Energy Stress Regulates the Hippo–YAP Pathway

The tumor-suppressive Hippo pathway is a critical regulator of organ size, and dysregulation of Hippo signaling has been implicated in tumorigenesis. Activation of the Hippo pathway induces a kinase cascade that results in the phosphorylation, cytoplasmic retention, and inhibition of the transcriptional coactivators YAP and TAZ, which regulate the expression of genes involved in multiple cellular functions, such as proliferation, apoptosis, migration, and differentiation. Previous studies have shown that YAP phosphorylation and localization can be modulated by various upstream signals, including cell–cell contact, mechanical forces, and cytoskeletal reorganization. DeRan, Yang, and colleagues investigated whether nutrient and energy stress also regulate Hippo–YAP signaling using a high-content cellular imaging assay to monitor YAP nuclear translocation. Glucose deprivation or treatment of cells with energy stressors such as metformin and phenformin that activate the cellular metabolic sensor AMP-activated protein kinase (AMPK) resulted in increased YAP phosphorylation and cytoplasmic retention and inhibited the transcriptional activity of YAP independent of cell growth. Furthermore, activation of AMPK in response to energy stress suppressed YAP-dependent transformation and cancer cell proliferation in vitro. Mechanistically, energy stress–induced phosphorylation of YAP required the upstream core Hippo pathway kinases large tumor suppressor kinase 1 (LATS1) and LATS2 and was dependent on AMPK-mediated phosphorylation of angiomotin-like 1 (AMOTL1), a tight-junction protein that negatively regulates YAP, at Ser793, which resulted in increased stabilization of AMOTL1 protein. In sum, these data demonstrate that energy stress–induced AMPK activation inhibits YAP in part via phosphorylation of AMOTL1 and link cellular energy sensing to Hippo pathway regulation. In addition, these results suggest that cancer-associated mutations in AMOTL1 may disrupt this regulation and promote hyperactivation of YAP.

DeRan M, Yang J, Shen CH, Peters EC, Fitamant J, Chan P, et al. Energy stress regulates Hippo-YAP signaling involving AMPK-mediated regulation of angiomotin-like 1 protein. Cell Rep 2014;9:495–503.