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- Title
Localized Ras signaling at the leading edge regulates PI3K, cell polarity, and directional cell movement.
- Authors
Sasaki, Atsuo T.; Chun, Cheryl; Takeda, Kosuke; Firtel, Richard A.
- Abstract
During chemotaxis, receptors and heterotrimetric G-protein subunits are distributed and activated almost uniformly along the cell membrane, whereas P1(3,4,5)P3, the product of phosphatidylinositol 3-kinase (P13K), accumulates locally at the leading edge. The key intermediate event that creates this strong P1(3,4,5)P3 asymmetry remains unclear. Here, we show that Ras is rapidly and transiently activated in response to chemoattractant stimulation and regulates P13K activity. Ras activation occurs at the leading edge of chemotaxing cells, and this local activation is independent of the F-actin cytoskeleton, whereas P13K 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 P13K present on the plasma membrane and other Ras effectors required for chemotaxis. A feedback loop, mediated through localized F-actin polymerization, recruits cytosolic P13K to the leading edge to amplify the signal.
- Subjects
CHEMOTAXIS; G proteins; CELL membranes; CYTOSKELETON; POLYMERIZATION; BIOCHEMISTRY
- Publication
Journal of Cell Biology, 2004, Vol 167, Issue 3, p505
- ISSN
0021-9525
- Publication type
Article
- DOI
10.1083/jcb.200406177