Abstract
The Hippo (Hpo) pathway is a highly conserved tumor suppressor network that restricts developmental tissue growth and regulates stem cell proliferation and differentiation. At the heart of the Hpo pathway is the progrowth transcriptional coactivator Yorkie [Yki-Yes-activated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) in mammals]. Yki activity is restricted through phosphorylation by the Hpo/Warts core kinase cascade, but increasing evidence indicates that core kinase-independent modes of regulation also play an important role. Here, we examine Yki regulation in the Drosophila larval central nervous system and uncover a Hpo/Warts-independent function for the tumor suppressor kinase liver kinase B1 (LKB1) and its downstream effector, the energy sensor AMP-activated protein kinase (AMPK), in repressing Yki activity in the central brain/ventral nerve cord. Although the Hpo/Warts core cascade restrains Yki in the optic lobe, it is dispensable for Yki target gene repression in the late larval central brain/ventral nerve cord. Thus, we demonstrate a dramatically different wiring of Hpo signaling in neighboring cell populations of distinct developmental origins in the central nervous system.
Highlights
The Hippo (Hpo) pathway is a highly conserved tumor suppressor network that restricts developmental tissue growth and regulates stem cell proliferation and differentiation
The key effector of the Hpo pathway is the transcriptional coactivator Yki [Yes-activated protein (YAP)/ transcriptional coactivator with PDZ-binding motif (TAZ) in mammals], which promotes the expression of a broad transcriptional program that includes proliferation/growth-promoting genes such as cyclin E, myc, and bantam microRNA and antiapoptotic genes such as death-associated inhibitor of apoptosis 1 [3,4,5,6,7], as well as upstream Hpo pathway components such as expanded, kibra, and four-jointed [8,9,10]
We identify a function for the energy-sensing module liver kinase B1 (LKB1)/AMPactivated protein kinase (AMPK) in restraining the activity of the Hpo pathway effector Yki in the larval neuronal stem cells of the central brain (CB) and ventral nerve cord (VNC)
Summary
Apoptosis and Proliferation Control Laboratory, The Francis Crick Institute, Lincoln’s Inn Fields Laboratory, London WC2A 3LY, United Kingdom. AMPK restores energy balance by promoting energy-efficient ATP generation through oxidative phosphorylation and antagonizing ATP-expending anabolic processes such as gluconeogenesis and fatty acid synthesis [52] Both LKB1 and AMPK have been reported to repress YAP activity in mammalian cell culture and cancer models [53,54,55,56,57], either by modulating the core kinase cascade or via direct phosphorylation of YAP by AMPK. We show that Yki is inhibited by the nutrient-sensing liver kinase B1 (LKB1)/AMPactivated protein kinase (AMPK) cascade independent of Hpo/ Warts in a population of neural progenitors in the developing Drosophila larval brain. This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. 1073/pnas.1505512112/-/DCSupplemental
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