TY - JOUR
T1 - Cofilin Activity Downstream of Pak1 Regulates Cell Protrusion Efficiency by Organizing Lamellipodium and Lamella Actin Networks
AU - Delorme, Violaine
AU - Machacek, Matthias
AU - DerMardirossian, Céline
AU - Anderson, Karen L.
AU - Wittmann, Torsten
AU - Hanein, Dorit
AU - Waterman-Storer, Clare
AU - Danuser, Gaudenz
AU - Bokoch, Gary M.
N1 - Funding Information:
We acknowledge the excellent technical assistance of B. Fowler. We thank J. Birkenfeld for cofilin constructs, M. Welch for antibodies to Arp3, J. Bamburg for antibodies to phosphorylated cofilin, B. Shin for help with microscopy, and J. Lim for images of PtK1 with actin alone. This work was supported by National Institutes of Health (NIH) grants GM39434 and GM44428 to G.M.B, grant GM67230 to C.W.-S. and G.D., and Cell Migration Consortium U54 grant GM64346 to G.D. V.D. is a fellow of the American Heart Association (Western States Affiliate), and M.M. is a Swiss National Science Foundation fellow. The electron microscopy portion of the work was supported by NIH Cell Migration Consortium U54 GM64346 to D.H.
PY - 2007/11/6
Y1 - 2007/11/6
N2 - Protrusion of the leading edge of migrating epithelial cells requires precise regulation of two actin filament (F-actin) networks, the lamellipodium and the lamella. Cofilin is a downstream target of Rho GTPase signaling that promotes F-actin cycling through its F-actin-nucleating, -severing, and -depolymerizing activity. However, its function in modulating lamellipodium and lamella dynamics, and the implications of these dynamics for protrusion efficiency, has been unclear. Using quantitative fluorescent speckle microscopy, immunofluorescence, and electron microscopy, we establish that the Rac1/Pak1/LIMK1 signaling pathway controls cofilin activity within the lamellipodium. Enhancement of cofilin activity accelerates F-actin turnover and retrograde flow, resulting in widening of the lamellipodium. This is accompanied by increased spatial overlap of the lamellipodium and lamella networks and reduced cell-edge protrusion efficiency. We propose that cofilin functions as a regulator of cell protrusion by modulating the spatial interaction of the lamellipodium and lamella in response to upstream signals.
AB - Protrusion of the leading edge of migrating epithelial cells requires precise regulation of two actin filament (F-actin) networks, the lamellipodium and the lamella. Cofilin is a downstream target of Rho GTPase signaling that promotes F-actin cycling through its F-actin-nucleating, -severing, and -depolymerizing activity. However, its function in modulating lamellipodium and lamella dynamics, and the implications of these dynamics for protrusion efficiency, has been unclear. Using quantitative fluorescent speckle microscopy, immunofluorescence, and electron microscopy, we establish that the Rac1/Pak1/LIMK1 signaling pathway controls cofilin activity within the lamellipodium. Enhancement of cofilin activity accelerates F-actin turnover and retrograde flow, resulting in widening of the lamellipodium. This is accompanied by increased spatial overlap of the lamellipodium and lamella networks and reduced cell-edge protrusion efficiency. We propose that cofilin functions as a regulator of cell protrusion by modulating the spatial interaction of the lamellipodium and lamella in response to upstream signals.
KW - CELLBIO
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U2 - 10.1016/j.devcel.2007.08.011
DO - 10.1016/j.devcel.2007.08.011
M3 - Article
C2 - 17981134
AN - SCOPUS:35548986594
SN - 1534-5807
VL - 13
SP - 646
EP - 662
JO - Developmental cell
JF - Developmental cell
IS - 5
ER -