Interplay between YAP/TAZ and Metabolism Ja Hyun Koo, Kun-Liang Guan  Cell Metabolism  Volume 28, Issue 2, Pages 196-206 (August 2018) DOI: 10.1016/j.cmet.2018.07.010 Copyright © 2018 Terms and Conditions

Figure 1 Regulation of the Hippo Pathway by Upstream Signals At high-cell-density conditions, adherens junctions and tight junctions in cell-cell contact points signal to inhibit YAP and TAZ via AMOT and α-catenin by activating LATS1/2 or directly binding YAP and TAZ. Mechanical cues such as stiffness and cell attachment regulate RhoA and actin cytoskeleton to affect YAP/TAZ activity via LATS-dependent or -independent mechanism. Soluble factors such as LPA, thrombin, and Wnt ligands act through GPCR to regulate YAP and TAZ. Various stress signals, such as oxidative stress, ER stress, and hypoxic stress, cause Hippo pathway activation and YAP/TAZ inhibition. While LATS1/2 is the responsible upstream regulator of YAP and TAZ in most circumstances, osmotic stress can act directly on YAP and TAZ or its transcription partner TEAD. Arrows, blunt ends, and dashed lines indicate activation, inhibition, and translocation, respectively. Cell Metabolism 2018 28, 196-206DOI: (10.1016/j.cmet.2018.07.010) Copyright © 2018 Terms and Conditions

Figure 2 YAP/TAZ Regulation by Metabolic Cues Under energy stress, AMPK directly phosphorylates and inhibits YAP and TAZ. AMOTL1 phosphorylation by AMPK also contributes to YAP/TAZ inhibition. Under high-glucose condition, OGT-mediated O-GlcNAcylation of YAP and TAZ prevents their degradation. Palmitate activates the cGAS-STING pathway to increase transcription of MST1, which in turn inhibits YAP and TAZ. Unsaturated fatty acids stabilize YAP and TAZ through Wnt signaling. The mevalonate pathway produces geranylgeranyl-pyrophosphate (geranylgeranyl-PP) from acetyl-CoA and HMG-CoA. Geranylgeranyl-PP is required for RhoA prenylation and membrane association, which is essential for RhoA function. GPCRs can either stimulate or inhibit YAP and TAZ in a manner dependent on which trimeric G proteins are activated. GPCRs that couple to Gαi/o, Gαq/11, and Gα12/13 activate YAP and TAZ, while those that couple to Gαs inhibit YAP and TAZ by stimulating PKA. Arrows and blunt ends indicate activation and inhibition, respectively. Dashed lines indicate translocation, translation, or degradation. Cell Metabolism 2018 28, 196-206DOI: (10.1016/j.cmet.2018.07.010) Copyright © 2018 Terms and Conditions

Figure 3 Cellular Metabolism Regulated by YAP and TAZ YAP and TAZ stimulate glucose metabolism by enhancing glucose uptake and glycolysis. YAP and TAZ stimulate GLUT3 transcription in many types of cancers. HK2 and PFKB3 are glycolytic enzymes, and their transcription is indirectly induced by YAP and TAZ. In the liver, YAP and TAZ repress transcription of gluconeogenic enzymes, such as G6PC and PEPCK, thereby reducing blood glucose level. YAP and TAZ also stimulate amino acid metabolism through transcription of amino acid transporters, such as SLC1A5, SLC7A5, and SLC38A1. GLS1, GLUL, GOT1, and PSAT1, the enzymes responsible for glutamine metabolism, are regulated by YAP and TAZ in a tissue context-dependent manner. UCP1 transcription in brown adipose tissue requires YAP and TAZ. UCP1 uncouples the mitochondrial electron transport chain and allows for faster lipid oxidation. Mitochondrial fusion proteins Marf (ortholog of MFN1/2) and Opa1 are also regulated by YAP and TAZ. Red and blue boxes indicate proteins up- and downregulated by YAP and TAZ, respectively. Asterisks indicate Drosophila proteins. Cell Metabolism 2018 28, 196-206DOI: (10.1016/j.cmet.2018.07.010) Copyright © 2018 Terms and Conditions