A great deal is known about the signaling molecules that invoke the motile response, but the mechanism by which this response becomes spatially localized within the cell to determine the site where motile structures, such as lamel-lipodia and filopodia, are generated is less well characterized. Future work in this area will rely on advances in imaging technology and new probes to permit the real-time visualization of activated states of signaling molecules with improved spatial resolution. As directional migration also requires the integration of microenvironmental information, including ECM composition, topography, and mechanics, systems that maintain or reproduce these parameters in vitro will greatly facilitate future study of migration within the physical and spatial context in which it normally proceeds.
Cytoskeleton: the network of protein filaments in the cytoplasm of eukaryotic cells that gives the cell shape, guides intracellular transport, and coordinates its movement and growth. Its most abundant components are actin microfilaments, microtubules, and intermediate filaments.
Focal adhesion: the localized, spot weld-like attachment site between the cytoskeleton and extracellular matrix that anchors the cell to its adhesive substrate. Attachment is mediated by tightly clustered, transmembrane integrin receptors and a variety of structural and signaling protein components.
Lamellipodia: flat, sheet-like, membrane protrusions supported by an intracellular meshwork of actin filaments that are extended outward at the leading edge of a migrating cell.
Etienne-Manneville, S., and Hall, A. (2002). Rho GTPases in cell biology. Nature 420, 629-635. A comprehensive overview of the role of the small GTPases in a variety of cellular processes including movement, proliferation, morphology and contraction, phagocytosis, and secretion. Geiger, B., Bershadsky, A., Pankov, R., and Yamada, K. M. (2001). Transmembrane crosstalk between the extracellular matrix-cytoskeleton crosstalk. Nat. Rev. Mol. Cell. Biol. 2, 793-805. An in-depth treatment of the molecular and mechanical signaling events that occur at sites of cell-matrix adhesion, with a special emphasis on the importance of local physical forces. Ingber, D. E. (2002). Mechanical signaling and the cellular response to extracellular matrix in angiogenesis and cardiovascular physiology. Circ. Res. 91, 877-887. Kaverina, I., Krylyshkina, O., and Small, J. V. (2002). Regulation of substrate adhesion dynamics during cell motility. Intl. J. Biochem. Cell. Biol. 34(7), 746-761. Sheetz, M. P., Felsenfeld, D. P., and Galbraith, C. G. (1998). Cell migration: Regulation of force on extracellular-matrix-integrin complexes. Trends Cell. Biol. 8, 51-54. Stossel, T. P., Hartwig, J. H., Janmey, P. A., and Kwiatkowski, D. J. (1999). Cell crawling two decades after Abercrombie. Biochem. Soc. Symp. 65, 267-280.
Webb, D. J., Parsons, J. T., and Horwitz, A. F. (2002). Adhesion assembly, disassembly and turnover in migrating cells—over and over and over again. Nat. Cell Biol. 4, E97-E100. The authors review the coordination of focal adhesion assembly, disassembly and turnover in migrating cells, as well as recent advances in imaging technology that have improved the characterization of these complexes.
Amy Brock, a graduate student in the Biomedical and Biosciences (BBS) program at Harvard University, is completing her Ph.D. dissertation on cell motility in the laboratory of Dr. Ingber.
Dr. Ingber has made significant contributions to the fields of angiogen-esis, matrix biology, and mechanoregulation, and cellular engineering. He is the Judah Folkman Professor of Vascular Biology in the department of Pathology at Harvard Medical School, and Senior Investigator in the Vascular Biology Program at Children's Hospital in Boston, Massachusetts. His work is supported by grants from the NIH. NASA, DARPA, ARO and DOD.
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