The Hippo Pathway, YAP/TAZ, and the Plasma Membrane

Plasma membrane structures direct dynamic and context-specific cellular signaling via the Hippo pathway.Hippo pathway components ‘moonlight’ via interactions with plasma membrane structures.YAZ and TAZ drive expression of components involved in the generation of specialized plasma membrane domains.The Hippo pathway is integrated into multiple levels of cellular feedback. 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. 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. The plasma membrane is essential for cell integrity and serves as an interface to sense and respond to changes in the extracellular environment [1Nicolson G.L. The fluid-mosaic model of membrane structure: still relevant to understanding the structure, function and dynamics of biological membranes after more than 40 years.Biochim. Biophys. Acta. 2014; 1838: 1451-1466Crossref PubMed Scopus (255) Google Scholar]. A large variety of plasma membrane domains, such as, adherens and tight junctions (see Glossary), focal adhesions (FAs), clathrin-coated pits (CCPs) or plaques, caveolae, and primary cilia [2Hansen C.G. Nichols B.J. Exploring the caves: cavins, caveolins and caveolae.Trends Cell Biol. 2010; 20: 177-186Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar, 3Lampe M. et al.Clathrin coated pits, plaques and adhesion.J. Struct. Biol. 2016; 196: 48-56Crossref PubMed Scopus (22) Google Scholar, 4McMahon H.T. Boucrot E. Molecular mechanism and physiological functions of clathrin-mediated endocytosis.Nat. Rev. Mol. Cell Biol. 2011; 12: 517-533Crossref PubMed Scopus (1079) Google Scholar, 5Parton R.G. Caveolae: structure, function, and relationship to disease.Annu. Rev. Cell Dev. Biol. 2018; 34: 111-136Crossref PubMed Scopus (19) Google Scholar, 6Burridge K. Focal adhesions: a personal perspective on a half century of progress.FEBS J. 2017; 284: 3355-3361Crossref PubMed Scopus (26) Google Scholar, 7Anvarian Z. et al.Cellular signalling by primary cilia in development, organ function and disease.Nat. Rev. Nephrol. 2019; 15: 199-219Crossref PubMed Scopus (13) Google Scholar, 8Pinheiro D. Bellaiche Y. Mechanical force-driven adherens junction remodeling and epithelial dynamics.Dev. Cell. 2018; 47: 3-19Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar], allow the cell to dynamically relay chemical and mechanical stimuli, which are translated into direct cellular responses. The plasma membrane as a whole, but FAs in particular, strongly interacts with the extracellular matrix (ECM) [9Vogel V. Unraveling the mechanobiology of extracellular matrix.Annu. Rev. Physiol. 2018; 80: 353-387Crossref PubMed Scopus (20) Google Scholar]. The ECM is a dynamic noncellular matrix surrounding cells and tissues that acts as a scaffold for cell anchorage and mechanotransduction [9Vogel V. Unraveling the mechanobiology of extracellular matrix.Annu. Rev. Physiol. 2018; 80: 353-387Crossref PubMed Scopus (20) Google Scholar]. The signals perceived by plasma membrane elements are integrated and transmitted by a variety of signaling pathways. One central pathway, which enables the cell to respond to various signals, is the Hippo pathway (Box 1) [10Hansen C.G. et al.YAP and TAZ: a nexus for Hippo signaling and beyond.Trends Cell Biol. 2015; 25: 499-513Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar, 11Panciera T. et al.Mechanobiology of YAP and TAZ in physiology and disease.Nat. Rev. Mol. Cell Biol. 2017; 18: 758-770Crossref PubMed Scopus (155) Google Scholar, 12Moroishi T. et al.The emerging roles of YAP and TAZ in cancer.Nat. Rev. Cancer. 2015; 15: 73-79Crossref PubMed Scopus (0) Google Scholar, 13Moya I.M. Halder G. Hippo-YAP/TAZ signalling in organ regeneration and regenerative medicine.Nat. Rev. Mol. Cell Biol. 2019; 20: 211-226Crossref PubMed Scopus (0) Google Scholar]. By highly context specific responses the Hippo pathway regulates cellular homeostasis and plays central roles in carcinogenesis and regenerative processes [10Hansen C.G. et al.YAP and TAZ: a nexus for Hippo signaling and beyond.Trends Cell Biol. 2015; 25: 499-513Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar,12Moroishi T. et al.The emerging roles of YAP and TAZ in cancer.Nat. Rev. Cancer. 2015; 15: 73-79Crossref PubMed Scopus (0) Google Scholar,13Moya I.M. Halder G. Hippo-YAP/TAZ signalling in organ regeneration and regenerative medicine.Nat. Rev. Mol. Cell Biol. 2019; 20: 211-226Crossref PubMed Scopus (0) Google Scholar]. The Hippo pathway is extracellularly regulated by mechanical stimuli and diffusible chemicals. These signals are sensed in great part by receptors, such as G-protein coupled receptors (GPCRs) and adherence complexes embedded in the plasma membrane [1Nicolson G.L. The fluid-mosaic model of membrane structure: still relevant to understanding the structure, function and dynamics of biological membranes after more than 40 years.Biochim. Biophys. Acta. 2014; 1838: 1451-1466Crossref PubMed Scopus (255) Google Scholar,10Hansen C.G. et al.YAP and TAZ: a nexus for Hippo signaling and beyond.Trends Cell Biol. 2015; 25: 499-513Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar, 11Panciera T. et al.Mechanobiology of YAP and TAZ in physiology and disease.Nat. Rev. Mol. Cell Biol. 2017; 18: 758-770Crossref PubMed Scopus (155) Google Scholar, 12Moroishi T. et al.The emerging roles of YAP and TAZ in cancer.Nat. Rev. Cancer. 2015; 15: 73-79Crossref PubMed Scopus (0) Google Scholar, 13Moya I.M. Halder G. Hippo-YAP/TAZ signalling in organ regeneration and regenerative medicine.Nat. Rev. Mol. Cell Biol. 2019; 20: 211-226Crossref PubMed Scopus (0) Google Scholar, 14Luo J. Yu F.X. GPCR-Hippo signaling in cancer.Cells. 2019; (Published online May 8, 2019)https://doi.org/10.3390/cells8050426Crossref Google Scholar, 15Karaman R. Halder G. Cell junctions in Hippo signaling.Cold Spring Harb. Perspect. Biol. 2018; (Published online May 1, 2018)https://doi.org/10.1101/cshperspect.a028753Crossref PubMed Scopus (8) Google Scholar, 16Fulford A. et al.Upstairs, downstairs: spatial regulation of Hippo signalling.Curr. Opin. Cell Biol. 2018; 51: 22-32Crossref PubMed Scopus (20) Google Scholar]. To ensure a highly specific response, junctional complexes and receptors accumulate in distinct membrane structures and their plasma membrane abundance is furthermore dynamically regulated by exo- and endocytosis [3Lampe M. et al.Clathrin coated pits, plaques and adhesion.J. Struct. Biol. 2016; 196: 48-56Crossref PubMed Scopus (22) Google Scholar,4McMahon H.T. Boucrot E. Molecular mechanism and physiological functions of clathrin-mediated endocytosis.Nat. Rev. Mol. Cell Biol. 2011; 12: 517-533Crossref PubMed Scopus (1079) Google Scholar,7Anvarian Z. et al.Cellular signalling by primary cilia in development, organ function and disease.Nat. Rev. Nephrol. 2019; 15: 199-219Crossref PubMed Scopus (13) Google Scholar,17Hansen C.G. Nichols B.J. Molecular mechanisms of clathrin-independent endocytosis.J. Cell Sci. 2009; 122: 1713-1721Crossref PubMed Scopus (189) Google Scholar]. Junctional complexes provide robust cellular sensitivity of Hippo signaling to cell polarity and cell–cell contacts [10Hansen C.G. et al.YAP and TAZ: a nexus for Hippo signaling and beyond.Trends Cell Biol. 2015; 25: 499-513Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar,15Karaman R. Halder G. Cell junctions in Hippo signaling.Cold Spring Harb. Perspect. Biol. 2018; (Published online May 1, 2018)https://doi.org/10.1101/cshperspect.a028753Crossref PubMed Scopus (8) Google Scholar,16Fulford A. et al.Upstairs, downstairs: spatial regulation of Hippo signalling.Curr. Opin. Cell Biol. 2018; 51: 22-32Crossref PubMed Scopus (20) Google Scholar]. Catenins [18Kim N.G. et al.E-cadherin mediates contact inhibition of proliferation through Hippo signaling-pathway components.Proc. Natl. Acad. Sci. U. S. A. 2011; 108: 11930-11935Crossref PubMed Scopus (333) Google Scholar,19Yang C.C. et al.Differential regulation of the Hippo pathway by adherens junctions and apical-basal cell polarity modules.Proc. Natl. Acad. Sci. U. S. A. 2015; 112: 1785-1790Crossref PubMed Scopus (0) Google Scholar], protein tyrosine phosphatase nonreceptor (PTPN)14 [20Liu X. et al.PTPN14 interacts with and negatively regulates the oncogenic function of YAP.Oncogene. 2013; 32: 1266-1273Crossref PubMed Scopus (92) Google Scholar,21Wang W. et al.PTPN14 is required for the density-dependent control of YAP1.Genes Dev. 2012; 26: 1959-1971Crossref PubMed Scopus (100) Google Scholar], and the angiomotin family [22Varelas X. et al.The Crumbs complex couples cell density sensing to Hippo-dependent control of the TGF-beta-SMAD pathway.Dev. Cell. 2010; 19: 831-844Abstract Full Text Full Text PDF PubMed Scopus (408) Google Scholar, 23Zhao B. et al.Angiomotin is a novel Hippo pathway component that inhibits YAP oncoprotein.Genes Dev. 2011; 25: 51-63Crossref PubMed Scopus (354) Google Scholar, 24Mana-Capelli S. McCollum D. Angiomotins stimulate LATS kinase autophosphorylation and act as scaffolds that promote Hippo signaling.J. Biol. Chem. 2018; 293: 18230-18241Crossref PubMed Scopus (2) Google Scholar, 25Wang W. et al.Angiomotin-like proteins associate with and negatively regulate YAP1.J. Biol. Chem. 2011; 286: 4364-4370Crossref PubMed Scopus (160) Google Scholar, 26Moleirinho S. et al.Regulation of localization and function of the transcriptional co-activator YAP by angiomotin.eLife. 2017; (Published online May 3, 2017)https://doi.org/10.7554/eLife.23966Crossref PubMed Google Scholar] play central roles in this regulation as direct YAP-binding proteins. Both PTPN14 and AMOT interact via PPxY motifs with WW domains of YAP and TAZ, and consequently, this interaction does not directly require YAP and TAZ Hippo-pathway-mediated phosphorylation [20Liu X. et al.PTPN14 interacts with and negatively regulates the oncogenic function of YAP.Oncogene. 2013; 32: 1266-1273Crossref PubMed Scopus (92) Google Scholar, 21Wang W. et al.PTPN14 is required for the density-dependent control of YAP1.Genes Dev. 2012; 26: 1959-1971Crossref PubMed Scopus (100) Google Scholar, 22Varelas X. et al.The Crumbs complex couples cell density sensing to Hippo-dependent control of the TGF-beta-SMAD pathway.Dev. Cell. 2010; 19: 831-844Abstract Full Text Full Text PDF PubMed Scopus (408) Google Scholar, 23Zhao B. et al.Angiomotin is a novel Hippo pathway component that inhibits YAP oncoprotein.Genes Dev. 2011; 25: 51-63Crossref PubMed Scopus (354) Google Scholar]. Several of the Hippo pathway components temporally localize to junctional complexes, including YAP and TAZ, KIBRA, LATS1/2, neurofibromatosis type 2 (NF2), and MST1/2 [24Mana-Capelli S. McCollum D. Angiomotins stimulate LATS kinase autophosphorylation and act as scaffolds that promote Hippo signaling.J. Biol. Chem. 2018; 293: 18230-18241Crossref PubMed Scopus (2) Google Scholar,26Moleirinho S. et al.Regulation of localization and function of the transcriptional co-activator YAP by angiomotin.eLife. 2017; (Published online May 3, 2017)https://doi.org/10.7554/eLife.23966Crossref PubMed Google Scholar, 27Yin F. et al.Spatial organization of Hippo signaling at the plasma membrane mediated by the tumor suppressor Merlin/NF2.Cell. 2013; 154: 1342-1355Abstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar, 28Li Y. et al.Angiomotin binding-induced activation of Merlin/NF2 in the Hippo pathway.Cell Res. 2015; 25: 801-817Crossref PubMed Scopus (42) Google Scholar, 29Mao X. et al.CRB3 regulates contact inhibition by activating the Hippo pathway in mammary epithelial cells.Cell Death Dis. 2017; 8: e2546Crossref PubMed Scopus (11) Google Scholar]. At the junctional location the upstream Hippo pathway components are activated, and consequently, YAP/TAZ are inhibited. As cellular junctions function as mechanical cellular transducers, this spatiotemporal localization of Hippo pathway components brings them proximal to sense the exerted forces. The interplay between cellular junctions and the Hippo pathway is well established [10Hansen C.G. et al.YAP and TAZ: a nexus for Hippo signaling and beyond.Trends Cell Biol. 2015; 25: 499-513Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar,15Karaman R. Halder G. Cell junctions in Hippo signaling.Cold Spring Harb. Perspect. Biol. 2018; (Published online May 1, 2018)https://doi.org/10.1101/cshperspect.a028753Crossref PubMed Scopus (8) Google Scholar,16Fulford A. et al.Upstairs, downstairs: spatial regulation of Hippo signalling.Curr. Opin. Cell Biol. 2018; 51: 22-32Crossref PubMed Scopus (20) Google Scholar]. Here, we discuss recent evidence highlighting that additional plasma membrane domains, such as FAs, CCPs and plaques, caveolae, and primary cilia provide cellular feedback via the Hippo pathway.Box 1The Hippo Pathway and Regulation of YAP/TAZThe core Hippo pathway signaling cascade in mammals is comprised of a serine/threonine kinase cascade consisting of MST1/2 (homologs of the Drosophila kinase Hippo), interacting with the scaffolding proteins Salvador homolog 1 (SAV1) and neurofibromatosis type 2 (NF2/Merlin), as well as LATS1/2, which interact with MOB kinase activator 1A and B (MOB1A and B) [10Hansen C.G. et al.YAP and TAZ: a nexus for Hippo signaling and beyond.Trends Cell Biol. 2015; 25: 499-513Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar,16Fulford A. et al.Upstairs, downstairs: spatial regulation of Hippo signalling.Curr. Opin. Cell Biol. 2018; 51: 22-32Crossref PubMed Scopus (20) Google Scholar,154Meng Z. et al.Mechanisms of Hippo pathway regulation.Genes Dev. 2016; 30: 1-17Crossref PubMed Scopus (380) Google Scholar,155Gundogdu R. Hergovich A. MOB (Mps one Binder) proteins in the Hippo pathway and cancer.Cells. 2019; (Published online June 10, 2019)https://doi.org/10.3390/cells8060569Crossref PubMed Google Scholar] (Figure I). In the canonical Hippo pathway (components highlighted in magenta), MST1/2 interact with SAV1 and phosphorylate LATS1/2, which are activated and phosphorylate YAP/TAZ on five (YAP) and four (TAZ) conserved serine residues. These inhibitory phosphorylations of YAP and its paralog TAZ is a signal for the cytoplasmic retention and YAP/TAZ binding to 14-3-3 protein or YAP/TAZ degradation [10Hansen C.G. et al.YAP and TAZ: a nexus for Hippo signaling and beyond.Trends Cell Biol. 2015; 25: 499-513Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar,154Meng Z. et al.Mechanisms of Hippo pathway regulation.Genes Dev. 2016; 30: 1-17Crossref PubMed Scopus (380) Google Scholar]. This activation of MST1/2 and LATS1/2 denotes the Hippo pathway on state, where YAP/TAZ are inactive. In addition, Hippo (MST1/2)-independent, LATS1/2-mediated regulation of YAP/TAZ also occurs via the MAP4K kinase family [154Meng Z. et al.Mechanisms of Hippo pathway regulation.Genes Dev. 2016; 30: 1-17Crossref PubMed Scopus (380) Google Scholar], as well as by STK25 [156Lim S. et al.Identification of the kinase STK25 as an upstream activator of LATS signaling.Nat. Commun. 2019; 10: 1547Crossref PubMed Scopus (1) Google Scholar]. Under certain circumstances the nuclear dbf2-related1/2 kinases (NDR1/2), substrates of MAP4K, MST1/2, and STK24 (MST3), directly phosphorylate and inhibit YAP [157Stegert M.R. et al.Regulation of NDR protein kinase by hydrophobic motif phosphorylation mediated by the mammalian Ste20-like kinase MST3.Mol. Cell. Biol. 2005; 25: 11019-11029Crossref PubMed Scopus (113) Google Scholar, 158Zhang L. et al.NDR functions as a physiological YAP1 kinase in the intestinal epithelium.Curr. Biol. 2015; 25: 296-305Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, 159Chiba S. et al.MST2- and Furry-mediated activation of NDR1 kinase is critical for precise alignment of mitotic chromosomes.Curr. Biol. 2009; 19: 675-681Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar, 160Vichalkovski A. et al.NDR kinase is activated by RASSF1A/MST1 in response to Fas receptor stimulation and promotes apoptosis.Curr. Biol. 2008; 18: 1889-1895Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar, 161Selimoglu R.B.A. Joffre C. Meunier B. Parrini M.C. et al.RalA GTPase and MAP4K4 function through NDR1 activation in stress response and apoptotic signaling.J. Cell Biol. Cell Metab. 2014; (Published online August 18, 2014)https://doi.org/10.24966/CBCM-1943/100001Crossref Google Scholar]. This additional network of kinases (highlighted in blue in Figure I) provides additional means for signal input, cellular adaptability, and robustness. Unphosphorylated YAP/TAZ translocate into the nucleus where they primarily interact with TEAD1–4 to regulate gene transcription [13Moya I.M. Halder G. Hippo-YAP/TAZ signalling in organ regeneration and regenerative medicine.Nat. Rev. Mol. Cell Biol. 2019; 20: 211-226Crossref PubMed Scopus (0) Google Scholar,49Zhao B. et al.Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control.Genes Dev. 2007; 21: 2747-2761Crossref PubMed Scopus (1392) Google Scholar,59Zhao B. et al.TEAD mediates YAP-dependent gene induction and growth control.Genes Dev. 2008; 22: 1962-1971Crossref PubMed Scopus (1086) Google Scholar,162Hillmer R.E. Link B.A. The roles of Hippo signaling transducers Yap and Taz in chromatin remodeling.Cells. 2019; (Published online May 24, 2019)https://doi.org/10.3390/cells8050502Crossref PubMed Google Scholar]. The activity of the Hippo pathway core kinases is regulated by various stimuli; for example, cell–cell contact, extracellular signals, cell polarity, metabolic state, and mechanotransduction [10Hansen C.G. et al.YAP and TAZ: a nexus for Hippo signaling and beyond.Trends Cell Biol. 2015; 25: 499-513Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar,11Panciera T. et al.Mechanobiology of YAP and TAZ in physiology and disease.Nat. Rev. Mol. Cell Biol. 2017; 18: 758-770Crossref PubMed Scopus (155) Google Scholar,33Dupont S. et al.Role of YAP/TAZ in mechanotransduction.Nature. 2011; 474: 179-183Crossref PubMed Scopus (1826) Google Scholar,59Zhao B. et al.TEAD mediates YAP-dependent gene induction and growth control.Genes Dev. 2008; 22: 1962-1971Crossref PubMed Scopus (1086) Google Scholar]. In addition, SRC-activating phosphorylation of YAP and SRC-inhibitory phosphorylation of LATS facilitate YAP nuclear localization and induction of gene transcription [32Kim N.G. Gumbiner B.M. Adhesion to fibronectin regulates Hippo signaling via the FAK-Src-PI3K pathway.J. Cell Biol. 2015; 210: 503-515Crossref PubMed Scopus (0) Google Scholar,36Elbediwy A. et al.Integrin signalling regulates YAP and TAZ to control skin homeostasis.Development. 2016; 143: 1674-1687Crossref PubMed Scopus (86) Google Scholar,61Calvo F. et al.Mechanotransduction and YAP-dependent matrix remodelling is required for the generation and maintenance of cancer-associated fibroblasts.Nat. Cell Biol. 2013; 15: 637-646Crossref PubMed Scopus (450) Google Scholar,163Li P. et al.alphaE-catenin inhibits a Src-YAP1 oncogenic module that couples tyrosine kinases and the effector of Hippo signaling pathway.Genes Dev. 2016; 30: 798-811Crossref PubMed Scopus (56) Google Scholar,164Si Y. et al.Src inhibits the Hippo tumor suppressor pathway through tyrosine phosphorylation of Lats1.Cancer Res. 2017; 77: 4868-4880Crossref PubMed Scopus (26) Google Scholar]. Additional kinase mediated regulation of YAP/TAZ via NLK [119Hong A.W. et al.Osmotic stress-induced phosphorylation by NLK at Ser128 activates YAP.EMBO Rep. 2017; 18: 72-86Crossref PubMed Scopus (29) Google Scholar,120Moon S. et al.Phosphorylation by NLK inhibits YAP-14-3-3-interactions and induces its nuclear localization.EMBO Rep. 2017; 18: 61-71Crossref PubMed Scopus (35) Google Scholar], 5′ AMP-activated protein kinase (AMPK), cyclin-dependent kinase (CDK), and others are also incorporated [13Moya I.M. Halder G. Hippo-YAP/TAZ signalling in organ regeneration and regenerative medicine.Nat. Rev. Mol. Cell Biol. 2019; 20: 211-226Crossref PubMed Scopus (0) Google Scholar,16Fulford A. et al.Upstairs, downstairs: spatial regulation of Hippo signalling.Curr. Opin. Cell Biol. 2018; 51: 22-32Crossref PubMed Scopus (20) Google Scholar,154Meng Z. et al.Mechanisms of Hippo pathway regulation.Genes Dev. 2016; 30: 1-17Crossref PubMed Scopus (380) Google Scholar]. The quality of the integrated signals leads either to activation or inhibition of the cotranscriptional activators YAP and TAZ, and allows a specific and timely regulation of gene transcription [10Hansen C.G. et al.YAP and TAZ: a nexus for Hippo signaling and beyond.Trends Cell Biol. 2015; 25: 499-513Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar,11Panciera T. et al.Mechanobiology of YAP and TAZ in physiology and disease.Nat. Rev. Mol. Cell Biol. 2017; 18: 758-770Crossref PubMed Scopus (155) Google Scholar,13Moya I.M. Halder G. Hippo-YAP/TAZ signalling in organ regeneration and regenerative medicine.Nat. Rev. Mol. Cell Biol. 2019; 20: 211-226Crossref PubMed Scopus (0) Google Scholar,16Fulford A. et al.Upstairs, downstairs: spatial regulation of Hippo signalling.Curr. Opin. Cell Biol. 2018; 51: 22-32Crossref PubMed Scopus (20) Google Scholar,162Hillmer R.E. Link B.A. The roles of Hippo signaling transducers Yap and Taz in chromatin remodeling.Cells. 2019; (Published online May 24, 2019)https://doi.org/10.3390/cells8050502Crossref PubMed Google Scholar]. The core Hippo pathway signaling cascade in mammals is comprised of a serine/threonine kinase cascade consisting of MST1/2 (homologs of the Drosophila kinase Hippo), interacting with the scaffolding proteins Salvador homolog 1 (SAV1) and neurofibromatosis type 2 (NF2/Merlin), as well as LATS1/2, which interact with MOB kinase activator 1A and B (MOB1A and B) [10Hansen C.G. et al.YAP and TAZ: a nexus for Hippo signaling and beyond.Trends Cell Biol. 2015; 25: 499-513Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar,16Fulford A. et al.Upstairs, downstairs: spatial regulation of Hippo signalling.Curr. Opin. Cell Biol. 2018; 51: 22-32Crossref PubMed Scopus (20) Google Scholar,154Meng Z. et al.Mechanisms of Hippo pathway regulation.Genes Dev. 2016; 30: 1-17Crossref PubMed Scopus (380) Google Scholar,155Gundogdu R. Hergovich A. MOB (Mps one Binder) proteins in the Hippo pathway and cancer.Cells. 2019; (Published online June 10, 2019)https://doi.org/10.3390/cells8060569Crossref PubMed Google Scholar] (Figure I). In the canonical Hippo pathway (components highlighted in magenta), MST1/2 interact with SAV1 and phosphorylate LATS1/2, which are activated and phosphorylate YAP/TAZ on five (YAP) and four (TAZ) conserved serine residues. These inhibitory phosphorylations of YAP and its paralog TAZ is a signal for the cytoplasmic retention and YAP/TAZ binding to 14-3-3 protein or YAP/TAZ degradation [10Hansen C.G. et al.YAP and TAZ: a nexus for Hippo signaling and beyond.Trends Cell Biol. 2015; 25: 499-513Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar,154Meng Z. et al.Mechanisms of Hippo pathway regulation.Genes Dev. 2016; 30: 1-17Crossref PubMed Scopus (380) Google Scholar]. This activation of MST1/2 and LATS1/2 denotes the Hippo pathway on state, where YAP/TAZ are inactive. In addition, Hippo (MST1/2)-independent, LATS1/2-mediated regulation of YAP/TAZ also occurs via the MAP4K kinase family [154Meng Z. et al.Mechanisms of Hippo pathway regulation.Genes Dev. 2016; 30: 1-17Crossref PubMed Scopus (380) Google Scholar], as well as by STK25 [156Lim S. et al.Identification of the kinase STK25 as an upstream activator of LATS signaling.Nat. Commun. 2019; 10: 1547Crossref PubMed Scopus (1) Google Scholar]. Under certain circumstances the nuclear dbf2-related1/2 kinases (NDR1/2), substrates of MAP4K, MST1/2, and STK24 (MST3), directly phosphorylate and inhibit YAP [157Stegert M.R. et al.Regulation of NDR protein kinase by hydrophobic motif phosphorylation mediated by the mammalian Ste20-like kinase MST3.Mol. Cell. Biol. 2005; 25: 11019-11029Crossref PubMed Scopus (113) Google Scholar, 158Zhang L. et al.NDR functions as a physiological YAP1 kinase in the intestinal epithelium.Curr. Biol. 2015; 25: 296-305Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, 159Chiba S. et al.MST2- and Furry-mediated activation of NDR1 kinase is critical for precise alignment of mitotic chromosomes.Curr. Biol. 2009; 19: 675-681Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar, 160Vichalkovski A. et al.NDR kinase is activated by RASSF1A/MST1 in response to Fas receptor stimulation and promotes apoptosis.Curr. Biol. 2008; 18: 1889-1895Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar, 161Selimoglu R.B.A. Joffre C. Meunier B. Parrini M.C. et al.RalA GTPase and MAP4K4 function through NDR1 activation in stress response and apoptotic signaling.J. Cell Biol. Cell Metab. 2014; (Published online August 18, 2014)https://doi.org/10.24966/CBCM-1943/100001Crossref Google Scholar]. This additional network of kinases (highlighted in blue in Figure I) provides additional means for signal input, cellular adaptability, and robustness. Unphosphorylated YAP/TAZ translocate into the nucleus where they primarily interact with TEAD1–4 to regulate gene transcription [13Moya I.M. Halder G. Hippo-YAP/TAZ signalling in organ regeneration and regenerative medicine.Nat. Rev. Mol. Cell Biol. 2019; 20: 211-226Crossref PubMed Scopus (0) Google Scholar,49Zhao B. et al.Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control.Genes Dev. 2007; 21: 2747-2761Crossref PubMed Scopus (1392) Google Scholar,59Zhao B. et al.TEAD mediates YAP-dependent gene induction and growth control.Genes Dev. 2008; 22: 1962-1971Crossref PubMed Scopus (1086) Google Scholar,162Hillmer R.E. Link B.A. The roles of Hippo signaling transducers Yap and Taz in chromatin remodeling.Cells. 2019; (Published online May 24, 2019)https://doi.org/10.3390/cells8050502Crossref PubMed Google Scholar]. The activity of the Hippo pathway core kinases is regulated by various stimuli; for example, cell–cell contact, extracellular signals, cell polarity, metabolic state, and mechanotransduction [10Hansen C.G. et al.YAP and TAZ: a nexus for Hippo signaling and beyond.Trends Cell Biol. 2015; 25: 499-513Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar,11Panciera T. et al.Mechanobiology of YAP and TAZ in physiology and disease.Nat. Rev. Mol. Cell Biol. 2017; 18: 758-770Crossref PubMed Scopus (155) Google Scholar,33Dupont S. et al.Role of YAP/TAZ in mechanotransduction.Nature. 2011; 474: 179-183Crossref PubMed Scopus (1826) Google Scholar,59Zhao B. et al.TEAD mediates YAP-dependent gene induction and growth control.Genes Dev. 2008; 22: 1962-1971Crossref PubMed Scopus (1086) Google Scholar]. In addition, SRC-activating phosphorylation of YAP and SRC-inhibitory phosphorylation of LATS facilitate YAP nuclear localization and induction of gene transcription [32Kim N.G. Gumbiner B.M. Adhesion to fibronectin regulates Hippo signaling via the FAK-Src-PI3K pathway.J. Cell Biol. 2015; 210: 503-515Crossref PubMed Scopus (0) Google Scholar,36Elbediwy A. et al.Integrin signalling regulates YAP and TAZ to control skin homeostasis.Development. 2016; 143: 1674-1687Crossref PubMed Scopus (86) Google Scholar,61Calvo F. et al.Mechanotransduction and YAP-dependent matrix remodelling is required for the generation and maintenance of cancer-associated fibroblasts.Nat. Cell Biol. 2013; 15: 637-646Crossref PubMed Scopus (450) Google Scholar,163Li P. et al.alphaE-catenin inhibits a Src-YAP1 oncogenic module that couples tyrosine kinases and the effector of Hippo signaling pathway.Genes Dev. 2016; 30: 798-811Crossref PubMed Scopus (56) Google Scholar,164Si Y. et al.Src inhibits the Hippo tumor suppressor pathway through tyrosine phosphorylation of Lats1.Cancer Res. 2017; 77: 4868-4880Crossref PubMed Scopus (26) Google Scholar]. Additional kinase mediated regulation of YAP/TAZ via NLK [119Hong A.W. et al.Osmotic stress-induced phosphorylation by NLK at Ser128 activates YAP.EMBO Rep. 2017; 18: 72-86Crossref PubMed Scopus (29) Google Scholar,120Moon S. et al.Phosphorylation by NLK inhibits YAP-14-3-3-interactions and induces its nuclear localization.EMBO Rep. 201