Transient proliferation by reversible YAP-mediated increase of the cyclin D1/p27 ratio.
Overview
abstract
UNLABELLED: Hippo-YAP signaling orchestrates epithelial tissue repair and is therefore an attractive target in regenerative medicine. Yet it is unresolved how YAP controls the underlying transient proliferative response. Here we show that YAP-TEAD activation increases the nuclear cyclin D1/p27 protein ratio in G1 phase, towards a threshold level that dictates whether individual cells enter or exit the cell cycle. YAP increases this ratio indirectly, by increasing EGFR and other receptor activities that signal primarily through ERK. Conversely, contact inhibition suppresses YAP activity which gradually downregulates mitogen signaling and the cyclin D1/p27 ratio. Increasing YAP activity by ablating the suppressor Merlin/NF2 reveals a robust balancing mechanism in which YAP can still be inhibited after cell division further increases local cell density. Thus, critical for tissue repair, the proliferation response is intrinsically transient since the YAP-induced and mitogen-mediated increase in the cyclin D1/p27 ratio is reliably reversed through delayed contact inhibition of YAP. HIGHLIGHTS: YAP signaling controls cell cycle entry and exit by up- and down-regulating the cyclin D1/p27 ratio above and below a conserved thresholdYAP-induced proliferation is intrinsically transient since contact inhibition of YAP suppresses EGFR signaling after a delay to reduce this cyclin D1/p27 ratioYAP can still be robustly inhibited after Merlin/NF2 ablation but only at higher local cell densityThe YAP-regulated cyclin D1/p27 ratio is primarily controlled by MEK-ERK rather than mTOR activity.
