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Actin Reorganization by a Protein Kinase

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Actin Reorganization by a Protein Kinase Commentary Creating a niche in the cytoskeleton: Actin reorganization by a protein kinase Paul A. Janmey* Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, PA 19104 ne of the most apparent differences Obetween normal cells and their ma- lignantly transformed counterparts and between immature and fully differentiated cells is the shape of the cells (1). Cell morphology is controlled largely by the structure of the cytoskeleton, a system of three distinct types of filamentous poly- mers that assemble into networks and bundles of various kinds to link the cell interior physically with the plasma mem- brane and endow the cell with viscoelastic properties. The transformation of cyto- plasm from a liquid to a solid was ob- served by early microscopists to be tightly associated with the cells’ ability to move, and this sol-to-gel transition is now known to be caused by changes in the state of polymerization and organization of the protein actin, one of the three types of filaments comprising the cytoskeleton (2). COMMENTARY When something goes wrong in the com- plex system of control proteins and mes- sengers that signals for changes in the actin system, as can happen with genetic mutations or by the insertion of viral genes coding for maliciously altered control pro- teins, cells may migrate and divide inap- propriately, because the signals for divi- sion or motility cannot be stopped. One such control factor is the protooncogene Fig. 1. Three types of proteins that form bundles of actin filaments. In addition to specific protein– protein Abl. In addition to its implication protein bonds formed by the Top and Middle examples, release of divalent and other small ions (small blue in human leukemias, the tyrosine kinase dots) by multivalent cations with surfaces compatible with the actin filament contour also contribute to Abl also is an important regulator of the stabilization of actin bundles. the actin system involved in neuronal cell function and early neuronal develop- ment (3, 4). additional actin binding site that allows it unambiguously that a particular actin- Abl is part of the signaling pathways to reorganize cellular actin and to form containing structure has been directed to that control the actin cytoskeleton and actin filament bundles in vitro by a mech- form by a specific protein. Although there associates with large actin-containing cel- anism that does not require its kinase are only a handful of proteins that bind lular structures, because it has two actin activity. The finding that a member of the actin monomers, there are over 100 that binding sites at its C-terminal domain (6). Abl tyrosine kinase family can act directly bind polymeric (F)-actin, and many of Abl’s ability to control cell function re- as a cellular actin bundling factor suggests them such as like Arg cause F-actin to quires its actin binding function, presum- a new mechanism for this class of cell form bundles (8). The dozens of actin ably because such targeting to the cy- regulatory proteins. bundling factors fall into the three classes toskeleton directs its kinase activity to The report by Wang et al. highlights shown in Fig. 1. Some such as ␣-actinin appropriate targets (6). Most cells, includ- several features of the actin cytoskeleton appear to have only one actin binding site ing neurons, also express other proteins that are central to understanding its bio- but can link two actin filaments together, similar to Abl including most prominently logical roles. One challenge to under- because they form homodimers with the a protein called the Abl-related gene (Arg; standing the functions of actin-binding ref. 3). Although Abl and Arg share many proteins is that there are so many of them, features in common, Wang et al. (7) report and they can be coexpressed at high levels See companion article on page 14865. in this issue of PNAS that Arg contains an in most cells, making it difficult to show *E-mail: [email protected]. www.pnas.org͞cgi͞doi͞10.1073͞pnas.011601598 PNAS ͉ December 18, 2001 ͉ vol. 98 ͉ no. 26 ͉ 14745–14747 Downloaded by guest on September 30, 2021 actin binding sites exposed on opposite binding site in Arg resides within a cat- properties, because remodeling the corti- faces of the dimer. A common actin bind- ionic region of the protein. cal actin network can both generate inter- ing motif, present in several bundling fac- In principle the actin bundles formed by nal forces and resist those imposed from tors, is formed by two repeats of a calpo- the first two classes of proteins should outside the cell. This is a difficult problem, nin homology domain, also present in Arg. have the filaments arranged in a specific in part because there is no complete the- Other actin bundling factors are mono- polarity. Actin filaments are asymmetric oretical model for the elasticity of polymer meric polypeptides, but they possess two both in structure and dynamics due to the networks formed by the open meshworks distinct actin binding sites, each of which asymmetric structure of the monomers of relatively stiff polymers as are found in binds a separate actin filament. Arg falls and the hydrolysis of ATP that follows the the cytoskeleton. Unlike most synthetic into this class, although it also may self- addition of monomers to the faster- gels that are formed by highly flexible assemble into dimers and higher oli- growing end of the filament (11). There- coils where network elasticity can be pre- dicted accurately from the polymer con- gomers. However, many proteins reported fore, the polarity of the filaments in the centration and the density of crosslinks to bundle actin in vitro have no obvious bundles will, for example, depend on between the strands, the situation with sequence homology to other actin binding whether the homodimeric crosslinkers are arranged in parallel or antiparallel ar- F-actin is different. The fact that the poly- sites but have in common a large positive mers in the network are so stiff that on the surface charge that interacts strongly with rangements and on the spatial relationship of the two classes of actin binding sites in length scale of the distance between fila- the highly anionic actin filament. The first proteins such as Arg. Experimentally, a ment contacts (the mesh size) they are two classes of actin bundlers rely on highly mixed polarity of filaments is found usu- approximately straight makes the macro- specific protein–protein binding inter- ally in actin bundles formed in vitro, and scopic stiffness dependent on not only the faces such as those characteristic of bind- even in the cell actin-containing bundles number of crosslinks but also their geom- ing between two protein monomers (9). that look similar in light micrographs dis- etry and flexibility. Therefore, it is not The third type of interaction, while not play a range of polarities when examined easy to predict whether areas of the actin- excluding docking of two complementary by electron microscopy (12). Such a mixed rich cell cortex at which Arg has induced protein interfaces, does not require it, and polarity may reflect either the flexibility actin to bundle become stiffer. The me- the binding energy depends on the en- of bundling proteins or the contribution of chanical effect will depend on factors such tropy gained when small ions, mostly di- electrostatic mechanisms that are only as the kinds of crosslinks already formed 2ϩ valent Mg , are released as the higher weakly affected by the polar nature of the by other proteins and the total polymer valence polycation binds the side of the filament. The polarity of the bundles made concentration. filament (10). This type of bundling is by Arg has not been determined yet, but Proteins such as Arg, which can link closely analogous to the polyelectrolyte this feature would affect the possible func- actin filaments together, do so in a variety effects driving condensation of DNA by tions of such bundles for allowing contrac- of geometries as shown in Fig. 2. The first multivalent counterions and is a topic of tion or other directed motions. actin crosslinker reported, filamin A, is a much current theoretical work. Of course A next step in understanding the cellu- large homodimer with actin binding re- the two kinds of bundling mechanisms are lar function of Arg-mediated actin re- gions at the ends of two 90-nm-long flex- not mutually exclusive, and it is possibly structuring is to relate the morphology of ible arms (13). The crosslinks it forms tend to have angles distributed around 90°, and relevant that the newly reported actin actin-rich networks to their mechanical this finding has led to the idea that filamin A is especially potent at forming orthog- onal networks that maximize elasticity at a minimum of polymer mass. A second class of crosslinkers is exemplified by the Arp2͞3 complex, a relatively compact multisubunit complex that drives the for- mation of dendritic structures at which filaments are more prone to branch at angles centered around 70° than they are to form uniform three-dimensional net- works (14). These types of crosslinkers have distinct mechanical effects in cells, as shown in a recent report that the flat lamellae required for motility of mela- noma cells requires the crosslinking by filamin A, a function that cannot be taken over by Arp2͞3 (15). The effect of actin bundlers on the elasticity of actin is likely to be more subtle than the effects of linkers that form more open networks. In the absence of other crosslinks, the formation of actin bundles has only a small effect on elasticity, based for example on the smooth scaling of elastic modulus with concentration as ac- Fig.
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