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    • br Acknowledgments We thank Drs Yasuhiro Saito and Mitsuru

    2022-07-26


    Acknowledgments We thank Drs. Yasuhiro Saito and Mitsuru Futakuchi for helpful discussion. We also thank Drs. Kohei Miyazono and Tadashi Matsuda for cells. This work was supported by Grant-in-Aids for Scientific Research on Innovative Area (16H06373; 16K15273) from MEXT, Japan (to M.H.) and by Project for Cancer Research and Therapeutic Evolution (P-CREATE) (160200000291) from AMED, Japan (to M.H.).
    Main Text The Hippo signaling pathway confers cells the ability to sense and respond to microenvironment cues originating from alterations in mechanical forces, extracellular matrix, metabolites, and growth factors and convert these signals into robust gene expression changes. The Hippo pathway is composed of a conserved set of signals that activate the LATS family of kinases, LATS1 and LATS2, which in turn phosphorylate the transcriptional regulators YAP and TAZ (YAP/TAZ) (Yu et al., 2015). Phosphorylation restricts nuclear YAP/TAZ accumulation and consequently results in reduced YAP/TAZ-mediated transcription. YAP/TAZ direct cellular processes that impact cell proliferation, cell survival, and cell fate, playing essential functions in organ patterning, regeneration, and homeostasis. Dysregulated YAP/TAZ activity contributes to a range of disease phenotypes, most notably driving oncogenic features associated with cancers. However, how dysregulated activation of YAP/TAZ occurs in disease has not been clear, and thus, major research efforts have focused on understanding the mechanisms of YAP/TAZ control. In this issue of Molecular Cell, Han et al. (2018) identify phosphatidic KPT-276 (PA) as an inhibitor of the LATS kinases, showing that elevated PA levels potently induce nuclear YAP/TAZ activity and may contribute to aberrant YAP/TAZ activation in cancer. PA is a key metabolite that is central to membrane phospholipid biosynthesis. Studies over the past decades have shown that PA also serves as an important signaling molecule that potentiates cancer cell growth (Park et al., 2012). The study by Han et al. (2018) suggests that the biological roles for PA are directed, at least in part, by the activation of the transcriptional regulator YAP. Han et al. (2018) show that exogenous PA strongly inhibits the phosphorylation of human YAP on Ser127, a residue known to be modified by the LATS kinases. They tested the metabolic pathways known to generate PA and found that phospholipase D (PLD)-mediated production of PA inhibited the phosphorylation and activation of YAP in cultured cancer cell lines. Elevated PLD activity has been reported in many different cancers and thus offers a potential mechanism for YAP dysregulation in disease. Consistent with this premise, Han et al. (2018) observed that high expression of the PLD1 gene correlates with YAP-regulated gene expression in breast cancer data available from The Cancer Genome Atlas (TCGA). Given that PLD1/2 deletion or inhibition was sufficient to restrict nuclear YAP localization and activity in the cancer cells used in this study, the PLD1/2 proteins appear attractive as targets for cancers with elevated YAP activity. Han et al. (2018) further offer mechanistic insight into how PA activates nuclear YAP activity. Through a series of biochemical experiments, they showed that PA directly binds to multiple regions within the LATS1 kinase, including a region that is important for association with MOB1 (Ni et al., 2015), which is a scaffold protein that directs LATS1 kinase activation (Hergovich et al., 2006). PA binding to LATS1 was shown to disrupt binding to MOB1 but did not affect LATS1 enzymatic activity, suggesting that PA guides the scaffolding of LATS kinases with key regulatory proteins for activation. Such regulatory roles for PA appear to extend beyond the LATS kinases within the Hippo pathway, as PA was also shown to bind to Neurofibromin-2 (NF2, also known as Merlin). PA binding to NF2 inhibited LATS1 recruitment to the cell membrane, which is an event important for coupling the LATS kinases with upstream activating kinases (Yin et al., 2013). PA binding did not affect NF2 membrane recruitment but, interestingly, was shown to bind to the FERM domain within NF2, a domain previously shown to associate with phosphorylated phosphoinositides, such as phosphatidylinositol 4,5-bisphosphate (PIP2) (Mani et al., 2011). PIP2 has been reported to induce NF2 recruitment to the plasma membrane and promotes an active structural conformation that leads to stronger (approximately 10-fold) binding to LATS1 (Chinthalapudi et al., 2018, Mani et al., 2011). Therefore, it appears that different phospholipids have distinct and possibly competing functions on NF2 to direct Hippo pathway signaling. These observations also raise the possibility that signals that activate PLD and the subsequent formation of PA may also lead to PIP2 breakdown, potentially leading to a shift of NF2 from a PIP2 to a PA-bound form, thereby modifying LATS kinase activation.