Abstract IA29: The Hippo pathway integrates PI3K-Akt signals with mechanical cues to control tissue growth

Abstract

Abstract The Hippo signaling pathway restricts cell proliferation in animal tissues by inhibiting YAP (or YAP1) and TAZ (or WWTR1), coactivators of the Scalloped (Sd or TEAD) DNA-binding transcription factor. Drosophila has a 24 single YAP/TAZ homolog named Yorkie (Yki) that can be mechanically regulated during development. Here we show that Yki translocates to the nucleus to drive Sd-mediated cell proliferation in the ovarian follicle cell epithelium in response to mechanical stretching caused by the growth of the germline. Importantly, mechanically induced Yki nuclear translocalization also requires nutritionally induced Insulin/IGF-1 signaling via PI3K, PDK1, and Akt in the follicular epithelium. We find similar results in the developing Drosophila wing, where Yki becomes nuclear in the mechanically stretched cells of the wing pouch during larval feeding, which induces Insulin/IGF-1 signaling, but translocates to the cytoplasm upon cessation of feeding in the third instar stage. Ectopic activation of PI3K or Akt is sufficient to maintain nuclear Yki in the wing disc even after feeding ceases. An Akt phosphorylation site in the Hpo kinase domain is required to attenuate Hpo kinase activity, enabling further inhibition of Hippo signaling by mechanical stimuli to drive Yki activation. Finally, Insulin/IGF-1 signaling also promotes YAP nuclear localization in response to mechanical cues in mammalian skin epithelia. Thus, the Hippo pathway has a physiologic function as an integrator of mechanical and nutritional cues to control cell proliferation and tissue growth in both Drosophila and mammals. Citation Format: Barry Thompson. The Hippo pathway integrates PI3K-Akt signals with mechanical cues to control tissue growth [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr IA29.