Figure 7.

Gin4 controls inner leaflet PtdEth and Cdc42-GTP level. During progression through the cell cycle, Gin4 localizes at the incipient bud site, and phosphorylates and inhibits Fpk1 at the same location, preventing flippase activation and keeping PtdEth level on the inner leaflet low. Because inner leaflet PtdEth promotes Cdc42-GTP inactivation (Saito et al., 2007; Das et al., 2012), Gin4-imposed reduction in PtdEth allows for buildup of Cdc42-GTP to stimulate recruitment and function of effectors, like formin Bni1, that promote bud emergence. Further accumulation of Gin4 at the septin collar will continue to suppress the inner leaflet PtdEth level, allowing for localized protection of Cdc42-GTP, perhaps facilitating recruitment and activation of effectors required for efficient cytokinesis. Despite a normally beneficial role, flippase function also permits entry of toxic xenobiotics. To help prevent an influx of such noxious agents when the PM barrier is already compromised by heat stress or other membrane-perturbing or -damaging agents, an independent stress response mediated by protein kinase Ypk1 also down-regulates flippase function by inhibiting Fpk1. Full Ypk1 activity requires its stimulation by two PM-associated protein kinases: eisosome-bound Pkh1 and the TORC2 complex.