Bridging cytoskeletal intersections

Abstract

As we complete the first year of the new millennium, a more integrated view of the cytoskeleton has begun to emerge. While the individual cytoskeletal components retain their identity, these networks rely heavily on one another, employing connections for such diverse functions as cytoskeletal stability, intracellular trasport and trafficking, cytokinesis, cell polarity, and tissue morphogenesis. Key genetic evidence underscores the importance of cytoskeletal connector proteins to cellular architecture and structural integrity in these processes. The recent emergence of linker proteins that bridge between microtubules, actin, and/or IF networks and their accessories, combined with their ancient origins and utmost importance to cell survival and genetic disease, opens a new and fascinating area of cell biology. Perhaps the most surprising finding to emerge in the past few years is that actin-microtubule associations not only serve to pave the intersections between these cytoskeletal roadways but are also required for cytoskeletal dynamics in a highly regulated fashion. Plectin appears to mediate the cytoskeletal reorganizations that take place on activation by the Rho family of small GTPases, while in yeast budding, the actin-microtubule dynamics appear to be mediated by a constellation of smaller proteins, some of which associate predominantly with actin, others of which interact predominantly with microtubules, and still others that associate with small GTPases. A similar process may occur at the leading edge of migrating mammalian cells, where proteins such as ACF7/kakapo may play a key role. An intriguing parallel at these sites is that the actin-microtubule connection appears to be important in regulating the turnover of focal adhesions, necessary for cellular migration. Actinmicrotubule connections are also likely to be pivotal in regulating epithelial polarity and intercellular adhesion, where adherens junction formation, known to involve actin polymerization and reorganization, has recently been found to occur concomitantly with a reorganization in ACF7 localization and a dramatic change in microtubule localization and stabilization. In all of these scenarios, the actin-microtubule crosslinker proteins appear to participate in conducting cytoskeletal dynamics in a directed fashion. In this "music," they can no longer be considered as mere violinists within the orchestra. The cytoskeletal connector proteins are Goliaths in both the protein and the isoform world. It is quite likely that up to 20 or even more splice forms exist for some of the plakin genes, which encode proteins of up to 600 kD in size. Judging from the known partnerships of plectin, the complexities are likely to be enormous, and it is quite likely that only the tip of the iceberg has been met so far. The protein surface of these connector proteins remains largely unexplored, and there is plenty of room for as yet unidentified interacting partners. On the basis of their recent functions in cytoskeletal dynamics and cellular movements, some likely candidates include small GTPases and other cytoskeletal regulatory proteins, as well as the docking sites for a variety of membrane surfaces, including vesicles, mitochondria, golgi, and nuclei. In this regard, we posit that during evolution, genes encoding cytoskeletal linker proteins may have expanded in size and complexity so that they could better coordinate the tailored cytoskeletal dynamics required by specialized cells. Given the enhanced activity and interest in the field of cytoskeletal cross-linking proteins, future research seems certain to continue to reveal new insights into these fascinating regulatory and structural molecules.