Abstract
In a role distinct from and perhaps more ancient than that in signal transduction, PIP3 and Ras help to spatially organize the actin cytoskeleton into macropinocytic cups. These large endocytic structures are extended by actin polymerization from the cell surface and have at their core an intense patch of active Ras and PIP3, around which actin polymerizes, creating cup-shaped projections. We hypothesize that active Ras and PIP3 self-amplify within macropinocytic cups, in a way that depends on the structural integrity of the cup. Signalling that triggers macropinocytosis may therefore be amplified downstream in a way that depends on macropinocytosis. This argument provides a context for recent findings that signalling to Akt (an effector of PIP3) is sensitive to cytoskeletal and macropinocytic inhibitors.
Highlights
One of the most rapid and dramatic effects of growth factors on responsive cells is to stimulate their actin cytoskeleton into a brief period of ruffling and macropinocytosis [1]
This can be mimicked with oncogenic Ras [2] and blocked by phosphoinositide 3-kinase (PI3K) inhibitors [3], yet its physiological purpose is not clear. Why should this signalling pathway trigger the actin cytoskeleton? At the same time, including in a recent issue of this journal, there are reports that signalling to PI3K can be amplified in a way that depends on the actin cytoskeleton [4,5]. These two strands of work may be tied together by evidence that Ras/PIP3 signalling triggers macropinosome formation, but is a spatial organizer of macropinocytic cups, which role we propose necessitates a degree of signal amplification within the cup
Macropinosomes form from cups several microns in diameter that are extended from the cell surface by a ring of protrusive actin polymerization beneath the plasma membrane
Summary
One of the most rapid and dramatic effects of growth factors on responsive cells is to stimulate their actin cytoskeleton into a brief period of ruffling and macropinocytosis [1]. Macropinosomes form from cups several microns in diameter that are extended from the cell surface by a ring of protrusive actin polymerization beneath the plasma membrane. WAVE complex (green) is recruited to the periphery of these patches (reported by PIP3, red) where it activates the Arp2/3 complex to trigger actin polymerization.
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