Spectrin regulates Hippo signaling by modulating cortical actomyosin activity

Abstract

The Hippo pathway controls tissue growth through a core kinase cascade that impinges on the transcription of growth-regulatory genes. Understanding how this pathway is regulated in development remains a major challenge. Recent studies suggested that Hippo signaling can be modulated by cytoskeletal tension through a Rok-myosin II pathway. How cytoskeletal tension is regulated or its relationship to the other known upstream regulators of the Hippo pathway remains poorly defined. In this study, we identify spectrin, a contractile protein at the cytoskeleton-membrane interface, as an upstream regulator of the Hippo signaling pathway. We show that, in contrast to canonical upstream regulators such as Crumbs, Kibra, Expanded, and Merlin, spectrin regulates Hippo signaling in a distinct way by modulating cortical actomyosin activity through non-muscle myosin II. These results uncover an essential mediator of Hippo signaling by cytoskeleton tension, providing a new entry point to dissecting how mechanical signals regulate Hippo signaling in living tissues.DOI: http://dx.doi.org/10.7554/eLife.06567.001

YAP and TAZ: a nexus for Hippo signaling and beyond

“…The forces elicited by these interactions are dynamically regulated and are especially important during processes where the cell experiences drastic changes, such as during development, cell differentiation, and regeneration [74,135–138] – all processes where the Hippo pathway has been shown to be an important mediator [3,74,84,137,140]. RHO activity and the actin cytoskeletal organization are robust regulators of YAP/TAZ activity [52,139,141–145]. YAP/TAZ localizes to the nucleus and is transcriptionally active in cells grown on high-rigidity substrate, under static or cyclic high tension, or in cells lacking cell–cell contact [139–142,146,147].…”

Cellular Organization and Cytoskeletal Regulation of the Hippo Signaling Network

“…Spectrins were found to influence Hippo signaling, both in Drosophila and in cultured mammalian cells, in three independent studies [115-117]. Two of these suggested that Spectrins might be regulated by cytoskeletal tension, and help transduce the effects of tension onto Hippo signaling, possibly through upstream regulators of Hippo signaling including Crumbs, Merlin, and Kibra [115, 116].…”

“…Two of these suggested that Spectrins might be regulated by cytoskeletal tension, and help transduce the effects of tension onto Hippo signaling, possibly through upstream regulators of Hippo signaling including Crumbs, Merlin, and Kibra [115, 116]. The other study, by contrast, reported that Spectrins influence myosin phosphorylation, and suggested that Spectrins might influence Hippo signaling by affecting actomyosin contractility [117]. Thus, while Spectrins clearly have an influence on Hippo signaling, defining the mechanism by which they regulate the Hippo network requires further study.…”

Control of Proliferation and Cancer Growth by the Hippo Signaling Pathway

“…The mechanical cues involved in the regulation of Hippo signaling include proteins that bind to intercellular junctions such as tight and adherence junctions as well as components of the cytoskeleton, including F-actin, microtubules, actomyosin, and possibly centrosomes (61–66). Specifically, the interactions with centrosomes may also be relevant to the regulation of cell cycle progression by Hippo signaling.…”