Regulation of the leading edge motility by PI (4,5)P2-dependent lipid microdomains

The lipid second messenger PI(4,5)P2 modulates actin dynamics, and its local
accumulation at plasmalemmal microdomains (rafts) might mediate regulation of
protrusive motility. However, how PI(4,5)P2-rich rafts regulate surface motility is
not well understood. In this study, we show that upon signals promoting cell
surface motility, PI(4,5)P2 directs the assembly of dynamic raft-rich plasmalemmal
patches, which promote and sustain protrusive motility. The accumulation of
PI(4,5)P2 at rafts, together with Cdc42, promotes patch assembly through NWASP.
The patches exhibit locally regulated PI(4,5)P2 turnover and reduced
diffusion-mediated exchange with their environment. Patches capture
microtubules (MTs) through IQGAP1, to stabilize MTs at the leading edge.
Captured MTs in turn deliver PKA to patches, to promote higher order patch
clustering through further PI(4,5)P2 accumulation in response to cAMP. Patch
clustering restricts, spatially confines and polarizes protrusive motility. Thus,
PI(4,5)P2-dependent raft-rich patches enhance local signaling for motility, and
their assembly into clusters is regulated through captured MTs and PKA, coupling
local regulation of motility to cell polarity and organization.