Regulation of the Hippo pathway in mammals. The Hippo pathway is regulated by diverse signals: 1) Determinants of cell polarity and cell-cell junctions, such as SCRIB that interacts with MST1/2 and LATS1/2, AMOT, PTPN14, and α-Catenin, which can sequester YAP/TAZ to cell junctions; 2) Mechanical cues, such as stiffness, cell contact, cell geometry, and cell attachment status that regulate the Hippo pathway by modulating activity of Rho GTPases, remodeling the actin cytoskeleton, or altering cellular tension. Both apical and basolateral spectrin networks may function as sensors for mechanical cues in Hippo pathway regulation; 3) Soluble factors, especially ligands for GPCRs, regulate LATS1/2 likely through Rho GTPases and actin dynamics; 4) Metabolic status, such as cellular energy and oxygen stress, also regulate Hippo signaling. Many other proteins such as protein phosphatase 2A (PP2A), protein phosphatase 1 (PP1), WBP2, CDK1, MASK, and HIPK can also regulate activities of different Hippo pathway components (refer to ()). Arrows, blunt ends, and dashed lines indicate activation, inhibition, and indirect regulation, respectively.