Creating a niche in the cytoskeleton: Actin reorganization by a protein kinase.

O of the most apparent differences between normal cells and their malignantly 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 polymers that assemble into networks and bundles of various kinds to link the cell interior physically with the plasma membrane and endow the cell with viscoelastic properties. The transformation of cytoplasm from a liquid to a solid was observed 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). When something goes wrong in the complex system of control proteins and messengers 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 proteins, cells may migrate and divide inappropriately, because the signals for division or motility cannot be stopped. One such control factor is the protooncogene protein Abl. In addition to its implication in human leukemias, the tyrosine kinase Abl also is an important regulator of the actin system involved in neuronal cell function and early neuronal development (3, 4). Abl is part of the signaling pathways that control the actin cytoskeleton and associates with large actin-containing cellular structures, because it has two actin binding sites at its C-terminal domain (6). Abl’s ability to control cell function requires its actin binding function, presumably because such targeting to the cytoskeleton directs its kinase activity to appropriate targets (6). Most cells, including neurons, also express other proteins similar to Abl including most prominently a protein called the Abl-related gene (Arg; ref. 3). Although Abl and Arg share many features in common, Wang et al. (7) report in this issue of PNAS that Arg contains an additional actin binding site that allows it to reorganize cellular actin and to form actin filament bundles in vitro by a mechanism that does not require its kinase activity. The finding that a member of the Abl tyrosine kinase family can act directly as a cellular actin bundling factor suggests a new mechanism for this class of cell regulatory proteins. The report by Wang et al. highlights several features of the actin cytoskeleton that are central to understanding its biological roles. One challenge to understanding the functions of actin-binding proteins is that there are so many of them, and they can be coexpressed at high levels in most cells, making it difficult to show unambiguously that a particular actincontaining structure has been directed to form by a specific protein. Although there are only a handful of proteins that bind actin monomers, there are over 100 that bind polymeric (F)-actin, and many of them such as like Arg cause F-actin to form bundles (8). The dozens of actin bundling factors fall into the three classes shown in Fig. 1. Some such as -actinin appear to have only one actin binding site but can link two actin filaments together, because they form homodimers with the