AMPK modulates Hippo pathway activity to regulate energy homeostasis

Abstract

The Hippo pathway was discovered as a conserved tumour suppressor pathway restricting cell proliferation and apoptosis. However, the upstream signals that regulate the Hippo pathway in the context of organ size control and cancer prevention are largely unknown. Here, we report that glucose, the ubiquitous energy source utilised for ATP generation, regulates the Hippo pathway downstream effector YAP. We show that both the Hippo pathway and AMP-activated protein kinase (AMPK) were activated during glucose starvation, resulting in phosphorylation of YAP and contributing to its inactivation. We also identified glucose-transporter 3 (GLUT3) as a YAP-regulated gene involved in glucose metabolism. Together, these results demonstrate that glucose-mediated energy homeostasis is an upstream event involved in regulation of the Hippo pathway and, potentially, an oncogenic function of YAP in promoting glycolysis, thereby providing an exciting link between glucose metabolism and the Hippo pathway in tissue maintenance and cancer prevention.

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

“…Although Nguyen et al describe an AMPKindependent and partially LATS-independent pathway for YAP inhibition by LKB1 (54), Mohseni et al show that LKB1 acts via microtubule affinity-regulating kinase 1 (MARK1)/Par-1 to promote the localization of the polarity determinant Scrib, which in turn has been proposed to scaffold the Hpo core kinase cascade (19,53). In contrast, three recent studies suggest that AMPK may be a key YAP regulator downstream of LKB1 (55)(56)(57). First, AMPK can inhibit YAP by phosphorylating and stabilizing the junctional protein angiomotin-like 1 (AMOTL1), thereby promoting YAP inhibitory phosphorylation by LATS1 (55).…”

“…For example, AMPK inhibits protein and lipid synthesis and gluconeogenesis while promoting glucose transport, glycolysis, fatty acid oxidation, and autophagy (87). Interestingly, energy stress elicited by glucose withdrawal/ 2-deoxy-glucose treatment or the AMPK activator metformin led to YAP inactivation and reduced tumor cell growth both in cell culture and in xenograft experiments, even in cells lacking LATS1/2 (55)(56)(57). A tissue-specific role of AMPK in regulation of Yki activity in the CB/VNC may therefore reflect the need for adjustment of proliferation rates of different tissues under low energy conditions, although the Drosophila larval nervous system is also buffered from systemic nutrient restrictions during late larval development through a process known as sparing (88).…”

“…First, AMPK can inhibit YAP by phosphorylating and stabilizing the junctional protein angiomotin-like 1 (AMOTL1), thereby promoting YAP inhibitory phosphorylation by LATS1 (55). Second, energy stress reduced YAP activity both via AMPKmediated induction of Lats1/2 activity and also through direct phosphorylation of YAP by AMPK (55)(56)(57). The outcome of YAP phosphorylation by AMPK [reduced binding to TEAD (TEAdomain) transcription factors or a distinct mechanism], as well as the sites involved, vary between the two studies (56,57).…”

“…S4 C and D). Very recently, AMPK was shown to phosphorylate YAP directly in mammalian cells (56,57). We performed an in vitro kinase assay with purified Yki and human AMPK and LKB1 (Fig.…”

“…Recently, 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. Here, we find that loss of LKB1 leads to Yki activation and accelerated proliferation in the Drosophila larval central brain (CB) and ventral nerve cord (VNC).…”