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Published 8 November 2004. doi:10.1083/jcb.200406177
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 167, Number 3, 505-518
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Article

 Localized Ras signaling at the leading edge regulates PI3K, cell polarity, and directional cell movement

Atsuo T. Sasaki, Cheryl Chun, Kosuke Takeda, and Richard A. Firtel

Section of Cell and Developmental Biology, Division of Biological Sciences, and Center for Molecular Genetics, University of California, San Diego, La Jolla, CA 92093

Correspondence to R.A. Firtel: rafirtel{at}ucsd.edu

During chemotaxis, receptors and heterotrimeric G-protein subunits are distributed and activated almost uniformly along the cell membrane, whereas PI(3,4,5)P3, the product of phosphatidylinositol 3-kinase (PI3K), accumulates locally at the leading edge. The key intermediate event that creates this strong PI(3,4,5)P3 asymmetry remains unclear. Here, we show that Ras is rapidly and transiently activated in response to chemoattractant stimulation and regulates PI3K activity. Ras activation occurs at the leading edge of chemotaxing cells, and this local activation is independent of the F-actin cytoskeleton, whereas PI3K localization is dependent on F-actin polymerization. Inhibition of Ras results in severe defects in directional movement, indicating that Ras is an upstream component of the cell's compass. These results support a mechanism by which localized Ras activation mediates leading edge formation through activation of basal PI3K present on the plasma membrane and other Ras effectors required for chemotaxis. A feedback loop, mediated through localized F-actin polymerization, recruits cytosolic PI3K to the leading edge to amplify the signal.

Abbreviations used in this paper: GEF, GDP/GTP exchange factor; LatA, latrunculin A; myr, myristoyl; PI3K, phosphatidylinositol 3-kinase.


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