Control of actin filament treadmilling in cell motility.

Recent advances in structural, biochemical, biophysical, and live cell imaging approaches have furthered our understanding of the molecular mechanisms by which regulated assembly dynamics of actin filaments drive motile processes. Attention is focused on lamellipodium protrusion, powered by the turnover of a branched filament array. ATP hydrolysis on actin is the key reaction that allows filament treadmilling. It regulates barbed-end dynamics and length fluctuations at steady state and specifies the functional interaction of actin with essential regulatory proteins such as profilin and ADF/cofilin. ATP hydrolysis on actin and Arp2/3 acts as a timer, regulating the assembly and disassembly of the branched array to generate tropomyosin-mediated heterogeneity in the structure and dynamics of the lamellipodial network. The detailed molecular mechanisms of ATP hydrolysis/Pi release on F-actin remain elusive, as well as the mechanism of filament branching with Arp2/3 complex or that of the formin-driven processive actin assembly. Novel biophysical methods involving single-molecule measurements should foster progress in these crucial issues.

[1]  T. L. Hill,et al.  A model for actin polymerization and the kinetic effects of ATP hydrolysis. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[2]  L. Blanchoin,et al.  Cofilin increases the bending flexibility of actin filaments: implications for severing and cell mechanics. , 2008, Journal of molecular biology.

[3]  H. Kueh,et al.  Dynamic stabilization of actin filaments , 2008, Proceedings of the National Academy of Sciences.

[4]  M. Welch,et al.  WHAMM Is an Arp2/3 Complex Activator That Binds Microtubules and Functions in ER to Golgi Transport , 2008, Cell.

[5]  Crystal structures of monomeric actin bound to cytochalasin D. , 2008, Journal of molecular biology.

[6]  A. Makhov,et al.  Coronin 1B Antagonizes Cortactin and Remodels Arp2/3-Containing Actin Branches in Lamellipodia , 2008, Cell.

[7]  Dmitri I Svergun,et al.  X-ray scattering study of activated Arp2/3 complex with bound actin-WCA. , 2008, Structure.

[8]  D. Pantaloni,et al.  Direct evidence for ADP-Pi-F-actin as the major intermediate in ATP-actin polymerization. Rate of dissociation of Pi from actin filaments. , 1986, Biochemistry.

[9]  Y. Maéda,et al.  Molecular determination by electron microscopy of the actin filament end structure. , 2007, Journal of molecular biology.

[10]  M. Carlier,et al.  Probing the mechanism of ATP hydrolysis on F-actin using vanadate and the structural analogs of phosphate BeF-3 and A1F-4. , 1988, The Journal of biological chemistry.

[11]  Klemens Rottner,et al.  Arp2/3 complex interactions and actin network turnover in lamellipodia , 2008, The EMBO journal.

[12]  J. Olivo-Marin,et al.  WAFL, a new protein involved in regulation of early endocytic transport at the intersection of actin and microtubule dynamics. , 2009, Experimental cell research.

[13]  E. Egelman,et al.  High-resolution cryo-EM structure of the F-actin–fimbrin/plastin ABD2 complex , 2008, Proceedings of the National Academy of Sciences.

[14]  Léa Trichet,et al.  VASP governs actin dynamics by modulating filament anchoring. , 2007, Biophysical journal.

[15]  T. Pollard,et al.  Profilin-mediated competition between capping protein and formin Cdc12p during cytokinesis in fission yeast. , 2005, Molecular biology of the cell.

[16]  T. Pollard,et al.  Inhibition of the Arp2/3 complex-nucleated actin polymerization and branch formation by tropomyosin , 2001, Current Biology.

[17]  E. Yarmola,et al.  How depolymerization can promote polymerization: the case of actin and profilin , 2009, BioEssays : news and reviews in molecular, cellular and developmental biology.

[18]  Niels Volkmann,et al.  The structural basis of actin filament branching by the Arp2/3 complex , 2008, The Journal of cell biology.

[19]  Gaudenz Danuser,et al.  Cofilin activity downstream of Pak1 regulates cell protrusion efficiency by organizing lamellipodium and lamella actin networks. , 2007, Developmental cell.

[20]  G. Danuser.  Testing the lamella hypothesis: the next steps on the agenda , 2009, Journal of Cell Science.

[21]  Edward H. Egelman,et al.  How does ATP hydrolysis control actin's associations? , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[22]  C. Schutt,et al.  The structure of crystalline profilin–β-actin , 1993, Nature.

[23]  M. Carlier,et al.  Activation of Arp2/3 Complex by Wiskott-Aldrich Syndrome Protein Is Linked to Enhanced Binding of ATP to Arp2* , 2001, The Journal of Biological Chemistry.

[24]  T. Pollard,et al.  Interactions of ADF/cofilin, Arp2/3 complex, capping protein and profilin in remodeling of branched actin filament networks , 2000, Current Biology.

[25]  C. Rivera,et al.  Defining mechanisms of actin polymerization and depolymerization during dendritic spine morphogenesis , 2009, The Journal of cell biology.

[26]  F. Lafuma,et al.  A biomimetic motility assay provides insight into the mechanism of actin-based motility , 2003, The Journal of cell biology.

[27]  M. Carlier,et al.  Actin polymerization and ATP hydrolysis. , 1987, Advances in biophysics.

[28]  R. Mullins,et al.  Capping Protein Increases the Rate of Actin-Based Motility by Promoting Filament Nucleation by the Arp2/3 Complex , 2008, Cell.

[29]  Reinhard Lipowsky,et al.  Actin polymerization and depolymerization coupled to cooperative hydrolysis. , 2009, Physical review letters.

[30]  Y. Maéda,et al.  Dual Roles of Gln137 of Actin Revealed by Recombinant Human Cardiac Muscle α-Actin Mutants* , 2008, Journal of Biological Chemistry.

[31]  Marie-France Carlier,et al.  Forces generated during actin-based propulsion: a direct measurement by micromanipulation. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[32]  T. Pollard,et al.  The Role of the FH1 Domain and Profilin in Formin-Mediated Actin-Filament Elongation and Nucleation , 2008, Current Biology.

[33]  Guenter P. Resch,et al.  Clustering of VASP actively drives processive, WH2 domain‐mediated actin filament elongation , 2008, The EMBO journal.

[34]  K. Trybus,et al.  Crystal Structures of Expressed Non-polymerizable Monomeric Actin in the ADP and ATP States* , 2006, Journal of Biological Chemistry.

[35]  M. Carlier,et al.  Control of Actin Dynamics in Cell Motility , 1999, The Journal of Biological Chemistry.

[36]  S. Ono.  Regulation of actin filament dynamics by actin depolymerizing factor/cofilin and actin-interacting protein 1: new blades for twisted filaments. , 2003, Biochemistry.

[37]  H. Kueh,et al.  Coronin-1A stabilizes F-actin by bridging adjacent actin protomers and stapling opposite strands of the actin filament. , 2008, Journal of molecular biology.

[38]  T. Pollard,et al.  Insertional assembly of actin filament barbed ends in association with formins produces piconewton forces. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[39]  J. Iwasa,et al.  Spatial and Temporal Relationships between Actin-Filament Nucleation, Capping, and Disassembly , 2007, Current Biology.

[40]  Albrecht Wegner,et al.  Mechanism of ATP hydrolysis by polymeric actin. , 1994, Biochimica et biophysica acta.

[41]  Zachary Pincus,et al.  Emergence of Large-Scale Cell Morphology and Movement from Local Actin Filament Growth Dynamics , 2007, PLoS biology.

[42]  Gary G. Borisy,et al.  Arp2/3 Complex and Actin Depolymerizing Factor/Cofilin in Dendritic Organization and Treadmilling of Actin Filament Array in Lamellipodia , 1999, The Journal of cell biology.

[43]  Liang Cai,et al.  Coronin 1B Coordinates Arp2/3 Complex and Cofilin Activities at the Leading Edge , 2007, Cell.

[44]  Thomas D Pollard,et al.  Pathway of Actin Filament Branch Formation by Arp2/3 Complex* , 2008, Journal of Biological Chemistry.

[45]  Marie-France Carlier,et al.  How profilin promotes actin filament assembly in the presence of thymosin β4 , 1993, Cell.

[46]  A. Wegner,et al.  Head to tail polymerization of actin. , 1976, Journal of molecular biology.

[47]  A. Kolomeisky,et al.  ATP hydrolysis stimulates large length fluctuations in single actin filaments. , 2005, Biophysical journal.

[48]  K. Rottner,et al.  Differentially oriented populations of actin filaments generated in lamellipodia collaborate in pushing and pausing at the cell front , 2008, Nature Cell Biology.

[49]  T. Pollard,et al.  The Arp2/3 complex nucleates actin filament branches from the sides of pre-existing filaments , 2001, Nature Cell Biology.

[50]  W. Kabsch,et al.  Atomic model of the actin filament , 1990, Nature.

[51]  Beáta Bugyi,et al.  How do in vitro reconstituted actin‐based motility assays provide insight into in vivo behavior? , 2008, FEBS letters.

[52]  Gary G. Borisy,et al.  Dendritic organization of actin comet tails , 2001, Current Biology.

[53]  T. L. Hill.  Theoretical study of a model for the ATP cap at the end of an actin filament. , 1986, Biophysical journal.

[54]  E. Egelman,et al.  A change in actin conformation associated with filament instability after Pi release. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[55]  E. Yarmola,et al.  Effects of Profilin and Thymosin β4 on the Critical Concentration of Actin Demonstrated in Vitro and in Cell Extracts with a Novel Direct Assay* , 2004, Journal of Biological Chemistry.

[56]  W. Kabsch,et al.  Atomic structure of the actin: DNase I complex , 1990, Nature.

[57]  T. Pollard,et al.  Energetic Requirements for Processive Elongation of Actin Filaments by FH1FH2-formins* , 2009, Journal of Biological Chemistry.

[58]  E. Larquet,et al.  How ATP Hydrolysis Controls Filament Assembly from Profilin-Actin , 2007, Journal of Biological Chemistry.

[59]  M. Carlier,et al.  Control of Actin Dynamics in Cell Motility , 1999, The Journal of Biological Chemistry.

[60]  R. Dominguez,et al.  Understanding the role of the G-actin-binding domain of Ena/VASP in actin assembly. , 2006, Journal of structural biology.

[61]  D. Purich,et al.  Force generation by cytoskeletal filament end-tracking proteins. , 2004, Biophysical journal.

[62]  T. Pollard,et al.  Hydrolysis of ATP by polymerized actin depends on the bound divalent cation but not profilin. , 2002, Biochemistry.

[63]  Yoav Freund,et al.  Lamellipodial Actin Mechanically Links Myosin Activity with Adhesion-Site Formation , 2007, Cell.

[64]  P. Gounon,et al.  The Arp2/3 complex branches filament barbed ends: functional antagonism with capping proteins , 2000, Nature Cell Biology.

[65]  Marie-France Carlier,et al.  Arp2/3 controls the motile behavior of N-WASP-functionalized GUVs and modulates N-WASP surface distribution by mediating transient links with actin filaments. , 2008, Biophysical journal.

[66]  M. Geli,et al.  Actin in the endocytic pathway: From yeast to mammals , 2008, FEBS letters.

[67]  Ikuko Fujiwara,et al.  Microscopic analysis of polymerization dynamics with individual actin filaments , 2002, Nature Cell Biology.

[68]  Adam C. Martin,et al.  Arp2/3 ATP hydrolysis-catalysed branch dissociation is critical for endocytic force generation , 2006, Nature Cell Biology.

[69]  E. Korn,et al.  The mechanisms of ATP hydrolysis accompanying the polymerization of Mg-actin and Ca-actin. , 1987, The Journal of biological chemistry.

[70]  O. Destaing,et al.  Actin machinery and mechanosensitivity in invadopodia, podosomes and focal adhesions , 2009, Journal of Cell Science.

[71]  T. Pollard,et al.  Control of the Assembly of ATP- and ADP-Actin by Formins and Profilin , 2006, Cell.

[72]  M. Eck,et al.  Mechanism and function of formins in the control of actin assembly. , 2007, Annual review of biochemistry.

[73]  Thomas D Pollard,et al.  Regulation of actin filament assembly by Arp2/3 complex and formins. , 2007, Annual review of biophysics and biomolecular structure.

[74]  Thomas E. Schaus,et al.  Self-organization of actin filament orientation in the dendritic-nucleation/array-treadmilling model , 2007, Proceedings of the National Academy of Sciences.

[75]  M. Carlier,et al.  ATP hydrolysis on actin-related protein 2/3 complex causes debranching of dendritic actin arrays , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[76]  J. Taunton,et al.  Mechanism of Actin Network Attachment to Moving Membranes: Barbed End Capture by N-WASP WH2 Domains , 2007, Cell.

[77]  Nathaniel M Vacanti,et al.  An open model of actin dendritic nucleation. , 2009, Biophysical journal.

[78]  H. Kueh,et al.  Actin disassembly by cofilin, coronin, and Aip1 occurs in bursts and is inhibited by barbed-end cappers , 2008, The Journal of cell biology.

[79]  Ina Weisswange,et al.  The rate of N-WASP exchange limits the extent of ARP2/3-complex-dependent actin-based motility , 2009, Nature.

[80]  G. Danuser,et al.  Two Distinct Actin Networks Drive the Protrusion of Migrating Cells , 2004, Science.

[81]  G. Danuser,et al.  Cell migration without a lamellipodium , 2005, The Journal of cell biology.

[82]  K. Mallick,et al.  Nonequilibrium self-assembly of a filament coupled to ATP/GTP hydrolysis. , 2008, Biophysical journal.

[83]  Simon Hippenmeyer,et al.  Conformational changes in the Arp2/3 complex leading to actin nucleation , 2005, Nature Structural &Molecular Biology.

[84]  Gaudenz Danuser,et al.  Fluctuations of intracellular forces during cell protrusion , 2008, Nature Cell Biology.

[85]  J. Small.  Getting the actin filaments straight: nucleation-release or treadmilling? , 1995, Trends in cell biology.

[86]  Marileen Dogterom,et al.  Direct measurement of force generation by actin filament polymerization using an optical trap , 2007, Proceedings of the National Academy of Sciences.

[87]  J. Lepault,et al.  Filament Assembly from Profilin-Actin* , 1999, The Journal of Biological Chemistry.

[88]  Dimitrios Vavylonis,et al.  Actin polymerization kinetics, cap structure, and fluctuations. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[89]  Marie-France Carlier,et al.  Formin Is a Processive Motor that Requires Profilin to Accelerate Actin Assembly and Associated ATP Hydrolysis , 2004, Cell.

[90]  T. Pollard,et al.  Quantitative analysis of the effect of Acanthamoeba profilin on actin filament nucleation and elongation. , 1984, Biochemistry.

[91]  Beáta Bugyi,et al.  How tropomyosin regulates lamellipodial actin‐based motility: a combined biochemical and reconstituted motility approach , 2010, The EMBO journal.

[92]  J. Hartwig,et al.  Importance of free actin filament barbed ends for Arp2/3 complex function in platelets and fibroblasts , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[93]  E. Yarmola,et al.  Effect of profilin on actin critical concentration: a theoretical analysis. , 2008, Biophysical journal.

[94]  B. Trask,et al.  Human Subtelomeric WASH Genes Encode a New Subclass of the WASP Family , 2007, PLoS genetics.

[95]  K. Ohashi,et al.  Cofilin promotes stimulus-induced lamellipodium formation by generating an abundant supply of actin monomers , 2007, The Journal of cell biology.

[96]  Thomas D Pollard,et al.  Real-time measurements of actin filament polymerization by total internal reflection fluorescence microscopy. , 2005, Biophysical journal.

[97]  T. Pollard,et al.  Model of formin-associated actin filament elongation. , 2006, Molecular cell.

[98]  Harini Ravi,et al.  Aip1 and cofilin promote rapid turnover of yeast actin patches and cables: a coordinated mechanism for severing and capping filaments. , 2006, Molecular biology of the cell.

[99]  E. Korn,et al.  Evidence for an ATP cap at the ends of actin filaments and its regulation of the F-actin steady state. , 1984, The Journal of biological chemistry.

[100]  Edward H. Egelman,et al.  Actin Structure and Function: What We Still Do Not Understand* , 2007, Journal of Biological Chemistry.

[101]  Thomas D. Pollard,et al.  Interaction of WASP/Scar proteins with actin and vertebrate Arp2/3 complex , 2000, Nature Cell Biology.

[102]  J. Condeelis,et al.  Spatial regulation of actin dynamics: a tropomyosin-free, actin-rich compartment at the leading edge , 2002, Journal of Cell Science.

[103]  E. Korn,et al.  Polymerization of ADP-actin and ATP-actin under sonication and characteristics of the ATP-actin equilibrium polymer. , 1985, The Journal of biological chemistry.

[104]  Giorgio Scita,et al.  IRSp53: crossing the road of membrane and actin dynamics in the formation of membrane protrusions. , 2008, Trends in cell biology.

[105]  E. Yarmola,et al.  Depolymerization of Actin Filaments by Profilin , 2003, Journal of Biological Chemistry.

[106]  S. Narumiya,et al.  Actin turnover–dependent fast dissociation of capping protein in the dendritic nucleation actin network: evidence of frequent filament severing , 2006, The Journal of cell biology.

[107]  T. Pollard,et al.  Kinetics of the formation and dissociation of actin filament branches mediated by Arp2/3 complex. , 2006, Biophysical journal.

[108]  T. Pollard,et al.  Cofilin Dissociates Arp2/3 Complex and Branches from Actin Filaments , 2009, Current Biology.

[109]  J. Zuchero,et al.  p53-cofactor JMY is a Multifunctional Actin Nucleation Factor , 2009, Nature Cell Biology.

[110]  Andrea Disanza,et al.  Eps8 controls actin-based motility by capping the barbed ends of actin filaments , 2004, Nature Cell Biology.

[111]  J. Small,et al.  Unravelling the structure of the lamellipodium , 2008, Journal of microscopy.

[112]  B. Andrews,et al.  Direct regulation of Arp2/3 complex activity and function by the actin binding protein coronin , 2002, The Journal of cell biology.

[113]  Laurent Blanchoin,et al.  Coronin switches roles in actin disassembly depending on the nucleotide state of actin. , 2009, Molecular cell.

[114]  S. Ono,et al.  Tropomyosin inhibits ADF/cofilin-dependent actin filament dynamics , 2002, The Journal of cell biology.

[115]  Beáta Bugyi,et al.  Spire and Cordon-bleu: multifunctional regulators of actin dynamics. , 2008, Trends in cell biology.

[116]  Yuichiro Maéda,et al.  The nature of the globular- to fibrous-actin transition , 2009, Nature.

[117]  P. Vallotton,et al.  Shifting views on the leading role of the lamellipodium in cell migration: speckle tracking revisited , 2009, Journal of Cell Science.

[118]  T. Pollard,et al.  Review of the mechanism of processive actin filament elongation by formins. , 2009, Cell motility and the cytoskeleton.