Transient proliferation by reversible YAP and mitogen control of the cyclin D1/p27 ratio.

Hippo-YAP signaling orchestrates transient proliferation during tissue repair and is therefore an attractive target in regenerative medicine. However, it is unclear how YAP integrates mitogen and contact signals to start and stop proliferation. Here we show that reduced contact inhibition, increased mitogen signaling, and YAP-TEAD activation converge on increasing the nuclear cyclin D1/p27 protein ratio during early G1 phase, towards a threshold ratio that dictates whether individual cells enter or exit the cell cycle. YAP increases this ratio in concert with inducing mitogen signaling, by increasing EGFR and other receptors that signal primarily through ERK. After a delay, contact inhibition suppresses YAP activity, which gradually downregulates mitogen signaling and the cyclin D1/p27 ratio. Thus, critical for regeneration without cancer initiation, robust proliferation responses result from a YAP-induced and receptor-mediated prolonged increase in the cyclin D1/p27 ratio, which is reversed by delayed suppression of receptor signaling after contact inhibition of YAP.