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Published online
doi:10.1083/jcb.200611138
The Journal of Cell Biology, Vol. 178, No. 2, 185-191
The Rockefeller University Press, 0021-9525 $30.00
© Sasaki et al.
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G protein–independent Ras/PI3K/F-actin circuit regulates basic cell motility



Atsuo T. Sasaki1,2, Chris Janetopoulos3,4, Susan Lee1, Pascale G. Charest1, Kosuke Takeda1, Lauren W. Sundheimer1, Ruedi Meili1, Peter N. Devreotes4, and Richard A. Firtel1

1 Section of Cell and Developmental Biology, Division of Biological Sciences, and Center for Molecular Genetics, University of California, San Diego, La Jolla, CA 92093
2 Department of Systems Biology and Division of Signal Transduction, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115
3 Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205
4 Department of Biological Sciences, Vanderbilt University, Nashville, TN 37235

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

Phosphoinositide 3-kinase (PI3K){gamma} and Dictyostelium PI3K are activated via G protein–coupled receptors through binding to the Gß{gamma} subunit and Ras. However, the mechanistic role(s) of Gß{gamma} and Ras in PI3K activation remains elusive. Furthermore, the dynamics and function of PI3K activation in the absence of extracellular stimuli have not been fully investigated. We report that gß null cells display PI3K and Ras activation, as well as the reciprocal localization of PI3K and PTEN, which lead to local accumulation of PI(3,4,5)P3. Simultaneous imaging analysis reveals that in the absence of extracellular stimuli, autonomous PI3K and Ras activation occur, concurrently, at the same sites where F-actin projection emerges. The loss of PI3K binding to Ras–guanosine triphosphate abolishes this PI3K activation, whereas prevention of PI3K activity suppresses autonomous Ras activation, suggesting that PI3K and Ras form a positive feedback circuit. This circuit is associated with both random cell migration and cytokinesis and may have initially evolved to control stochastic changes in the cytoskeleton.

Abbreviations used in this paper: LatB, Latrunculin B; PHcrac, PH domain of CRAC; PI3K, phosphoinositide 3-kinase; PKB, protein kinase B; RBD, Ras binding domain; TOR, target of rapamycin; TORC, TOR complex.


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