G protein-independent Ras/PI3K/F-actin circuit regulates basic cell motility.
Phosphoinositide 3-kinase (PI3K)gamma and Dictyostelium PI3K are activated via G protein-coupled receptors through binding to the Gbetagamma subunit and Ras. However, the mechanistic role(s) of Gbetagamma 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 gbeta 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)P(3). 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.
Sasaki
Atsuo T
AT
Section of Cell and Developmental Biology, Division of Biological Sciences, and Center for Molecular Genetics, University of California, San Diego, La Jolla, CA 92093, USA.
Janetopoulos
Chris
C
Lee
Susan
S
Charest
Pascale G
PG
Takeda
Kosuke
K
Sundheimer
Lauren W
LW
Meili
Ruedi
R
Devreotes
Peter N
PN
Firtel
Richard A
RA
D000199:Actins / Q000378:metabolism*; D000818:Animals; D002465:Cell Movement / Q000502:physiology*; D004023:Dictyostelium / Q000166:cytology / Q000378:metabolism; D004789:Enzyme Activation; D025461:Feedback, Physiological / Q000502:physiology; D019204:GTP-Binding Proteins / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D018129:Phosphatidylinositol Phosphates / Q000096:biosynthesis; D018631:ras Proteins / Q000378:metabolism*
D000199:Actins; D018129:Phosphatidylinositol Phosphates; C060974:phosphatidylinositol 3,4,5-triphosphate; D019869:Phosphatidylinositol 3-Kinases; D051059:PTEN Phosphohydrolase; D019204:GTP-Binding Proteins; D018631:ras Proteins