ReviewActin machinery: pushing the envelope
Introduction
Progress in understanding complex phenomena has often been achieved by reconstituting elements of a system to display some functional capacity. The movement of test beads powered by the molecular motors kinesin or dynein on microtubules and myosin on actin filaments are classic examples. The protrusive activities of a cell’s leading edge, however, have posed a more formidable challenge, presumably because of the greater complexity of the processes involved.
One promising approach to this problem has been developed from the ‘rocket-like’ motion of the microbial pathogen, Listeria, in the cytoplasm of infected cells, which was discovered by Tilney and Portnoy [1] to involve a subversion of the cell’s actin machinery to aid the microbe’s attempt to infect neighboring cells without subjecting itself to immune surveillance. Similar rocketing movements have since been reported not only for a variety of bacteria and viruses (see 2, 3 for reviews), but also for endosomes [4•], external particles [5] and unidentified endogenous vesicles and structures 6, 7•, suggesting that the rocketing motion reflects a normal cytoplasmic process. The finding that cell-free extracts can support bacterial motion [8] has allowed the functional assay of the molecular components involved in the rocketing system. In this review, we attempt to synthesize the results of the past year, as well as earlier contributions, and to provide a coherent overview of the molecular basis of protrusive motility.
Section snippets
The molecular players
Through a combination of biochemical, genetic and cell biological approaches, an expanding cast of characters has been identified to be involved in actin filament nucleation, including components of a signaling cascade leading from small GTPases through members of the WASP family to the Arp2/3 complex 9••, 10••, 11••, 12••, 13•• (reviewed by Mullins (pp 91–96) in this issue). Supporting players are molecules that modulate the dynamic properties of actin filaments by coupling them to the surface
The array treadmilling model
The funneling condition, however, cannot be maintained without auxiallary hypotheses. The few growing filaments will elongate at the expense of the depolymerizing capped filaments, which will ultimately disappear. Thus, the true steady state for funneling requires the continuous production of new filaments. This could be achieved by severing old filaments, as proposed by the ‘treadsevering’ model [66]. In this model, as the privileged growing filaments elongate, their distal ends are severed,
Conclusions
Many pieces in the puzzle of motility have been fitted together in the past year, and now seems to be a good time to step back and look at the picture. We have attempted to do so in this review. Although the puzzle remains incomplete and some of our suggestions may be wrong in detail, the benefit of an overview is that it provides a conceptual framework in which to evaluate the pieces yet to come.
Although this account has focused exclusively on the mechanism of actin polymerization-driven
Acknowledgements
We thank Tom Pollard, Vic Small, Laura Machesky, Marie-France Carlier and John Cooper for stimulating discussions and John Peloquin and Lisa Cameron for a critical reading of the manuscript. This work was supported by a grant from the American Cancer Society and by NIH grant GM 25062.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
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