What do mechanotransduction, Hippo, Wnt, and TGFβ have in common? YAP and TAZ as key orchestrating molecules in ocular health and disease

Abstract

Cells in vivo are exposed to a complex signaling environment. Biochemical signaling modalities, such as secreted proteins, specific extracellular matrix domains and ion fluxes certainly compose an important set of regulatory signals to cells. However, these signals are not exerted in isolation, but rather in concert with biophysical cues of the surrounding tissue, such as stiffness and topography. In this review, we attempt to highlight the biophysical attributes of ocular tissues and their influence on cellular behavior. Additionally, we introduce the proteins YAP and TAZ as targets of biophysical and biochemical signaling and important agonists and antagonists of numerous signaling pathways, including TGFβ and Wnt. We frame the discussion around this extensive signaling crosstalk, which allows YAP and TAZ to act as orchestrating molecules, capable of integrating biophysical and biochemical cues into a broad cellular response. Finally, while we draw on research from various fields to provide a full picture of YAP and TAZ, we attempt to highlight the intersections with vision science and the exciting work that has already been performed.

Keywords: TAZ; TGFβ; Wnt; YAP; biophysical cueing; hippo; mechanotransduction.

Figure 1. YAP/TAZ Influences Multiple Signaling Pathways

YAP/TAZ are best known as the primary targets of Hippo signaling and have recently been implicated in biophysical signaling. Additionally, YAP/TAZ expression, phosphorylation, and localization regulate TGFβ, Wnt, and a host of other proliferation and differentiation control pathways. Note: This schematic is simplified to clarify the major interactions in YAP/TAZ signaling, and is not intended to exhaustively represent all known YAP/TAZ interactions.

Figure 2. The Hippo Pathway in Drosophila and Mammals

Canonical Hippo pathway complexes act to phosphorylate Yki or YAP/TAZ and prevent assembly of the Sd or TEAD transcriptional complexes with MASK. Phosphorylated YAP/TAZ is cytoplasmically retained by 14-3-3σ and targeted for degradation. Similar coloration is used to highlight the level of homology and conservation of the pathway between Drosophila and mammals. Note: This schematic is simplified to clarify the major components in Hippo pathway.

Figure 3. Cell-cell Contact and YAP/TAZ

Cell-cell contact can inhibit YAP/TAZ transcriptional activity both by sequestration to adherins junctions (AJ) in an α-catenin dependent fashion and through E-cadherin/catentin dependant activation of the Hippo pathway. Additionally, AMOT can sequester YAP/TAZ regardless of phosphorylation status. Note: This schematic is simplified to highlight the major factors in cell contact inhibition of YAP/TAZ.

Figure 4. Mechanical regulation of the Hippo pathway

Hippo is regulated by multiple signals generated by the physical (matrix stiffness) and biochemical (LPA, S1P, thrombin) environment. Importantly, many of these signals are modulated by tension in the actinomyosin cytoskeleton. Modulation of cytoskeletal mechanics through G-protein coupled receptors and matrix biophysics can likewise inhibit YAP/TAZ directly at the nuclear translocation stage or through activation of Hippo components. Note: This schematic is simplified to clarify the major components in the mechanical regulation of YAP/TAZ signaling.

Figure 5. Crosstalk between YAP/TAZ and TGFβ

TGF β superfamily signaling (especially TGFβ and BMP) is initiated by the binding of an extracellular ligand, which leads to the phosphorylation of the R-SMADs (SMADs 1/5 and 2/3 shown) and the formation of a complex with R-SMADs and a Co-SMAD (SMAD4). After translocation to the nucleus, these complexes initiate the TGFβ/BMP transcriptional program. Through direct interaction with TAZ, SMAD2/3 can be retained in either the cytoplasm or nucleus, depending on the localization of TAZ. Additionally, YAP can enhance the inhibitory effects of SMAD7 or enhance the transcription of SMAD1/5. Note: This schematic is simplified to clarify the major intersections of YAP/TAZ and TGFβ.

Figure 6. Crosstalk between YAP/TAZ and Wnt

Canonical Wnt is initiated by the binding of a Wnt ligand to the Fzd/LRP receptor complex. This induces the inhibitory behavior of Dvl on the Axin/APC/GSK3β complex, freeing β-catenin to complex with Dvl and the transcription factor TCF/LEF and initiate the Wnt transcriptional program. YAP/TAZ can inhibit Wnt signaling through inhibition of Dvl in the cytoplasm (TAZ) or in the nucleus (YAP) or cytoplasmic sequestration of β-catenin (YAP). Alternatively, YAP can encourage the transcriptional activity of β-catenin. Note: This schematic is simplified to clarify the major intersections of YAP/TAZ and Wnt signaling.