Regulation and function of the Hippo pathway in growth control

PROJECT SUMMARY The Hippo pathway is a key regulator of development, regeneration, tissue homeostasis and organ size, whose dysregulations have been frequently observed in human diseases like cancer. In mammals, the Hippo pathway is composed of a core kinase cascade that comprises two Ser/Thr kinases MST and LATS as well as their adaptor proteins SAV1 and MOB1, respectively, downstream effector protein YAP, and nuclear transcription factor TEAD. Upon Hippo pathway activation, MST phosphorylates and activates LATS, which in turn phosphorylates YAP, resulting in its cytoplasmic retention and degradation. Un-phosphorylated YAP is translocated into the nucleus, where it binds TEAD to drive the transcription of genes involved in various growth-related events. Recent studies in both Drosophila and mammals have further revealed MAP4K-family kinases (MAP4Ks) and PP2A phosphatase complex STRIPAK as additional components of the Hippo pathway, where MAP4Ks act in parallel to MST to phosphorylate and activate LATS, while STRIPAK inhibits MST and MAP4Ks to control the Hippo core kinase cascade. Multiple growth-related signaling events, such as growth factors, glucose/energy homeostasis, cell-cell contact, mechanical cues and a series of stress signals, have been uncovered to regulate the Hippo pathway and its downstream YAP-dependent transcriptional program. However, precisely how these upstream signaling stimuli feed into the Hippo pathway core components has not been fully understood. In the past grant period, we shed light on this long-standing question by characterizing phosphatidic acid and its-associated lipid metabolic pathway in transducing the Hippo pathway upstream signaling events to the Hippo pathway kinase LATS. In the current grant period, we propose to re-examine the Hippo pathway in energy stress response that was discovered by us a few years ago. Specifically, we will elucidate the molecular mechanisms underlying the energy stress-induced Hippo pathway activation by characterizing the role of the AMPK-STRIPAK-MAP4Ks axis in this process (Aim 1). In addition, we will investigate a YAP-independent function of the Hippo pathway in promoting cell survival against energy stress (Aim 2). Collectively, completion of this project will reveal mechanistically how energy stress activates the Hippo pathway and provide functional insights into the Hippo pathway in growth control and cancer development.