Growth control by committee: intercellular junctions, cell polarity, and the cytoskeleton regulate Hippo signaling

Abstract

Over the past decade, the Hippo tumor suppressor pathway has emerged as a central regulator of growth in epithelial tissues. Research in Drosophila and in mammals has shown that this kinase signaling cascade regulates the activity of the transcriptional coactivator and oncoprotein Yorkie/Yap. In this review, we discuss recent findings that emphasize the cell cortex-specifically the actin cytoskeleton, intercellular junctions, and protein complexes that determine cell polarity-as a key site for Hippo pathway regulation. We also highlight where additional research is needed to integrate known functional interactions between Hippo pathway components.

Figure 1. Functionally conserved components of the Hippo tumor suppressor pathway

The FERM domain proteins Merlin and Expanded/FMD6 have been proposed to function upstream of the core kinase signaling cassette together with the WW domain protein Kibra. The sterile 20 kinase Tao-1 directly phosphorylates Hippo and MST kinases in vitro and promotes pathway activation in vivo. The scaffolding proteins Salvador/WW45 and Mats/Mob promote Hippo/MST and Warts/Lats kinase activity, respectively. Hippo/MST phosphorylates Warts/Lats, which in turn phosphorylates Yorkie/Yap to promote 14-3-3 binding. 14-3-3 sequesters Yorkie/Yap in the cytoplasm, preventing the transcription of target genes that promote tissue growth. In addition, Fat signaling (not shown) has been shown to regulate Warts stability and Yorkie activation in parallel to Hippo.

Figure 2. Yorkie/Yap activity is regulated by apical junctions and polarity proteins

In Drosophila, the FERM domain protein Expanded has been shown to physically interact with Yorkie at the cell membrane and prevent its translocation to the nucleus. The adhesion molecule Echinoid co-immunoprecipitates with several Hippo pathway components in S2 cells including Yorkie and promotes pathway activation. Fat and Crumbs are both large transmembrane proteins that localize to the subapical membrane and adherens junctions, respectively, and regulate the subcellular localization of Expanded. In addition, Fat is believed to regulate the Hippo/Salvador/Warts (HSW) kinase cascade independently of Expanded. In mammals, the adherens junction (AJ) protein α-catenin inhibits Yap activity by recruiting it to the cell membrane. In a similar fashion, the TJ protein AMOT and the subapical Crumbs complex (Crb3, Pals1 and PatJ) were recently shown to sequester Yap/Taz to the TJ, thereby inhibiting its oncogenic activity. For clarity, interactions with the HSW cascade have been omitted from the mammalian cell.