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

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

VGLL4 Protects against Oxidized-LDL-Induced Endothelial Cell Dysfunction and Inflammation by Activating Hippo-YAP/TEAD1 Signaling Pathway

“…The occurrence of diseases is often related to the dysfunction of key signaling pathways, such as the Hippo-YAP signaling pathway [ 23 , 24 ]. As we all know, the Hippo-YAP signaling pathway plays an important role in the development of the heart and participates in various physiological and pathological processes, including cardiovascular development, cardiac hypertrophy, angiogenesis, and regeneration [ 25 – 27 ]. Healen et al have confirmed that cardiac-specific knockout of SAV1 can block the Hippo-YAP/TEAD1 signaling pathway, significantly reduce the level of Yap phosphorylation, and lead to cardiac hypertrophy, which has also been verified in MST1/2 and LATS2 knockout mice [ 28 – 30 ].…”

Genome-wide interrogation of gene functions through base editor screens empowered by barcoded sgRNAs

“…12c-d), we found that RPE1 cells, as a non-transformed cell line, were susceptible to perturbations in core Hippo-YAP/TAZ signaling, in agreement with previous studies that aberrant activation of YAP is sufficient to drive uncontrolled cell growth of normal cell types 46 . However, in HeLa -the cancer cell line, in which Hippo pathway is believed to be dysregulated [47][48][49][50] , these selected genes were distributed in both central and peripheral YAP/TAZ signaling pathways 51 .…”

YAP regulates alveolar epithelial cell differentiation and AGER via NFIB/KLF5/NKX2-1

“…In the absence of this phosphorylation, YAP is shuttled to the nucleus where it interacts with transcriptional co-factors, including TEADs 1-4, to regulate transcription of genes associated with cell proliferation, migration, and differentiation ( Varelas, 2014 ; Yu et al., 2015 ; Zhao et al., 2011 ; Pfleger, 2017 ). YAP interacts with several developmental pathways to regulate cell behaviors ( Piersma et al., 2015 ; van Soldt and Cardoso, 2020 ), including Wnt signaling to control cell proliferation and differentiation ( Gokey et al, 2018 ). In the developing airway, YAP directs basal cell fate decisions, with both nuclear and cytoplasmic YAP playing independent roles ( Mahoney et al., 2014 ; Lange et al., 2015 ; Zhao et al., 2014 ; van Soldt et al, 2019 ).…”