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Hippo‐Yap/Taz signaling: Complex network interactions and impact in epithelial cell behavior

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Abstract The Hippo pathway has emerged as a crucial integrator of signals in biological events from development to adulthood and in diseases. Although extensively studied in Drosophila and in cell cultures, major gaps of knowledge still remain on how this pathway functions in mammalian systems. The pathway consists of a growing number of components, including core kinases and adaptor proteins, which control the subcellular localization of the transcriptional co‐activators Yap and Taz through phosphorylation of serines at key sites. When localized to the nucleus, Yap/Taz interact with TEAD transcription factors to induce transcriptional programs of proliferation, stemness, and growth. In the cytoplasm, Yap/Taz interact with multiple pathways to regulate a variety of cellular functions or are targeted for degradation. The Hippo pathway receives cues from diverse intracellular and extracellular inputs, including growth factor and integrin signaling, polarity complexes, and cell–cell junctions. This review highlights the mechanisms of regulation of Yap/Taz nucleocytoplasmic shuttling and their implications for epithelial cell behavior using the lung as an intriguing example of this paradigm. This article is categorized under: Gene Expression and Transcriptional Hierarchies > Regulatory Mechanisms Signaling Pathways > Cell Fate Signaling Establishment of Spatial and Temporal Patterns > Cytoplasmic Localization
Overview of the Hippo‐Yap/Taz signaling pathway. Core components of the mammalian Hippo pathway and their regulation through phosphorylation events. (Left, canonical Hippo pathway): Hippo signaling inactive, nuclear Yap/Taz accumulation and activation of TEAD‐mediated transcriptional programs. Yap/Taz phosphorylation by the Hippo kinases (ultimately by Lats1/2) leading to cytoplasmic sequestration for interactions with other pathways, degradation and other functions (bottom). Mst1/2 and Lats1/2 are also activated by non‐canonical kinases Tao‐1, PKA and MAP4K (top and right)
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Hippo‐Yap/Taz crosstalks with metabolic pathways. (a) mTORC‐related metabolic pathways and Yap/Taz interact at multiple levels. Nuclear Yap/Taz: (1) induces mTORC activity through miR‐29 induction, which inhibits PTEN, a potent mTORC inhibitor; (2) enhances Akt activity by a currently unclear mechanism leading to increased mTORC activity; (3) induces expression of Lat1, a Leucine transporter, increasing amino acid uptake, which further stimulates mTORC activity. mTORC sustains nuclear Yap/Taz by inhibiting Amot through phosphorylation, which disables Amot‐Mst1/2 inhibitory interaction (4). This effect is enhanced by Akt inhibition of Mst1/2 activity (5). Integrin‐FAK‐Cdc42‐PP1 signaling inhibits Yap/Taz phosphorylation leading to nuclear accumulation enhancing mTORC activity (6). (b) mTORC‐independent pathways and Hippo. Nuclear Yap/Taz: (1) upregulates Ogt leading to O‐GlcNAcylation of Yap/Taz and inhibition of Lats1/2‐mediated phosphorylation; (2) upregulates Glut3, increasing glucose uptake, which further stimulates Yap/Taz O‐GlcNAcylation and prevents glucose starvation. Glucose starvation inhibits Yap/Taz nuclear accumulation by activating AMPK (3). AMPK promotes Yap/Taz cytoplasmic sequestration by activating Lats1/2 (3), directly phosphorylating Yap/Taz (4) and promoting Amot‐Yap/Taz inhibitory interaction through LKB1 (5)
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Hippo‐Yap/Taz crosstalks with Tgfβ, Notch, Egf, Igf, GPRCs. (a) Tgfβ signaling: (1) Tgfβ‐Smad2/3/4 signaling induces Taz. (2) Crumbs‐dependent Yap/Taz phosphorylation, subsequent binding to Smad2/3/4 and sequestration to cytoplasm prevents Tgfβ target gene expression. (3) Nuclear Yap inhibits AP‐1‐induced Smad7 induction. (4) Yap‐Smad7 interactions inhibits Tgfβ signaling. (b) Notch signaling: induction of Notch receptor and ligand expression by nuclear Yap/Taz. (c) Egf signaling: Egfr binding to Areg, Ereg or Egf induces a signaling cascade that inhibits both the degradation of Yap/Taz and the activity of Lats1/2, which promotes nuclear Yap/Taz accumulation and transcriptional activity. Yap/Taz targets include Egfr and Areg, establishing a positive feedback loop. (d) Igf signaling: Igf‐Igfr activation inhibits Mst1/2 activity through an Akt‐PI3K‐PDK1 signaling cascade resulting in Yap/Taz nuclear accumulation and induction of Igfr1 expression. This further inhibits Yap signaling through a positive feedback loop. (e) GPCR signaling employs an intracellular trimeric G‐protein complex for downstream signaling. Four different α subunits participate in this complex, of which three promote nuclear Yap accumulation and one (Gαs) inhibits Yap nuclear accumulation through mechanisms still unclear. Gα12/13 inhibits Lats1/2 activity through Rho‐mediated F‐Actin accumulation
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Hippo‐Yap crosstalk with Wnt signaling. Hippo‐Wnt crosstalk occurs at multiple levels. Yap/Taz and β‐catenin (β‐Cat) cooperate in the nucleus to induce Wnt target genes (1). Hippo kinase activity phosphorylates Yap/Taz (2). When Wnt signaling is inactive (“Wnt OFF” (3)), phospho‐Yap/Taz induce β‐catenin degradation by interacting with β‐catenin directly and recruiting β‐TrCP (3), leading to β‐catenin ubiquitination and degradation. When Wnt signaling is active (“Wnt ON” (4)), the β‐catenin degradation complex is inhibited, allowing β‐catenin nuclear translocation and induction of canonical Wnt targets
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Regulation Yap/Taz subcellular localization by Cell‐ECM signaling and the actin cytoskeleton. (a) Yap/Taz phosphorylation/cytoplasmic sequestration is favored in the context of a relaxed Actin fiber cytoskeleton (1), which stimulates Mer or PKA activity, promoting Mst1/2 and Lats1/2 activity, respectively (2). (b) Integrin‐mediated Yap/Taz nuclear accumulation. Actin‐dependent regulation of Yap/Taz subcellular localization: mechanotransduction through Rho or Src‐MAPK activity (3), leading to stretching or accumulation of actin fibers (4). Actin‐independent mechanisms: Integrin‐ILK or integrin‐FAK‐induced Src blocking Mer activity (5). Src tyrosine phosphorylation of Yap also induces Yap transcriptional activity (6). Yap/Taz induction of laminin expression and basement membrane deposition (7)
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Yap/Taz cytoplasmic sequestration by cell–cell junctions and polarity determinants. (a,b) Cell–cell‐contacts establish adherens junction (AJ) and tight junctions (TJ). At the AJ α‐catenin (α‐Cat) bound to β‐catenin (β‐Cat)‐E‐cadherin functions as a scaffold for interactions of Ajuba with Lats1/2 and 14–3‐3 with phospho‐Yap/Taz, leading to local cytoplasmic sequestration. Merlin (Mer) sequestered to TJ (Claudin/Occludin/ZO1) functions as a scaffold for Lats1/2, Amot‐Yap/Taz and Par3 (not represented). (c–e) At the apical domain Merlin‐WWC1‐Frmd6 form an apical scaffold for Merlin recruitment of Mst1/2 and Lats1/2 and their subsequent phosphorylation. Par‐1 inhibits Mst1/2 activity by both destabilizing Sav1 and phosphorylating Mst1/2 at Serine 30 residues. Dlg5 reinforces these Par‐1 effects. Lats1/2 may also be phosphorylated by PKA. Also at the apical domain, phosphorylated Lats1/2 recruited by Crumbs3 (Crb3) promotes efficient phosphorylation of Yap/Taz transported apically in part by direct interaction with Frmd6. (f) At the basal‐lateral domain, Scribble sequesters Mst1/2, Lats1/2, and Yap/Taz preventing their phosphorylation or nuclear shuttling
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Nuclear Yap/Taz, target gene induction and nuclear import/export balance. Model proposed for continuous Yap/Taz nucleocytoplasmic shuttling, nuclear accumulation or cytoplasmic sequestration regulated by nuclear import/export rates. TEAD can regulate Yap/Taz nuclear export rate by mechanisms such as modulation of the nuclear pore channel CRM‐1 or by physically occluding a nuclear export signal (NES) at the TEAD‐Yap/Taz interface (not represented). Yap/Taz‐TEAD interactions can be blocked by competitors (Vg, E2F1), which bind to TEAD instead of Yap/Taz. RB (retinoblastoma) relieves such competition. TEAD‐Yap/Taz recruit chromatin remodelers (Brg, GAF, NCo6A) and induce downstream gene targets
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Establishment of Spatial and Temporal Patterns > Cytoplasmic Localization
Signaling Pathways > Cell Fate Signaling
Gene Expression and Transcriptional Hierarchies > Regulatory Mechanisms