Abstract
The evolutionarily conserved Hippo kinase signaling cascade governs cell proliferation, tissue differentiation and organ size, and can promote tumor growth and cancer metastasis when dysregulated. Unlike conventional signaling pathways driven by ligand-receptor binding to initiate downstream cascades, core Hippo kinases are activated not only by biochemical cues but also by mechanical ones generated from altered cell shape, cell polarity, cell-cell junctions or cell-extracellular matrix adhesion. In this review, we focus on recent advances showing how mechanical force acts through the actin cytoskeleton to regulate the Hippo pathway during cell movement and cancer invasion. We also discuss how this force affects YAP-dependent tissue growth and cell proliferation, and how disruption of that homeostatic relationship contributes to cancer metastasis.
Highlights
Hippo (Hpo) signaling was initially identified through a genetic screen for cell size control in Drosophila melanogaster, revealing a conserved pathway that regulates organ size, cell fate, tissue homeostasis and tumor progression
Overexpression of α-Catenin in low-density culture brings Yes-associated protein (YAP) to the plasma membrane, an outcome not observed upon overexpression of other components of adherens junctions such as E-Cadherin (Schlegelmilch et al, 2011). These findings suggest that α-Catenin is the mediator that transduces mechanical cues from E-Cadherin in fully confluent cultures, keeping YAP/α-Catenin/14-3-3 close to the plasma membrane and thereby preventing YAP activity in the nucleus
In a model of circulating cancer cells, YAP has been shown to transcriptionally activate ARHGAP29, an inhibitor of RhoA, thereby reducing the rigidity of the cytoskeleton network by escalating G- and F-actin turnover (Qiao et al, 2017). This model has been well acknowledged for investigating the mechanism of distal metastasis in cancers (Nagrath et al, 2007; Massague and Obenauf, 2016), and it provides a clear insight into how YAP promotes cancer cell motility by affecting actin dynamics
Summary
Hippo (Hpo) signaling was initially identified through a genetic screen for cell size control in Drosophila melanogaster, revealing a conserved pathway that regulates organ size, cell fate, tissue homeostasis and tumor progression. The Hpo network is primarily a core kinase cascade, involving Hpo/mammalian Ste20-like kinases 1/2 (MST1/2), Salvador (Sav)/SAV1, Mats/MOB kinase activator 1A/B (MOB1A/B), and Warts (Wts)/large tumor suppressor kinase 1/2 (LATS1/2). This latter phosphorylates the transcription factor Yorki (Yki)/Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) to prevent its nuclear translocation, thereby blocking target gene activation (Ma et al, 2019) (Figure 1). Since Hpo is an evolutionarily conserved pathway, components we describe include both Drosophila molecules and the corresponding vertebrate homologs
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