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• W2079597974 abstract "Motile processes at the origin of cell migration, cell division, synaptic plasticity, and endocytosis, but also morphogenetic processes that define anterior-posterior and ventral-dorsal polarity of the embryo, or left-right asymmetry, are driven by spatially and temporally controlled assembly of actin filaments (1Pollard T.D. Borisy G.G. Cell. 2003; 112: 453-465Abstract Full Text Full Text PDF PubMed Scopus (3209) Google Scholar, 2Rafelski S.M. Theriot J.A. Annu. Rev. Biochem. 2004; 73: 209-239Crossref PubMed Scopus (171) Google Scholar, 3Dormann D. Weijer C.J. Curr. Opin. Genet. Dev. 2006; 16: 367-373Crossref PubMed Scopus (54) Google Scholar, 4Kaksonen M. Toret C.P. Drubin D.G. Nat. Rev. Mol. Cell. Biol. 2006; 7: 404-414Crossref PubMed Scopus (549) Google Scholar). Cell biological studies and reconstituted motility assays indicate that polarized filament barbed end growth, at specific sites on the membrane, generates the forces responsible for lamellipodia and filopodia extension, as well as tensile forces that strengthen focal adhesions. Fluorescence speckle microscopy of actin and regulatory proteins in motile cells show that morphologically and dynamically distinct networks of actin filaments initiated at the plasma membrane coexist in the cell and define cellular compartments (5Ponti A. Machacek M. Gupton S.L. Waterman-Storer C.M. Danuser G. Science. 2004; 305: 1782-1786Crossref PubMed Scopus (590) Google Scholar, 6Iwasa J.H. Mullins R.D. Curr. Biol. 2007; 17: 395-406Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar). How are these different turnover rates coordinated to achieve directional movement in response to extracellular cues? How can regulatory proteins recognize distinct actin networks? What are the relationships between the force produced by filament barbed end growth that deforms the membrane and the molecular mechanism of the protein machineries that link barbed ends to the membrane? New insights into these issues have emerged from recent cellular, physical, and biochemical approaches. In living cells, actin filaments (F-actin) are assembled at a steady state and turn over via pointed end depolymerization balanced by barbed end polymerization, a process called treadmilling. The treadmilling of pure muscle actin is very slow (on the order of 0.1 subunit/s, meaning that a 3-μm-long filament is renewed in 2 h). Treadmilling is accelerated by 2 orders of magnitude in motile processes like lamellipodia or filopodia, due to the activity of ADF 2The abbreviations used are: ADF, actin-depolymerizing factor; N-WASP, neural Wiscott-Aldrich syndrome protein. /cofilins (7Carlier M.F. Ressad F. Pantaloni D. J. Biol. Chem. 1999; 274: 33827-33830Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar). In other structures like microvilli, treadmilling is slowed down by spatially regulated barbed end capping of, for example, actin bundles in the stereocilia of the inner ear (8Lin H.W. Schneider M.E. Kachar B. Curr. Opin. Cell Biol. 2005; 17: 55-61Crossref PubMed Scopus (55) Google Scholar). Treadmilling thus appears as a universal mechanism that drives actin dynamics in eukaryotes. The stationary concentration of polymerizable ATP-G-actin is determined by the overall flux of pointed end depolymerization and by the availability and reactivity of barbed ends. Both are finely regulated. Polymerizable monomeric ATP-actin consists of free ATP-G-actin and complexes of ATP-G-actin with profilin or with functional homologs of profilin like WH2-domain proteins of the actobindin family (9Paunola E. Mattila P.K. Lappalainen P. FEBS Lett. 2002; 513: 92-97Crossref PubMed Scopus (164) Google Scholar, 10Boquet I. Boujemaa R. Carlier M.F. Preat T. Cell. 2000; 102: 797-808Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar, 11Hertzog M. Yarmola E.G. Didry D. Bubb M.R. Carlier M.F. J. Biol. Chem. 2002; 277: 14786-14792Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 12Hertzog M. van Heijenoort C. Didry D. Gaudier M. Coutant J. Gigant B. Didelot G. Preat T. Knossow M. Guittet E. Carlier M.F. Cell. 2004; 117: 611-623Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar). These proteins make a complex with G-actin that participates in barbed end assembly specifically. Profilin and its functional homologs thus play a crucial role in barbed end growth and motility. Most often, ATP-G-actin is in rapid equilibrium with these proteins (called collectively Wi), whereas filament assembly is an actual process. Each G-actin-Wi complex associates with free barbed ends with its own rate constant, k+iB, and displays its own intrinsic barbed end critical concentration, CCiB. The steady-state concentrations of ATP-G-actin, [T]SS, and of the assembly-competent complexes, [TWi]SS, depend on the flux of pointed end depolymerization. Proteins of the ADF/cofilin family, acting in synergy with Aip1, enhance pointed end depolymerization in a signal-responsive fashion (13Ono S. Mohri K. Ono K. J. Biol. Chem. 2004; 279: 14207-14212Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar). By increasing the steady-state concentration of ATP-G-actin, they contribute to an increase in the rates of barbed end nucleation and growth. The specific localization of ADF in the lamellipodium has been explained recently by the fact that the ADF-activating Slingshot phosphatase (14Niwa R. Nagata-Ohashi K. Takeichi M. Mizuno K. Uemura T. Cell. 2002; 108: 233-246Abstract Full Text Full Text PDF PubMed Scopus (530) Google Scholar, 15Sarmiere P.D. Bamburg J.R. J. Neurobiol. 2004; 58: 103-117Crossref PubMed Scopus (174) Google Scholar) becomes active by binding the filaments that are initiated upon lamellipodium formation (16Nagata-Ohashi K. Ohta Y. Goto K. Chiba S. Mori R. Nishita M. Ohashi K. Kousaka K. Iwamatsu A. Niwa R. Uemura T. Mizuno K. J. Cell Biol. 2004; 165: 465-471Crossref PubMed Scopus (159) Google Scholar). The thermodynamic (CCiB) and kinetic (k+iB, k–iB) parameters are affected by proteins that associate with barbed ends and may block barbed end assembly and depolymerization (like capping proteins), slow down assembly and/or disassembly, or enhance barbed end growth like formins. Hence barbed ends are distributed in a variety of dynamically distinct classes. The values of [T]SS and [TWi]SS that are established at a given time in the cell depend on the number of filament pointed ends and on the number of barbed ends in each class (Fig. 1). The kinetic parameters of capping protein interaction with barbed ends vary greatly from one protein to the other. Capping protein αβ dissociates so slowly from barbed ends that this process could be limiting in motility. The uncapping activity of CARMIL (17Yang C. Pring M. Wear M.A. Huang M. Cooper J.A. Svitkina T.M. Zigmond S.H. Cell. 2005; 119: 209-221Google Scholar, 18Uruno T. Remmert K. Hammer J.A. II I J. Biol. Chem. 2006; 281: 10635-10650Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar) may therefore be important in the regulation of barbed end growth. The capping activity may also be integrated in a modular protein such as Eps8, which spatially and temporally restricts its function in response to local signals (19Disanza A. Carlier M.F. Stradal T.E. Didry D. Frittoli E. Confalonieri S. Croce A. Wehland J. Di Fiore P.P. Scita G. Nat. Cell Biol. 2004; 6: 1180-1188Crossref PubMed Scopus (150) Google Scholar). Finally, a protein known to sequester ADP-actin, twinfilin, has also been identified as a capping protein. One of the consequences of the combined activities of twinfilin is revealed in an integrated motility assay in which formin and twinfilin operate simultaneously. The sequestration of ADP-actin has a buffering effect on the level of barbed end capping by twinfilin. In turn this buffering effect maintains a low activity of formin (20Helfer E. Nevalainen E.M. Naumanen P. Romero S. Didry D. Pantaloni D. Lappalainen P. Carlier M.F. EMBO J. 2006; 25: 1184-1195Crossref PubMed Scopus (73) Google Scholar). These results should foster experiments aimed at testing the potential genetic interaction between twinfilin and formin. Conversely, the discovery of genetic interactions between two actin regulatory proteins should foster the design of reconstituted assays combining both proteins and leading toward the discovery of promising new properties. Most capping proteins are soluble; however, proteins that nucleate barbed ends or that regulate barbed end growth rate often operate at the plasma membrane in a signal-responsive fashion. The best example is provided by formins. The autoinhibited fold of formins is relieved in two consecutive steps by the binding of RhoGTPase (21Rose R. Weyand M. Lammers M. Ishizaki T. Ahmadian M.R. Wittinghofer A. Nature. 2005; 435: 513-518Crossref PubMed Scopus (212) Google Scholar), thus targeting activated formin at the membrane. The function of formins in actin filament dynamics is tightly regulated by profilin, a cofactor that is required for the activity of formins in vivo. In the absence of profilin, formins nucleate filaments and cap barbed ends more or less tightly. Cdc12 is a strong capper (22Kovar D.R. Kuhn J.R. Tichy A.L. Pollard T.D. J. Cell Biol. 2003; 161: 875-887Crossref PubMed Scopus (270) Google Scholar), whereas mDia1 and Bni1 are “leaky” cappers (23Li F. Higgs H.N. Curr. Biol. 2003; 13: 1335-1340Abstract Full Text Full Text PDF PubMed Scopus (340) Google Scholar). Formins use the property of profilin to couple ATP hydrolysis to filament assembly in order to catalyze rapid, processive, barbed end assembly, thus enhancing the rate constant for barbed end growth by 1 order of magnitude (28Romero S. Le Clainche C. Didry D. Egile C. Pantaloni D. Carlier M.F. Cell. 2004; 119: 419-429Abstract Full Text Full Text PDF PubMed Scopus (427) Google Scholar). Thus, rapid formin-based motile processes may occur concomitantly with other slower actin-based motile processes mediated by free barbed end growth, at a given steady-state concentration of ATP-G-actin. As a result, agents that lower the steady-state concentration of G-actin by stabilizing filaments (e.g. tropomyosin) are expected to further depress the formation of the branched filament array while still allowing formin-based motile processes. In conclusion, what we know from the biochemistry of actin and its regulators lets us anticipate that the assembly dynamics at individual barbed ends can vary to large extents in different regions of the cell. A more complex situation may occur if the diffusion of ATP-G-actin is low enough for significant gradients of G-actin to build up in regions of the cytoplasm. In addition to polymerizable G-actin, cells contain a pool of nonpolymerizable G-actin, which consists of ATP-G-actin (T) in complex with sequestering proteins (S) such as β-thymosins (24Safer D. Nachmias V.T. BioEssays. 1994; 16: 473-479Crossref PubMed Scopus (87) Google Scholar). β-Thymosin-actin complexes (TS) do not participate in filament assembly at either end and are in rapid equilibrium with free ATP-G-actin. Hence the amount of sequestered actin at steady state is determined at any time by the concentration of free ATP-G-actin, [T]SS, [TS]SS=[S0]ċ[TjcbSS/([TjcbSS+KS)1 where [S0] is the total concentration of sequestering agent, and KS ist he equilibrium dissociation constant for the TS complex. KS is higher than [T]SS, hence according to Equation 1, changes in [T]SS generate large changes in the pool of sequestered actin, reflected by changes in the amount of F-actin. G-actin sequesterers do not affect the velocity of motile processes, because the TS complex does not feed barbed end growth. However, they do affect the force produced, because they determine the amount of F-actin that builds up when the creation of new filaments in response to signals causes the relaxation of the steady state of actin assembly to a lower value of [T]SS. Note that this relaxation process takes place without any massive production of free ATP-G-actin. Measuring the concentrations of polymerizable and nonpolymerizable G-actin in vivo upon stimulus-induced changes in the motile state of the cell is a challenging task that will require refined imaging procedures that have not been developed yet. Forces produced by the growth of actin filaments against a membrane in response to signaling (25Ridley A.J. Trends Cell Biol. 2006; 16: 522-529Abstract Full Text Full Text PDF PubMed Scopus (859) Google Scholar) generate lamellipodial and filopodial protrusions, internalization of endocytic vesicles, or propulsion of endosomes. Actin polymerization against the surface of intracellular pathogens Listeria and Shigella causes their propulsion, which makes these bacteria the first natural functionalized particles mimicking the leading edge of migrating cells. The reconstitution of actin-based propulsion of a particle functionalized with N-WASP (26Loisel T.P Boujemaa R. Pantaloni D. Carlier M.F. Nature. 1999; 401: 613-616Crossref PubMed Scopus (796) Google Scholar, 27Wiesner S. Helfer E. Didry D. Ducouret G. Lafuma F. Carlier M.F. Pantaloni D. J. Cell Biol. 2003; 160: 387-398Crossref PubMed Scopus (167) Google Scholar) or formin (28Romero S. Le Clainche C. Didry D. Egile C. Pantaloni D. Carlier M.F. Cell. 2004; 119: 419-429Abstract Full Text Full Text PDF PubMed Scopus (427) Google Scholar) in a solution of F-actin maintained at steady state with ATP as an energy source validated the principle of treadmilling as the fuel of movement in cells and delineated the minimum number of required proteins (ADF and profilin for formin and additionally Arp2/3 and capping proteins for N-WASP). The same proteins were found essential for lamellipodium extension in vivo (29Rogers S.L Wiedemann U. Stuurman N. Vale R.D. J. Cell Biol. 2003; 162: 1079-1088Crossref PubMed Scopus (337) Google Scholar). Reconstituted motility assays also enabled controlled measurements of the force produced by actin polymerization (30Marcy Y. Prost J. Carlier M.F. Sykes C. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 5992-5997Crossref PubMed Scopus (202) Google Scholar). WASP family proteins use Arp2/3 complex to branch filaments at the leading edge, whereas formins may contribute to lamellipodium or filopodium or nerve growth cone extension or even supplement the absence of Arp2/3 (31Gupton S.L. Anderson K.L. Kole T.P. Fischer R.S. Ponti A. Hitchcock-DeGregori S.E. Danuser G. Fowler V.M. Wirtz D. Hanein D. Waterman-Storer C.M. J. Cell Biol. 2005; 168: 619-631Crossref PubMed Scopus (228) Google Scholar, 32Nardo A. Cicchetti G. Falet H. Hartwig J.H. Stossel T.P. Kwiatkowski D.J. Proc. Natl. Acad. Sci. U. S. A. 2005; 102: 16263-16268Crossref PubMed Scopus (50) Google Scholar). How does a lamellipodium start extending? Arp2/3 generates new filaments only by branching. When an N-WASP-coated bead or vesicle is placed in a reconstituted motility solution of barbed end-capped filaments, Arp2/3, ADF, and profilin, the filaments are never seen to adsorb onto N-WASP-Arp2/3 bound to the surface. The unpolarized actin meshwork that forms at the bead surface actually starts from G-actin. The treadmilling model accounts for this fact as follows. The motility medium maintains a steady-state concentration of ATP-G-actin well above the critical concentration of barbed ends, favoring nucleation. Nuclei that have free barbed ends either abort by binding a barbed end capper or branch at the bead surface upon transient interaction with the N-WASP-actin-Arp2/3 complex. Branching thus transiently protects from barbed end capping. It is likely that the same mechanism accounts for the initiation of the branched lamellipodial array. Similarly, formins use the dimer pre-nuclei present at steady state to initiate processive barbed end growth of new filaments at the leading edge. This process is more likely than the capture of barbed ends of existing filaments, which cannot diffuse rapidly in this confined cellular environment. How is actin assembly coordinated in the dendritic array and formin-induced bundles? How are the two arrays recognized by their specific regulators or bundling proteins? Reconstituted motility assays show that optimized actin-based movement is not obtained with the exact same medium composition for the WASP-Arp2/3 and formin systems. Propulsion of a WASP-functionalized particle by formation of a branched filament array relies on the balance between the sustained generation of new filaments at the particle surface by WASP-Arp2/3-induced filament branching and the disappearance of growing filaments by barbed end capping. This balance maintains a stationary number of growing filaments. The branched filament array thus contains an equal number of incorporated molecules of Arp2/3 and capping protein. Increasing the concentration of capping protein in the medium leads to an increase in the branching density of the meshwork (27Wiesner S. Helfer E. Didry D. Ducouret G. Lafuma F. Carlier M.F. Pantaloni D. J. Cell Biol. 2003; 160: 387-398Crossref PubMed Scopus (167) Google Scholar). In contrast, capping proteins, which compete with formin for barbed end binding, are negative regulators of the propulsion of formin-coated beads (28Romero S. Le Clainche C. Didry D. Egile C. Pantaloni D. Carlier M.F. Cell. 2004; 119: 419-429Abstract Full Text Full Text PDF PubMed Scopus (427) Google Scholar). In conclusion, in vitro capping proteins favor the formation of a highly densely branched array but inhibit formin-based processes. Remarkably, the same phenotype is observed in vivo (33Mejillano M.R. Kojima S. Applewhite D.A. Gertler F.B. Svitkina T.M. Borisy G.G. Cell. 2004; 118: 363-373Abstract Full Text Full Text PDF PubMed Scopus (334) Google Scholar): depletion of capping protein abolishes lamellipodia and favors formin-induced filopodia (34Shirenbeck A. Bretschneider T. Arasada R. Schleicher M. Faix J. Nat. Cell Biol. 2005; 7: 619-625Crossref PubMed Scopus (202) Google Scholar). In conclusion, the same physical-chemical principles govern the dynamics of individual machineries and organize the cross-talk between them. The fact that two populations of filaments with different dynamics may be regulated by different proteins is amazing. The possibility cannot be discarded that the machineries that control barbed end growth also control the structure of the filament over some distance (35Orlova A. Prochniewicz E. Egelman E.H. J. Mol. Biol. 1995; 245: 598-607Crossref PubMed Scopus (145) Google Scholar, 36Papp G. Bugyi B. Ujfalusi Z. Barko S. Hild G. Somogyi B. Nyitrai M. Biophys. J. 2006; 91: 2564-2572Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar). The actin filament has a versatile structure, and subtle structural changes induced by barbed end-binding regulators may favor the binding of, for example, distinctive bundling proteins, thus further differentiating the function of actin arrays. This might explain why bundling proteins like fascin (37Vignjevic D. Kojima S. Aratyn Y. Danciu O. Svitkina T. Borisy G.G. J. Cell Biol. 2006; 174: 863-875Crossref PubMed Scopus (358) Google Scholar) or espin (38Sekerkova G. Zheng L. Loomis P.A. Mugnaini E. Bartles J.R. Cell. Mol. Life Sci. 2006; 63: 2329-2341Crossref PubMed Scopus (53) Google Scholar) are found associated with bundles of filaments initiated by different machineries. The directionality of cell protrusions is determined and maintained by dynamic links between the membrane and the actin filaments. Different mechanisms were proposed to link the membrane to growing filaments. The force-velocity relationships predicted by the models derived from these different mechanisms are different. Protrusive force produced by the growth of a branched filament array has been most extensively studied. Activated Arp2/3 complex is proposed to associate with the sides of actin filaments in the lamellipodium to initiate lateral branches. Insertional polymerization would occur in the small interval made available by the fluctuations of the membrane between the barbed ends and the lipid bilayer, and filaments would never attach to the membrane (39Pollard T.D. Annu. Rev. Biophys. Biomol. Struct. 2007; 36: 461-477Crossref Scopus (702) Google Scholar). This model is unable to reasonably account for directional protrusion. The perpetuation of the polarized dendritic pattern during sustained lamellipodium extension requires some kind of cyclic connection (either transient or permanent) between the membrane and the filaments as they grow (40Takenawa T. Suetsugu S. Nat. Rev. Mol. Cell. Biol. 2007; 8: 37-48Crossref PubMed Scopus (681) Google Scholar). Biomimetic assays of propulsion of N-WASP-functionalized microspheres or vesicles have demonstrated that the actin tail is attached to the particle surface (30Marcy Y. Prost J. Carlier M.F. Sykes C. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 5992-5997Crossref PubMed Scopus (202) Google Scholar, 41Gerbal F. Laurent V. Ott A. Carlier M.F. Chaikin P. Prost J. Eur. Biophys. J. 2000; 29: 134-140Crossref PubMed Scopus (81) Google Scholar, 42Trichet L. Campas O. Sykes C. Plastino J. Biophys. J. 2007; 92: 1081-1089Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar), suggesting that similar bonds exist between the filaments and the membrane during protrusion. Lateral mobility of lipids appears strongly hampered at the leading edge by association of filament barbed ends with membrane components (43Weisswange I. Bretschneider T. Anderson K.I. J. Cell Sci. 2005; 118: 4375-4380Crossref PubMed Scopus (35) Google Scholar). What kind of link then could generate filament attachment, yet allow barbed end growth? Are the attachments permanent during filament growth or transient? Are the attachments linked to the filament branching activity of N-WASP, or are they independent of branching? These issues, which are central to physical models of protrusion, are no doubt to be solved only by a thorough analysis of the biochemical steps in the reactions of filament branching and elongation by using solution polymerization kinetics, structural analysis of the complexes involved, and microscopy assays of individual filaments initiated at a surface. Progress is still anticipated from all methods. Polymerization assays in bulk solution so far have provided conflicting results regarding the molecular mechanism of filament branching. Some data have favored side branching of filaments by Arp2/3 complex “activated” by N-WASP (44Amann K.J. Pollard T.D. Nat. Cell Biol. 2001; 3: 306-310Crossref PubMed Scopus (172) Google Scholar). Other data show that branching occurs at and requires free barbed ends (45Pantaloni D. Boujemaa R. Didry D. Gounon P. Carlier M.F. Nat. Cell Biol. 2000; 2: 385-391Crossref PubMed Scopus (201) Google Scholar, 46Boujemaa-Paterski R. Gouin E. Hansen G. Samarin S. Le Clainche C. Didry D. Dehoux P. Cossart P. Kocks C. Carlier M.F. Pantaloni D. Biochemistry. 2001; 40: 11390-11404Crossref PubMed Scopus (99) Google Scholar, 47Falet H. Hoffmeister K.M. Neujahr R. Italiano Jr., J.E. Stossel T.P. Southwick F.S. Hartwig J.H. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 16782-16787Crossref PubMed Scopus (65) Google Scholar). In the branching-activated Arp2/3 complex, the WH2 domain of N-WASP binds one molecule of G-actin, and the CA domain binds one molecule of Arp2/3. The WH2-actin subcomplex, like profilin-actin, can associate productively with barbed ends (48Egile C. Loisel T.P. Laurent V. Li R. Pantaloni D. Sansonetti P.J. Carlier M.F. J. Cell Biol. 1999; 146: 1319-1332Crossref PubMed Scopus (425) Google Scholar). Therefore N-WASP is an immobilized enzyme, either at the membrane or at the surface of Shigella or of beads. Arp2/3 complex, G-actin, and the filament are its substrates (49Pantaloni D. Le Clainche C. Carlier M.F. Science. 2001; 292: 1502-1506Crossref PubMed Scopus (550) Google Scholar). It has been proposed that N-WASP-actin-Arp2/3 complex associates with a filament via productive association of WH2-actin to the barbed end with CA-Arp2/3 initiating a lateral branch. The rate of detachment of the branch junction from N-WASP plays a determining role in propulsion. In motility assays, a pulse of fluorescent Arp2/3 led to initial labeling of N-WASP at the bead surface followed by diffusional penetration of fluorescent Arp2/3 from the bead surface into the actin tail at a rate identical to filament growth (27Wiesner S. Helfer E. Didry D. Ducouret G. Lafuma F. Carlier M.F. Pantaloni D. J. Cell Biol. 2003; 160: 387-398Crossref PubMed Scopus (167) Google Scholar). A model of “tethered ratchet” for actin-based motility was derived in which filaments are transiently attached to the bead surface (50Mogilner A. Oster G. Biophys. J. 2003; 84: 1591-1605Abstract Full Text Full Text PDF PubMed Scopus (392) Google Scholar, 51Mogilner A. Curr. Opin. Cell Biol. 2006; 18: 32-39Crossref PubMed Scopus (147) Google Scholar). Recent data show that the complex of the isolated WH2 domain with ATP-G-actin binds barbed ends and mediates the attachment of filaments at the bead-tail interface (52Co C. Wong D.T. Gierke S. Chang V. Taunton J. Cell. 2007; 128: 901-913Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar). The attachments appear dynamic when N-WASP, containing both WH2 and CA moieties, is able to branch filaments, whereas they remain quasi-permanent when only the WH2-actin moiety associates with barbed ends. It is possible that ATP hydrolysis causes dissociation of WH2 from the barbed end (53Le Clainche C. Pantaloni D. Carlier M.F. Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 6337-6342Crossref PubMed Scopus (68) Google Scholar). The Arp2/3 complex may also play a role in the transient attachment. In support of this view, the segregation of N-WASP at the rear of propelling giant liposomes appears to depend on Arp2/3 complex. 3V. Delatour, G. Romet-Lemonne, D. Didry, D. Pantaloni, E. Helfer, and M.-F. Carlier, submitted. Structural organization of the subunits of Arp2/3 complex at the branch junction is expected to provide mechanistic insight into the branching process. Conflicting orientations of the complex axis have been proposed (54Beltzner C.C. Pollard T.D. J. Mol. Biol. 2004; 336: 551-565Crossref PubMed Scopus (54) Google Scholar, 55Aguda A.H. Burtnick L.D. Robinson R.C. EMBO Rep. 2005; 6: 220-226Crossref PubMed Scopus (30) Google Scholar, 56Egile C. Rouiller I. Xu X.P. Volkmann N. Li R. Hanein D. PLoS Biol. 2005; 3: 30383Crossref Scopus (74) Google Scholar), and no information exists on the position of the WH2-bound actin incorporated in the branch. Biases may occur when computing differences in projection maps of branched filaments containing Arp2/3 associated or not with tags. In summary, the complete kinetic analysis of the elementary reactions involved in filament branching and the characterization of transient complexes in the cycle of filament attachment-branching are important future trends of research. Formins do maintain a permanent attachment to the filament barbed ends during processive growth and truly behave as end-tracking stepping motors (57Dickinson R.B. Caro L. Purich D.L. Biophys. J. 2004; 87: 2838-2854Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar). The molecular mechanism of the processivity of formins and the role of ATP hydrolysis associated with profilin-actin processive assembly are not fully understood. Noninvasive methods have not always been used to show evidence for processivity, and forces that maintain growing filament ends in the vicinity of the immobilized formin may bias the conclusions. Some data indicate that filaments can be assembled processively from ADP-actin as well as from ATP-actin and that profilin is not required (58Kovar D.R. Pollard T.D. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 14725-14730Crossref PubMed Scopus (351) Google Scholar, 59Kovar D.R. Harris E.S. Mahaffy R. Higgs H.N. Pollard T.D. Cell. 2006; 124: 423-435Abstract Full Text Full Text PDF PubMed Scopus (419) Google Scholar, 60Vavylonis D. Kovar D.R. O'Shaughnessy B. Pollard T.D. Mol. Cell. 2006; 21: 455-466Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar). Other data (28Romero S. Le Clainche C. Didry D. Egile C. Pantaloni D. Carlier M.F. Cell. 2004; 119: 419-429Abstract Full Text Full Text PDF PubMed Scopus (427) Google Scholar) indicate that formin uses a major property of profilin, which is to couple ATP hydrolysis to filament growth. The crystal structure of the formin-actin complex (61Otomo T. Tomchick D.R. Otomo C. Panchal S.C. Machius M. Rosen M.K. Nature. 2005; 433: 488-494Crossref PubMed Scopus (272) Google Scholar) shows that formin caps barbed ends and a structural change implying the weakening of a formin-actin contact is required to allow processive assembly. Recent data support the structural model. As long as ATP is not hydrolyzed following association of profilinactin to barbed ends, formin-bound profilin actually caps barbed ends (62Romero S. Didry D. Larquet E. Boisset N. Pantaloni D. Carlier M.F. J. Biol. Chem. 2007; 282: 8435-8445Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar). If ATP hydrolysis is involved in the processivity of formin, the forces developed by processive filament assembly may be much greater than the force of the order of a piconewton, which is produced by a freely fluctuating filament end (63Footer M.J. Kerssemakers J.W. Theriot J.A. Dogterom M. Proc. Natl. Acad. Sci. U. S. A. 2007; 104: 2181-2186Crossref PubMed Scopus (251) Google Scholar). This measurement has not been performed yet. Biochemical and structural analysis of the transient complexes that are formed at the formin-bound barbed end is needed to understand how molecular reactions control macroscopic behavior. Thus far formins and WASP/WAVE-Arp2/3 are the only known machineries that control barbed end nucleation and growth in motile processes. Other actin-binding proteins involved in morphogenetic or developmental processes are emerging. The WH2 domain protein Spire/Eg6 (64Wellington A. Emmons S. James B. Calley J. Grover M. Tolias P. Manseau L. Development (Camb.). 1999; 126: 5267-5274Crossref PubMed Google Scholar, 65Quinlan M.E. Heuser J.E. Kerkhoff E. Mullins R.D. Nature. 2005; 433: 382-388Crossref PubMed Scopus (255) Google Scholar, 66Le Goff C. Laurent V. Le Bon K. Tanguy G. Couturier A. Le Goff X. Le Guellec R. Biol. Cell. 2006; 98: 697-708Crossref PubMed Scopus (14) Google Scholar) plays a role in the definition of the anterior-posterior and dorso-ventral axes in early embryogenesis. Spire nucleates actin filaments in vitro (65Quinlan M.E. Heuser J.E. Kerkhoff E. Mullins R.D. Nature. 2005; 433: 382-388Crossref PubMed Scopus (255) Google Scholar). The phenotypes of mutants of Spire and of the formin Cappuccino are similar and are mimicked by profilin depletion, suggesting that some functional interplay links these three proteins to optimize barbed end growth in processes directing oocyte polarity. Self-assembly of actin filaments is at the heart of morphogenesis and movement in eukaryotic cells. The in vivo analysis of the dynamics of distinct actin arrays, the discovery of protein machineries that couple actin filaments to membrane dynamics and signaling, the development of reconstituted motility assays, and the use of nanophysics methods to measure forces developed by actin have largely contributed to the expansion of the actin field to boundary disciplines. It may not be a dream to imagine that, using reconstituted systems of increasing complexity, the coordinated motility of an artificial cell will eventually be mimicked. The intrinsic properties of actin itself and their potential use by regulators are constantly being unveiled in the light of cellular phenomena. However, in many instances the analysis of molecular events using classical biochemical and structural approaches remains the limiting factor in future progress." @default.
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• W2079597974 date "2007-08-01" @default.
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• W2079597974 title "Control of Actin Assembly Dynamics in Cell Motility" @default.
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• W2079597974 doi "https://doi.org/10.1074/jbc.r700020200" @default.
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