The Hippo Pathway, YAP/TAZ, and the Plasma Membrane. Rausch Valentina,Hansen Carsten G Trends in cell biology The plasma membrane allows the cell to sense and adapt to changes in the extracellular environment by relaying external inputs via intracellular signaling networks. One central cellular signaling pathway is the Hippo pathway, which regulates homeostasis and plays chief roles in carcinogenesis and regenerative processes. Recent studies have found that mechanical stimuli and diffusible chemical components can regulate the Hippo pathway primarily through receptors embedded in the plasma membrane. Morphologically defined structures within the plasma membrane, such as cellular junctions, focal adhesions, primary cilia, caveolae, clathrin-coated pits, and plaques play additional key roles. Here, we discuss recent evidence highlighting the importance of these specialized plasma membrane domains in cellular feedback via the Hippo pathway. 10.1016/j.tcb.2019.10.005

RHOA drives the development of diffuse gastric cancer through IGF1R-PAK1-YAP1 signaling. Science signaling Cancer-associated mutations in the guanosine triphosphatase (GTPase) RHOA are found at different locations from the mutational hotspots in the structurally and biochemically related RAS. Tyr-to-Cys (Y42C) and Leu-to-Val (L57V) substitutions are the two most prevalent RHOA mutations in diffuse gastric cancer (DGC). RHOA exhibits a gain-of-function phenotype and is an oncogenic driver in DGC. Here, we determined how RHOA promotes DGC growth. In mouse gastric organoids with deletion of , which encodes the cell adhesion protein E-cadherin, the expression of RHOA, but not of wild-type RHOA, induced an abnormal morphology similar to that of patient-derived DGC organoids. RHOA also exhibited a gain-of-function phenotype and promoted F-actin stress fiber formation and cell migration. RHOA retained interaction with effectors but exhibited impaired RHOA-intrinsic and GAP-catalyzed GTP hydrolysis, which favored formation of the active GTP-bound state. Introduction of missense mutations at KRAS residues analogous to Tyr and Leu in RHOA did not activate KRAS oncogenic potential, indicating distinct functional effects in otherwise highly related GTPases. Both RHOA mutants stimulated the transcriptional co-activator YAP1 through actin dynamics to promote DGC progression; however, RHOA additionally did so by activating the kinases IGF1R and PAK1, distinct from the FAK-mediated mechanism induced by RHOA. Our results reveal that RHOA and RHOA drive the development of DGC through distinct biochemical and signaling mechanisms. 10.1126/scisignal.adg5289

The Hippo Pathway: Biology and Pathophysiology. Ma Shenghong,Meng Zhipeng,Chen Rui,Guan Kun-Liang Annual review of biochemistry The Hippo pathway was initially discovered in as a key regulator of tissue growth. It is an evolutionarily conserved signaling cascade regulating numerous biological processes, including cell growth and fate decision, organ size control, and regeneration. The core of the Hippo pathway in mammals consists of a kinase cascade, MST1/2 and LATS1/2, as well as downstream effectors, transcriptional coactivators YAP and TAZ. These core components of the Hippo pathway control transcriptional programs involved in cell proliferation, survival, mobility, stemness, and differentiation. The Hippo pathway is tightly regulated by both intrinsic and extrinsic signals, such as mechanical force, cell-cell contact, polarity, energy status, stress, and many diffusible hormonal factors, the majority of which act through G protein-coupled receptors. Here, we review the current understanding of molecular mechanisms by which signals regulate the Hippo pathway with an emphasis on mechanotransduction and the effects of this pathway on basic biology and human diseases. 10.1146/annurev-biochem-013118-111829