Differential regulation of protrusion and polarity by PI3K during neutrophil motility in live zebrafish.
Cell polarity is crucial for directed migration. Here we show that phosphoinositide 3-kinase (PI(3)K) mediates neutrophil migration in vivo by differentially regulating cell protrusion and polarity. The dynamics of PI(3)K products PI(3,4,5)P(3)-PI(3,4)P(2) during neutrophil migration were visualized in living zebrafish, revealing that PI(3)K activation at the leading edge is critical for neutrophil motility in intact tissues. A genetically encoded photoactivatable Rac was used to demonstrate that localized activation of Rac is sufficient to direct migration with precise temporal and spatial control in vivo. Similar stimulation of PI(3)K-inhibited cells did not direct migration. Localized Rac activation rescued membrane protrusion but not anteroposterior polarization of F-actin dynamics of PI(3)K-inhibited cells. Uncoupling Rac-mediated protrusion and polarization suggests a paradigm of two-tiered PI(3)K-mediated regulation of cell motility. This work provides new insight into how cell signaling at the front and back of the cell is coordinated during polarized cell migration in intact tissues within a multicellular organism.
Yoo
Sa Kan
SK
Program in Cellular and Molecular Biology, University of Wisconsin-Madison, Madison, WI 53706, USA.
Deng
Qing
Q
Cavnar
Peter J
PJ
Wu
Yi I
YI
Hahn
Klaus M
KM
Huttenlocher
Anna
A
D000818:Animals; D030801:Animals, Genetically Modified; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D016764:Cell Polarity / Q000187:drug effects / Q000502:physiology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000502:physiology; D002867:Chromones / Q000494:pharmacology; D058544:Class Ib Phosphatidylinositol 3-Kinase; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000502:physiology; D009025:Morpholines / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015290:Second Messenger Systems; D015027:Zebrafish / Q000196:embryology / Q000235:genetics / Q000502:physiology*; D029961:Zebrafish Proteins / Q000502:physiology; D020830:rac1 GTP-Binding Protein / Q000502:physiology
D002867:Chromones; D058544:Class Ib Phosphatidylinositol 3-Kinase; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D018129:Phosphatidylinositol Phosphates; D000081082:Phosphoinositide-3 Kinase Inhibitors; D029961:Zebrafish Proteins; D020830:rac1 GTP-Binding Protein; C060974:phosphatidylinositol 3,4,5-triphosphate; C060980:phosphatidylinositol 3,4-diphosphate; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one