Two phases of actin polymerization display different dependencies on PI(3,4,5)P3 accumulation and have unique roles during chemotaxis.
The directional movement of cells in chemoattractant gradients requires sophisticated control of the actin cytoskeleton. Uniform exposure of Dictyostelium discoideum amoebae as well as mammalian leukocytes to chemoattractant triggers two phases of actin polymerization. In the initial rapid phase, motility stops and the cell rounds up. During the second slow phase, pseudopodia are extended from local regions of the cell perimeter. These responses are highly correlated with temporal and spatial accumulations of PI(3,4,5)P3/PI(3,4)P2 reflected by the translocation of specific PH domains to the membrane. The slower phase of PI accumulation and actin polymerization is more prominent in less differentiated, unpolarized cells, is selectively increased by disruption of PTEN, and is relatively more sensitive to perturbations of PI3K. Optimal levels of the second responses allow the cell to respond rapidly to switches in gradient direction by extending lateral pseudopods. Consequently, PI3K inhibitors impair chemotaxis in wild-type cells but partially restore polarity and chemotactic response in pten- cells. Surprisingly, the fast phase of PI(3,4,5)P3 accumulation and actin polymerization, which is relatively resistant to PI3K inhibition, can support inefficient but reasonably accurate chemotaxis.
Chen
Lingfeng
L
Department of Cell Biology, Johns Hopkins University, School of Medicine, Baltimore, Maryland 21205, USA.
Janetopoulos
Chris
C
Huang
Yi Elaine
YE
Iijima
Miho
M
Borleis
Jane
J
Devreotes
Peter N
PN
D000199:Actins / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D016764:Cell Polarity / Q000502:physiology; D002630:Chemotactic Factors / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects / Q000502:physiology*; D000242:Cyclic AMP / Q000494:pharmacology; D003599:Cytoskeleton / Q000378:metabolism* / Q000502:physiology; D004023:Dictyostelium / Q000378:metabolism* / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism* / Q000502:physiology; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism / Q000502:physiology; D011554:Pseudopodia / Q000378:metabolism / Q000502:physiology
D000199:Actins; D002630:Chemotactic Factors; D018129:Phosphatidylinositol Phosphates; D000242:Cyclic AMP; D019869:Phosphatidylinositol 3-Kinases