Energy Stress Regulates Hippo-YAP Signaling Involving AMPK-Mediated Regulation of Angiomotin-like 1 Protein

Abstract

SUMMARY Hippo signaling is a tumor suppressor pathway involved in organ size control and tumorigenesis, through the inhibition of YAP and TAZ. Here we show that energy stress induces YAP cytoplasmic retention and Ser127 phosphorylation and inhibits YAP transcriptional activity and YAP-dependent transformation. These effects require the central metabolic sensor AMP-activated protein kinase (AMPK), and the upstream Hippo pathway components Lats1/2 and Angiomotin-like 1 (AMOTL1). We further show that AMPK directly phosphorylates Ser793 of AMOTL1. AMPK activation stabilizes and increases AMOTL1 steady-state protein levels, contributing to YAP inhibition. The phosphorylation-deficient Ser793Ala mutant of AMOTL1 showed a shorter half-life and conferred resistance to energy stress-induced YAP inhibition. Our findings link energy sensing to the Hippo-YAP pathway, and suggest that YAP may integrate spatial (contact inhibition), mechanical and metabolic signals to control cellular proliferation and survival.

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

“…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). 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).…”

“…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).…”

“…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).…”