Robert R. Kay*, Thomas D. Williams, James D. Manton, David Traynor and Peggy Paschke
MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, UK
Macropinocytosis is used by a variety of amoebae for feeding on liquid medium. The amoebae project cups and ruffles from their plasma membrane, driven by actin polymerization, and eventually fuse these back to the membrane, entrapping droplets of medium into internal vesicles. These vesicles are of up to several microns in diameter and are processed through the lysosomal digestive system to extract nutrients. Recognizably the same process is used in metazoan cells for a number of medically important purposes, including the pathological growth of cancer cells. We describe the discovery of macropinocytosis in Dictyostelium amoebae, its genetic regulation by the NF1 RasGAP, and the tools available for its investigation. Work on Dictyostelium over the last 30 years has identified many genes that may be important for macropinocytosis, which are listed at dictyBase, and give a basis for mechanistic studies. We argue that the actin cytoskeleton is organized for macropinocytosis by a signalling patch of PIP3 and active Ras and Rac, together with their regulatory proteins and effectors, including the protein kinases Akt and SGK. The Scar/WAVE complex is recruited to the periphery of this patch, triggering the formation of a hollow ring of protrusive actin polymerization, and eventually a macropinocytic cup. Major problems to be addressed include: the dynamics sustaining macropinocytic patches and the mechanism of Scar/WAVE recruitment; the mechanisms of cup closure and of membrane fusion; the ecological situations where amoebae feed by macropinocytosis; and the evolutionary relationship between macropinocytosis and growth factor signalling.