Last week’s Cell also had an article on Spatiotemporal Feedback between Actomyosin and Focal-Adhesion Systems Optimizes Rapid Cell Migration, to which two of the giants of cell migration research (Martin Schwartz and Alan Horwitz) wrote a commentary that I can’t hope to top. Hence, consider everything below, both empasized in blockquotes and not, as from Schwartz and Horwitz.
Cell migration is fastest when the strength of the adhesion between the cell and the substrate is neither too strong nor too weak. In this issue of Cell, reveal how adhesion and cytoskeletal dynamics are integrated to optimize migration speed.
Gupton and Waterman-Storer (2006) interpret these data in terms of a beautifully simple mechanical model. The model drwas on previous work showing that rates of both adhesion assembly and disassembly are dependent on myosin-generated tension. Their key observation is that myosin phosphorylation increased only slightly from low to high fibronectin, whereas adhesion number and total area increased more dramatically. Thus, force per focal adhesion should be highest on low fibronectin and should decrease as fibronectin increases. They propose that on low fibronectin, the high force/adhesion ratio mediates the high rates of both adhesion assembly and disassembly; on high fibronectin, lower force/adhesionratios lead to slower assembly and turnover. These adhesion dynamics consequently mediate effects on actin dynamics and cell migration. The differential effects of myosin activation versus inhibition provide elegant support for the model.
The authors recognized that integrin signaling and regulatory pathways such as Rho family GTPases are likely also involved. Though not discussed, their data may fit well with available information on the activation of Rac, Rho, and Cdc42 by adhesion. All of these results can be reconciled by postulating that Rac activation is proportional to the total rate of new integrin ligation (binding to fibronectin) – that is, proportional to the number of small, dynamic adhesions within the cell.
This study has revealed some major insights and represents a large step in our understanding of cell migration. However, there are more chapters to be written. The actin-integrin linkage is a critical site that integrates adhesion, signaling, and protrusion; its regulation remains to be parsed. The “clutch” mechanisms by which myosin II-mediated tension regulates both adhesion assembly and disassembly may depend on the state of the adhesion, which remains to be defined. Finally, some highly motile cells do not show the highly organized adhesions and actin filaments seen in fibroblasts and epithelial cells migrating on fibronectin yet can show optima in migration speed that are dependent on substrate concentration. The fators that produce this relationship in these cells remain to be established.
- Integrating Adhesion, Protrusion, and Contraction during Cell Migration. Schwartz MA, Horwitz AR. Cell. 2006 Jun 30; 125(7):1223-5. Pubmed.
- Spatiotemporal Feedback between Actomyosin and Focal-Adhesion Systems Optimizes Rapid Cell Migration. Gupton SL, Waterman-Storer CM. Cell. 2006 Jun 30; 125(7):1361-74. Pubmed.