Differential control of Yorkie activity by LKB1/AMPK and the Hippo/Warts cascade in the central nervous system

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.

Control of YAP/TAZ Activity by Metabolic and Nutrient-Sensing Pathways

“…Meanwhile, none of the studies that found a link with AMPK in mammalian systems directly explored its potential regulation by LKB1. However, a recent study in Drosophila observed Yorkie regulation by LKB1 and AMPK: the inactivation of LKB1 in the developing central nervous system induced the activation of Yorkie and a corresponding overgrowth of larval tissues, while LKB1 overexpression induced Yorkie inhibition through AMPK [56]. In line with observations in mammalian systems, AMPK was able to directly phosphorylate Yorkie in vitro.…”

Hippo Pathway in Organ Size Control, Tissue Homeostasis, and Cancer

“…AMPK can phosphorylate AMOTL1, which in turn facilitates YAP phosphorylation by LATS1/2 (DeRan et al, 2014). A similar mechanism is also present in Drosophila , in which Ampk inactivates Yki and affects cell proliferation in the larval central brain and central nerve cord (Gailite et al, 2015). It appears that during energy stress, both AMPK and LATS1/2 are unleashed to restrict YAP activity.…”

The Hippo Pathway Regulates Neuroblasts and Brain Size in Drosophila melanogaster

“…It is known to regulate the proliferation of two cell populations in the larval D. melanogaster brain: glia and the neuroepithelium [10][11][12]. Although the Yorkie (Yki) transcription co-activator was recently linked to neuroblast biology downstream of the Lkb1 and AMPK kinases [13], a role for the Hippo pathway core kinases in control of neuroblasts, the stem cell population that produces 90% of adult brain cells, has not been reported. To investigate the Hippo pathway in brain development, we surveyed expression of key Hippo pathway proteins in the third-instar larval brain using endogenously tagged alleles of the kinases tao-1 and hippo (hpo) and a Yki antibody ( Figure S1).…”