rottner, K. (2002). The lamellipodium: where motility begins. Trends Cell Biol. 12, 112-120.[CrossRef][Medline]
Stradal, T. and Scita, G. (2006). Protein complexes regulating Arp2/3-mediated actin assembly. Curr. Opin. Cell Biol. 18, 4-10.[CrossRef][Medline]
Strasser, G., Rahim, N., VanderWaal, K., Gertler, F. and Lanier, L. (2004). Arp2/3 is a negative regulator of growth cone translocation. Neuron 43, 81-94.[CrossRef][Medline]
Vicente-Manzanares, M., Webb, D. and Horwitz, A. (2005). Cell migration at a glance. J. Cell Sci. 118, 4917-4919.
Yang, C., Pring, M., Wear, M., Huang, M., Cooper, J., Svitkina, T. and Zigmond, S. (2005). Mammalian CARMIL inhibits actin filament capping by capping protein. Dev. Cell 9, 209-221.[CrossRef][Medline]
Yarmola, E. and Bubb, M. (2004). Effects of profilin and thymosin ß4 on the critical concentration of actin demonstrated in vitro and in cell extracts with a novel direct assay. J. Biol. Chem. 279, 33519-33527.
Yin, H. and Janmey, P. (2003). Phosphoinositide regulation of the actin cytoskeleton. Annu. Rev. Physiol. 65, 761-789.[CrossRef][Medline]
This article has been cited by other articles:
|
|
 |
|
  H. Q. SUN and H. L. YIN The beta-Thymosin Enigma Ann. N.Y. Acad. Sci., September 1, 2007; 1112(1): 45 - 55. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. J. Kusner, C. R. Thompson, N. A. Melrose, S. M. Pitson, L. M. Obeid, and S. S. Iyer The Localization and Activity of Sphingosine Kinase 1 Are Coordinately Regulated with Actin Cytoskeletal Dynamics in Macrophages J. Biol. Chem., August 10, 2007; 282(32): 23147 - 23162. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. A. Horne and M. L. Dell'Acqua Phospholipase C Is Required for Changes in Postsynaptic Structure and Function Associated with NMDA Receptor-Dependent Long-Term Depression J. Neurosci., March 28, 2007; 27(13): 3523 - 3534. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
