CELL MIGRATION Traveling a Hard Road

Spreading or migrating fibroblasts explore their environment by extending lamellipodia, membrane extensions that are driven by actin polymerization. They sense the rigidity of the extracellular matrix (ECM) and migrate toward more rigid regions. Giannone et al. used total internal reflection fluorescence and differential interference contrast microscopy to investigate how cultured mouse embryo fibroblasts transduce the rigidity of the ECM into a contractile signal to direct migration. Lamellipodial extensions in spreading and migrating cells grown on fibronectin showed periodic localized contractions. These contractions, which depended on growth on a rigid substrate coated with fibronectin (which binds integrins), triggered integrin clustering and generated rearward movement of actin filaments that transported proteins including -actinin and myosin light-chain kinase (whose activity was required for contractions) from the leading edge of the lamellipodium to its base. The period of the contractions coincided with the time required for actin to cross the lamellipodium and was proportionally affected by manipulations that altered lamellipodial width. Cells transfected with constitutively activated Rac had wider lamellipodia and an increased period between contractions, whereas cells transfected with a constitutively active cofilin mutant or with a dominant-negative LIMK (LIM kinase) had narrower lamellipodia and a decreased period. The authors proposed a model in which contractile forces applied to a rigid integrin-binding substrate stimulate the generation of an actin-bound signaling complex that is carried by actin from the tip of the lamellipodium to its base and thereby initiates the next contraction-extension cycle. Ridley discusses this research in a Preview.

G. Giannone, B. J. Dubin-Thaler, H.-G. Döbereiner, N. Kieffer, A. R. Bresnick, M. P. Sheetz, Periodic lamellipodial contractions correlate with rearward actin waves. Cell 116, 431-443 (2004). [Online Journal]

A. J. Ridley, Pulling back to move forward. Cell 116, 357-358 (2004). [Online Journal]