Abstract
Author SummaryProcesses that control cell numbers are essential during normal development, when they are required to generate organs of the correct size, and during cancinogenesis, when they influence tumor growth. The Hippo pathway is an intercellular signaling pathway that relays information about cell-cell contact and cell polarity to a signal transduction pathway that regulates the transcription of genes controlling cell numbers. The role of Hippo signaling in controlling growth is conserved from fruit flies to humans, but many aspects of the Hippo signal transduction pathway remain poorly understood. In this article, we identify Zyx as a previously unknown component of the Hippo pathway in Drosophila, and characterize its role within the pathway. We show that Zyx plays an essential role in a branch of Hippo signaling that involves the transmembrane receptor protein Fat and its target Dachs, which is a myosin family protein. Our results suggest a model in which Fat regulates the localization of Dachs, Dachs subsequently binds Zyx, stimulating its binding with the kinase Warts/Lats, and thereby regulates downstream signaling events. Zyx is conserved in vertebrates and we suggest that vertebrate Zyx proteins might also be involved in the regulation of Hippo signaling and, thereby, organ growth.
Highlights
The Hippo pathway has emerged as an important regulator of growth during metazoan development, and its dysregulation is implicated in diverse cancers [1,2,3]
In a screen for additional components of the Fat and Hippo pathways, we examined a collection of transgenic flies expressing UAS-hairpin constructs, which mediate RNAi
Our characterization of Zyx identifies a role for it as a novel and integral component of the Hippo pathway, which is required for the Fat branch, but not the Ex branch, of Hippo signaling
Summary
The Hippo pathway has emerged as an important regulator of growth during metazoan development, and its dysregulation is implicated in diverse cancers [1,2,3]. Upstream branches of Hippo signaling have been characterized in Drosophila: Fat-dependent, Expanded-dependent, and Merlin-dependent [1,2,3]. These upstream branches converge on the kinase Warts (Wts), which can phosphorylate Yki. Phosphorylated Yki is retained in the cytoplasm, whereas unphosphorylated Yki can enter the nucleus and, in conjunction with DNA-binding partners, promote the transcription of downstream genes. Upstream branches of Hippo signaling regulate both the activity of Wts and its abundance. We describe the identification of Zyx102 (Zyx, FBgn0011642) as a novel component of Hippo signaling and characterize its role in the pathway
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