AMPK inhibits mTOR-driven keratinocyte proliferation after skin damage and stress.

Abstract Epidermal keratinocytes rapidly proliferate to repair the skin barrier and a strict control of division is necessary for healthy tissue homeostasis. However, the pathways that restrain proliferation after epidermal stress are not known. AMP-activated protein kinase (AMPK) is an important signaling mediator of energy metabolism previously associated with skin stress and cancer, yet its explicit impact on keratinocyte growth is not known. To examine the requirement of epidermal AMPK in physiologic skin repair, we genetically deleted AMPK within all adult, Keratin 14-expressing keratinocytes of mice. AMPK loss resulted in hyper-proliferation and hyperactive mTOR signaling following acute wounding, UVB exposure, and phorbol ester application. This excessive division could be completely blocked by the mTORC1 inhibitor rapamycin. Moreover, we establish that the diabetes drug metformin depends on AMPK to suppress stress-induced keratinocyte proliferation. Collectively, these findings show that keratinocyte AMPK restrains mTORC1 to control epidermal proliferation after tissue injury.