Abstract
Hippo pathways are ancient signaling systems that contribute to cell growth and proliferation in a wide diversity of eukaryotes, and have emerged as a conserved regulator of organ size control in metazoans. In budding yeast, a Hippo signaling pathway called the Regulation of Ace2 and Morphogenesis (RAM) network promotes polarized cell growth and the final event in the separation of mother and daughter cells. A crucial regulatory input for RAM network control of cell separation is phosphorylation of a conserved hydrophobic motif (HM) site on the NDR/LATS family kinase Cbk1. Here we provide the first direct evidence that the Hippo-like kinase Kic1 in fact phosphorylates the HM site of Cbk1, and show that Kic1 is allosterically activated by Hym1, a highly conserved protein related to mammalian MO25. Using the structure of mammalian MO25 in complex with the Kic1-related pseudokinase STRAD, we identified conserved residues on Kic1 that are required for interaction with Hym1. We find that Kic1 and Hym1 protein levels remain constant throughout the cell cycle but the proteins’ association is regulated, with maximal interaction coinciding with peak Cbk1 HM site phosphorylation. We show that this association is necessary but not sufficient for this phosphorylation, suggesting another level of regulation is required to promote the complex to act upon its substrates. This work presents a previously undiscovered cell cycle regulated interaction between a Hippo kinase and a broadly conserved allosteric activator. Because of the conserved nature of this pathway in higher eukaryotes, this work may also provide insight into the modularity of Hippo signaling pathways.
Highlights
Hippo pathways in yeast comprise core elements of an ancient signaling pathway that contributes to cell proliferation and morphogenesis in various eukaryotes
The Hippo pathway is an ancient signaling pathway that is conserved in metazoans and has been implicated in a wide variety of cellular functions ranging from cell morphology, proliferation, and apoptosis
We have discovered that the Kic1-Hym1 interaction is cell cycle regulated, suggesting that MO25 proteins can act as dynamically associating regulatory subunits
Summary
Hippo pathways in yeast comprise core elements of an ancient signaling pathway that contributes to cell proliferation and morphogenesis in various eukaryotes. First identified in Drosophila melanogaster, the Hippo/MST signaling pathway includes a set of genes responsible for controlling tissue size by regulating cell proliferation and cell death [1,2,3,4,5]. Mutations in these genes have been shown to cause abnormal cell growth and decreased cell death, suggesting that disruptions in the Hippo pathway can lead to tumorigenesis. This pathway is related to the RAM network (Regulation of Ace and Morphogenesis) and the mitotic exit network (MEN), both of which contain components that include a Hippo-like kinase and an NDR/LATS kinase [8]
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