Mammalian canonical and non-canonical Hippo signaling pathways. The core components of the mammalian Hippo pathway are the MST and LATS kinases, and the SAV1 and MOB adaptor proteins. The Hippo pathway is activated in response to increased cell density, cell tension, mechanical forces, stress stimuli, or G-protein-coupled receptor (GPCR) antagonists, and inhibits cell proliferation and other processes potentially contributing to tumorigenesis. Candidate sensory components upstream of the Hippo core include FAT4, DCHS1, ITGB1, CD44, NF2, FRMD6, KIBRA, TAO, and RASSF. Upon Hippo core activation, SAV1 binding to MST allows this kinase to phosphorylate MOB1. Phospho-MOB1 binding to LATS both enhances LATS catalytic activity and allows it to be phosphorylated by MST. Phospho-LATS then phosphorylates and inactivates YAP (or its paralog, TAZ), promoting their cytoplasmic retention through binding to 14-3-3 protein. LATS-phosphorylated YAP1 (or TAZ) is also degraded so transcription factors (such as the TEADs) promoting cell survival are not activated. In contrast, under conditions of low cell density or minimal stress, YAP dissociates from 14-3-3, translocates into the nucleus, and activates transcription factors that induce the expression of pro-survival genes. Solid lines indicate known direct interactions; dashed lines indicate unknown mechanisms. The non-canonical Hippo pathway operates in the tight and adherens junction complexes and involves AMOT in the Crumb complex in the tight junction, ZO-2 in the tight junction, and α-catenin, β-catenin and PTPN14 in the adherence junction. Each of these molecules can bind to phosphorylated YAP1 to control its localization and activity