Piecing Together Actin Assembly

For this article, Eugene Russo interviewed Marc Kirschner, Carl W. Walter professor of cell biology at Harvard Medical School. Data from the Web of Science (ISI, Philadelphia) show that Hot Papers are cited 50 to 100 times more often than the average paper of the same type and age. R. Rohatgi, L. Ma, H. Miki, M. Lopez, T. Kirchhausen, T. Takenawa, M.W. Kirschner, "The interaction between N-WASP and the Arp2/3 complex links Cdc42-dependent signals to actin assembly," Cell, 97:221-31, April 16, 1999. (Cited in 137 papers) Cells rely on their cytoskeletons to do just about everything--from migration to differentiation. Cell biologists must therefore understand the role of actin, a major cytoskeleton component, in order to comprehend the fundamental mechanisms of cellular responses. By the late 1990s, cell biologists had identified several molecules involved in actin assembly, including Cdc42, Neuronal Wiskott-Aldrich Syndrome protein (N-WASP), phosphatidylinositol (4,5) bisphosphate (PI(4,5)P2), and an actin nucleating complex called Arp2/3. But the authors of this paper were among the first to piece together the functions of the different players into a coherent pathway. Photo: ©2000 Stu RosnerMarc Kirschner"There were no components of this paper that were previously unknown," says Marc W. Kirschner, Carl W. Walter professor of cell biology at Harvard Medical School. "We didn't discover any new molecules." His group, however, did show how Cdc42 and PI(4,5)P2, which facilitate signals across the cell membrane, interact with N-WASP, an integrator of this signal, and with the Arp2/3 complex, to induce actin assembly. Using Xenopus egg extracts in vitro, Kirschner and his colleagues reproduced the connections between these molecules with purified components, clearly illustrating their direct linkage biochemically. Their model suggests that Cdc42 and PI(4,5)P2 activate N-WASP, which terminates the signal by folding back on, and inhibiting, itself. "It's sort of a switch," explains Kirschner. "It can open up just like a jackknife and reveal the site that activates actin polymerization." According to Kirschner, the idea of such a self-inhibiting complex came from the work of a group at the University of Tokyo.1 Two recent papers in the Journal of Cell Biology confirm this mechanism--one on N-WASP from Kirschner's lab2 and another on a closely related protein called WASP from Thomas Pollard's lab at The Salk Institute for Biological Studies in La Jolla, Calif.3 Kirschner suggests that the 1999 paper is one of the most satisfying examples of linking a complex cellular process like actin polymerization with signal transduction. "I think there are a lot of people trying to do that in many other systems," he says, adding that such research generally hasn't reached the level of explanation of the N-WASP system. Kirschner's lab is currently studying both the role of Cdc42 and PI(4,5)P2, and the role of other molecules that interact, localize, or regulate N-WASP--other molecules, says Kirschner, that can "flip open that jackknife." They include the N-WASP binding proteins Nck and WIP (WASP-Interacting Protein). In addition, they're studying the regulation of a WASP-related protein called Scar, which was first shown to enhance actin polymerization via the Arp2/3 complex in a highly-cited 1999 paper by Pollard's group.4 "That's [one] thing that's complicated about actin," comments Kirschner. "It's not just making it. It's making it at the right place, the right time, under the right circumstances." Eugene Russo can be contacted at erusso@the-scientist.com References 1. H. Miki H et al., "Induction of filopodium formation by a WASP-related actin-depolymerizing protein N-WASP," Nature, 391:93-6, 1998. 2. H.N. Higgs, T.D. Pollard, "Activation by Cdc42 and PIP2 of Wiskott-Aldrich syndrome protein (WASp) stimulates actin nucleation by Arp2/3 complex," Journal of Cell Biology, 150: 1311-20, September 18, 2000. 3. R. Rohatgi et al., "Mechanism of N-WASP activation by CDC42 and phosphatidylinositol 4,5-bisphosphate," Journal of Cell Biology, 150:1299-1309, September 18, 2000. 4. L.M. Machesky et al., "Scar, a WASp-related protein, activates nucleation of actin filaments by the Arp2/3 complex," Proceedings of the National Academy of Sciences, 96:3739-44, 1999.

Piecing Together Actin Assembly

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