YAP/TAZ upstream signals and downstream responses

Abstract

Cell behaviour is strongly influenced by physical, mechanical contacts between cells and their extracellular matrix. We review how the transcriptional regulators YAP and TAZ integrate mechanical cues with the response to soluble signals and metabolic pathways to control multiple aspects of cell behaviour, including proliferation, cell plasticity and stemness essential for tissue regeneration. Corruption of cell-environment interplay leads to aberrant YAP and TAZ activation that is instrumental for multiple diseases, including cancer.

Figure 1. Biomechanical signal transduction to YAP/TAZ.

Let top panel: cells respond to ECM rigidity by adjusting their tensional state through Integrin-mediated cell-ECM adhesions. Low ECM resistance corresponds to reduced adhesion and focal adhesion maturation, low actomyosin contractility and YAP/TAZ inactivation by yet unclear cytoplasmic or nuclear inhibitors (brown ring). Right panel: High ECM resistance favors integrin clustering and intracellular tension, disabling YAP/TAZ mechanically-regulated inhibitory mechanisms (red cross), allowing for YAP/TAZ function. Center: The F-actin cytoskeleton integrates mechanical strain arising from cell-ECM and cell-cell adhesions. These physical inputs are transduced into YAP/TAZ function. YAP/TAZ activation is mediated by release of YAP/TAZ from inhibitors but also entails modulation of YAP/TAZ nuclear-cytoplasmic shuttling. The F-actin cytoskeleton impacts on the mechanics and shape of the nucleus through Nesprin and SUN complexes, favoring YAP/TAZ nuclear entry by inducing nuclear deformation and increased permeability of the NPC. Bottom panels: Schematic representation of the signaling cascade that triggers actomyosin deposition and contractility at Integrin-mediated focal adhesions (left). ECM components Laminin and Agrin can signal to the actomyosin cytoskeleton through the dystroglycan-dystrophin complex (right). βPIX: PAK-interacting exchange factor; ECM: extracellular matrix; FAK: Focal adhesion kinase; NPC: nucelar pore complex; PAK: p-21 activated kinase; Rho GEFs: Rho Guanidine nucleotide exchange factors; ROCK: Rho-associated protein kinase; SUN: SUN domain-containing protein.

Figure 2. YAP/TAZ regulation by Hippo and Wnt signaling.

A) Schematic representation of the upstream components that activate the core module of the Hippo pathway, composed by the kinases MST1/2 and LATS1/2. The “Hippo ON” state results in YAP/TAZ phosphorylation with ensuing proteasomal degradation and/or cytoplasmic sequestration (left panel). In the “Hippo OFF” state YAP/TAZ are set free of inhibitory phosphorylations; in presence of other YAP/TAZ inducing/permissive extrinsic or intrinsic signals, YAP/TAZ activity is unleashed (right panel). B) YAP/TAZ - Wnt signaling interplay. The destruction complex is a multiprotein machinery at the core of the canonical Wnt pathway, controlling the intracellular levels of β-catenin. In the “Wnt OFF” state, YAP/TAZ associate with Axin to be incorporated in the destruction complex together with β-catenin. As such, the complex restrains both β-catenin and YAP/TAZ activity regulating their sequestration and/or degradation in the cytoplasm (left panel). In the presence of a “Wnt ON” state, the destruction complex is inhibited as Axin and GSK3 bind to the Wnt receptors LRP5/6 being internalized into MVBs. The disassembly of the complex by Wnt ligands abolishes both β-catenin and YAP/TAZ cytosolic inhibition, triggering their nuclear accumulation with consequent activation of transcriptional responses (right panel). The role of the destruction complex as checkpoint coordinating YAP/TAZ activity has been further corroborated by recent reports, including the findings that: i) SCD1 activity promotes the secretion of active (i.e., lipid-modified) Wnt ligands, leading to YAP/TAZ activation; ii) cytosolic TIAM1 is incorporated in the destruction complex to promote β-TrCP-dependent YAP/TAZ degradation and sequestration; iii) the actin regulator WIP stabilizes YAP/TAZ proteins by inhibiting the destruction complex into MVBs; iv) the tumor suppressor PKCζ associates with the destruction complex to inhibit YAP nuclear localization. APC: adenomatous polyposis coli; AMPK: AMP-activated protein kinase; βcat: β-catenin; β-TrCP: beta-transducin repeat containing protein; FZD: Frizzled; GSK3: Glycogen synthase kinase 3; LATS: large tumor suppressor kinase; LRP5/6: low-density lipoprotein receptor-related protein 5/6; MAP4K: MAP kinase kinase kinase kinase; MVB: multi-vesicular body; MST: mammalian Ste20-like kinase; NF2: neurofibromatosis type 2; PKCζ: protein kinase C, zeta; SAV1: Salvador 1; SCD1: stearoyl-CoA-desaturase 1; WIP: WASP-interacting protein.

Figure 3. YAP/TAZ nuclear activities and positive feedback mechanisms.

A. Active YAP/TAZ in the nucleus bind preferentially to TEAD co-transcription factors at cognate TEAD/AP-1 binding sequences. Complexes formed by YAP or TAZ with TEAD are in most cases formed at enhancer regions distal to the TSS, at which Pol-II is activated by chromatin looping. B. YAP/TAZ promote cell cycle progression by directly activating the transcription of different genes required for DNA replication, mitosis and checkpoint progression and indirectly by activating the transcription of other master transcription factors, as indicated. YAP/TAZ direct transcriptional target genes are shown in red.. C-I. Schematic representation of different physio-pathological and developmental conditions in which YAP/TAZ transcriptional program leads to the installment of a positive mechanical feedback. C) Mechanically activated MSCs; D) regenerating cardiomyocytes; E) activated myofibroblasts during liver fibrosis; F) lung branching morphogenesis; G) endothelial cells during vascular development,; H-I) activated CAFs and breast cancer cells,., AP-1: activator protein 1; CAFs: cancer associated fibroblasts; DGC: dystrophin-associated glycoprotein; FA: focal adhesions; MCM: mini chromosome maintenance; MSCs: mesenchymal stem cells; Pol-II: RNA polymerase II; Polα: DNA polymerase alpha; Polε : DNA polymerase epsilon; TEAD: TEA-domain family member; TSS: transcription start site.