Activation of polarized cell growth by inhibition of cell polarity

A key feature of cells is the capacity to activate new functional polarized domains contemporaneously to pre-existing ones. How cells accomplish this is not clear. Here, we show that in fission yeast inhibition of cell polarity at pre-existing domains of polarized cell growth is required to activate new growth. This inhibition is mediated by the ERM-related polarity factor Tea3, which antagonizes the activation of the Rho-GTPase Cdc42 by its co-factor Scd2. We demonstrate that Tea3 acts in a phosphorylation-dependent manner controlled by the PAK kinase Shk1 and that, like Scd2, Tea3 is direct substrate of Shk1. Importantly, we show that Tea3 and Scd2 compete for their binding to Shk1 in vitro, indicating that their biochemical competition for Shk1 underpins their antagonistic roles in controlling polarity. Mathematical modelling of an 9inhibitor-activator9 system mimicking the Tea3-Scd2 antagonism suggests that it can account for several major features of polarity control observed in cells, including the anti-correlated localizations of Tea3 and cell growth areas observed throughout the cell cycle, controlling the period of GTP-Cdc42 oscillations at the cell cortex and modulating the time at which cells trigger new polarized growth. Thus, by preventing pre-existing growth domains from becoming overpowering, polarity inhibition plays a key role in allowing cells to redistribute their polarity-activating machinery to prospective growth sites and control the timing of new growth activation - explaining how a polarity inhibitor can serve as an activator of new polarity zone formation.