Department of Cell Biology, University of Virginia, Charlottesville, VA 22908, USA
* Author for correspondence (e-mail: horwitz{at}virginia.edu)
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Introduction |
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The past 15 years have witnessed enormous advances in our understanding of the complexities and subtleties underlying the regulation of cell migration. This now includes the generation of temporal-spatial cues that result in cell adhesion, asymmetric polarization and individual and layered cell motility. A key discovery was the involvement of the actin cytoskeleton and its fine regulation in the maintenance of cellular integrity and the dynamic responses that drive migration. Such regulation requires multi-nodal control to ensure coordinated migration, which the organism can turn off and on depending on the requirements of a given situation. It also allows highly specialized modes of cell migration in different tissues. However, the overall process exhibits so many regulatory steps that any deficiency, either ectopic activation or hijacking by pathogens, can impair or enhance cell migration and have catastrophic consequences that include vascular disease, chronic inflammation, cancer, mental retardation, and virus and bacterial infection and dissemination.
Thus, a thorough understanding of the mechanisms underlying cell migration will facilitate development of therapies for the treatment of migration-related disorders.
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The model shown represents a polarized cell that has distinct leading and trailing edges. This is a common feature of both fibroblastic and amoeboid motility. The leading edge points in the direction of movement and is driven by actin-polymerization-mediated protrusion. Red spots represent points of interaction of the cell with the substrate. The larger spots represent stable adhesions (a classic feature of fibroblastic motility that is absent in faster-moving cells), and smaller spots at the periphery represent nascent adhesion complexes. Colour gradients within the spot represent the dynamics of adhesion turnover (at the front) and disassembly (at the back). Other structures depicted include the nucleus (light brown), the Golgi apparatus (dark brown) and the microtubule-organizing center (MTOC), from which the microtubule network (grey) radiates, as well as an actin-rich lamellipodium at the front. Insets show specific features within the migrating cell, such as the regulation of actin polymerization at the protrusion sites, adhesion dynamics, MTOC- and nucleus-based cell polarity and tail retraction, as well as a node map depicting some of the key molecules involved in regulation of the process.
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Actin polymerization |
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Unlike the Arp2/3 complex, formins bind to the barbed end of actin filaments and promote actin growth in a linear fashion. Formins are regulated by small GTPases (RhoA and Cdc42 for mDia1 and mDia2, respectively) and require interaction with G-actin-bound profilin to promote actin polymerization (Watanabe and Higashida, 2004). Profilin is also required for Ena/VASP-mediated actin polymerization at the barbed end, although its mode of action seems more related to anti-capping activity (Krause et al., 2003
). Both profilin and thymosin ß4 are G-actin-binding proteins. Whereas profilin can bind to different actin nucleators, thymosin ß4 cannot, and thus is regarded as a G-actin reservoir that can shuttle G-actin to profilin to promote actin filament growth (dos Remedios et al., 2003
).
Actomyosin-based contraction is controlled by the small Rho GTPases Cdc42, Rac and RhoA (Jaffe and Hall, 2005). Regulation by these GTPases is antagonistic. RhoA activates Rho-kinase (also called ROCK), which in turn phosphorylates and inactivates the phosphatase that dephosphorylates MLC, resulting in increased contractility. A similar mechanism has been shown for Cdc42, acting through MRCK. Conversely, Rac activates PAK, which phosphorylates and inactivates MLC kinase, thus leading to decreased contractility and promoting spreading. However, PAK may also phosphorylate MLC directly, which would increase contractility. The predominance of the first or the second mechanism seems to be regulated by spatial considerations or differential regulation of PAK activity. In addition, PAK also regulates cell polarity, through the activation of a PIX/PAK complex that is targeted to the leading edge during G-protein-coupled receptor-dependent migration (Li et al., 2003
). Finally, PAK regulates microtubules through stathmin phosphorylation, which results in decreased microtubule catastrophe (Wittmann et al., 2004
).
Capping proteins such as gelsolin block actin polymerization at the barbed end and are mainly regulated by phosphoinositides (Zigmond, 2004). Finally, cofilin severs actin filaments, and its activity is regulated by phosphorylation induced by LIMK, which is in turn regulated by PAK- or Rho-kinase-mediated Ser/Thr phosphorylation (Maciver and Hussey, 2002
).
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Adhesion dynamics |
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The molecular mechanisms underlying the `decision' of an adhesion to mature or turnover are unclear. Rho GTPases are critical effectors in this process. They in turn are controlled by signals emanating from adhesion-related signalling modules, such as a multi-protein complex that includes FAK, Src, paxillin, Crk, CAS, PAK and GIT. Cleavage of adhesion components by proteases, such as calpain, also regulates disassembly at the front, although its role has been established more clearly in rear adhesions during detachment (Franco et al., 2004). Finally, relaxation signals emanating from the tips of microtubules that target adhesions, probably involving dynamin, are also implicated in adhesion disassembly (Ezratty et al., 2005
).
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MTOC reorientation and nuclear positioning |
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Trailing edge retraction |
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Acknowledgments |
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References |
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