Differential Regulation of Protrusion and Polarity by PI(3)K during Neutrophil Motility in Live Zebrafish

Abstract

Summary 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)P3-PI(3,4)P2 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.

PLEKHG3 enhances polarized cell migration by activating actin filaments at the cell front

“…S8 C and E). These findings are consistent with previous reports that the photoactivation of Rac at the leading edge of the cell can rescue the protrusion defects induced by PI3K inhibition (27,28). PI3K is not required for the protrusion.…”

Integrins in Cell Migration

“…The mechanisms that regulate the decision to disassemble or to elongate and grow are not understood. However, these mechanisms are likely the regulators of the directed migration of mesenchymal cells and may also contribute to directional decision-making during pseudopod selection by amoeboid cells migrating in vitro (Andrew and Insall 2007) and in vivo (Cvejic et al 2008;Yoo et al 2010).…”

Vibsanin B Preferentially Targets HSP90β, Inhibits Interstitial Leukocyte Migration, and Ameliorates Experimental Autoimmune Encephalomyelitis

“…Ample evidence has indicated that the PI3K-Akt pathway controls the directionality of leukocyte chemotactic migration (1). In zebrafish embryos, the PI3Kg-Akt pathway promotes Racmediated actin polymerization around the leading edge, which guides leukocyte migration in vivo (32). To determine which pathways are involved in vibsanin B's inhibitory effect on leukocyte migration, we analyzed the alterations of selected pathways, including the PI3K-Akt pathway in THP-1 cells and zebrafish embryos upon vibsanin B treatment.…”