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• W2897615854 abstract "In this issue of Molecular Cell, Han et al., 2018Han H. Qi R. Zhou J.J. Ta A.P. Yang B. Nakaoka H.J. Guan K.L. Luo R. Wang W. Regulation of the Hippo pathway by phosphatidic acid-mediated lipid-protein interaction.Mol. Cell. 2018; 72 (this issue): 328-340Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar show that phosphatidic acid inhibits the action of the LATS kinases, key mediators of Hippo pathway signaling, which leads to an increase in the nuclear activity of the transcriptional regulator YAP. In this issue of Molecular Cell, Han et al., 2018Han H. Qi R. Zhou J.J. Ta A.P. Yang B. Nakaoka H.J. Guan K.L. Luo R. Wang W. Regulation of the Hippo pathway by phosphatidic acid-mediated lipid-protein interaction.Mol. Cell. 2018; 72 (this issue): 328-340Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar show that phosphatidic acid inhibits the action of the LATS kinases, key mediators of Hippo pathway signaling, which leads to an increase in the nuclear activity of the transcriptional regulator YAP. 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., 2015Yu F.X. Zhao B. Guan K.L. Hippo pathway in organ size control, tissue homeostasis, and cancer.Cell. 2015; 163: 811-828Abstract Full Text Full Text PDF PubMed Scopus (1323) Google Scholar). 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., 2018Han H. Qi R. Zhou J.J. Ta A.P. Yang B. Nakaoka H.J. Guan K.L. Luo R. Wang W. Regulation of the Hippo pathway by phosphatidic acid-mediated lipid-protein interaction.Mol. Cell. 2018; 72 (this issue): 328-340Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar identify phosphatidic acid (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., 2012Park J.B. Lee C.S. Jang J.H. Ghim J. Kim Y.J. You S. Hwang D. Suh P.G. Ryu S.H. Phospholipase signalling networks in cancer.Nat. Rev. Cancer. 2012; 12: 782-792Crossref PubMed Scopus (147) Google Scholar). The study by Han et al., 2018Han H. Qi R. Zhou J.J. Ta A.P. Yang B. Nakaoka H.J. Guan K.L. Luo R. Wang W. Regulation of the Hippo pathway by phosphatidic acid-mediated lipid-protein interaction.Mol. Cell. 2018; 72 (this issue): 328-340Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar suggests that the biological roles for PA are directed, at least in part, by the activation of the transcriptional regulator YAP. Han et al., 2018Han H. Qi R. Zhou J.J. Ta A.P. Yang B. Nakaoka H.J. Guan K.L. Luo R. Wang W. Regulation of the Hippo pathway by phosphatidic acid-mediated lipid-protein interaction.Mol. Cell. 2018; 72 (this issue): 328-340Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar 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., 2018Han H. Qi R. Zhou J.J. Ta A.P. Yang B. Nakaoka H.J. Guan K.L. Luo R. Wang W. Regulation of the Hippo pathway by phosphatidic acid-mediated lipid-protein interaction.Mol. Cell. 2018; 72 (this issue): 328-340Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar 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., 2018Han H. Qi R. Zhou J.J. Ta A.P. Yang B. Nakaoka H.J. Guan K.L. Luo R. Wang W. Regulation of the Hippo pathway by phosphatidic acid-mediated lipid-protein interaction.Mol. Cell. 2018; 72 (this issue): 328-340Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar 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., 2015Ni L. Zheng Y. Hara M. Pan D. Luo X. Structural basis for Mob1-dependent activation of the core Mst-Lats kinase cascade in Hippo signaling.Genes Dev. 2015; 29: 1416-1431Crossref PubMed Scopus (111) Google Scholar), which is a scaffold protein that directs LATS1 kinase activation (Hergovich et al., 2006Hergovich A. Schmitz D. Hemmings B.A. The human tumour suppressor LATS1 is activated by human MOB1 at the membrane.Biochem. Biophys. Res. Commun. 2006; 345: 50-58Crossref PubMed Scopus (142) Google Scholar). 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., 2013Yin F. Yu J. Zheng Y. Chen Q. Zhang N. Pan D. Spatial organization of Hippo signaling at the plasma membrane mediated by the tumor suppressor Merlin/NF2.Cell. 2013; 154: 1342-1355Abstract Full Text Full Text PDF PubMed Scopus (351) Google Scholar). 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., 2011Mani T. Hennigan R.F. Foster L.A. Conrady D.G. Herr A.B. Ip W. FERM domain phosphoinositide binding targets merlin to the membrane and is essential for its growth-suppressive function.Mol. Cell. Biol. 2011; 31: 1983-1996Crossref PubMed Scopus (34) Google Scholar). 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., 2018Chinthalapudi K. Mandati V. Zheng J. Sharff A.J. Bricogne G. Griffin P.R. Kissil J. Izard T. Lipid binding promotes the open conformation and tumor-suppressive activity of neurofibromin 2.Nat. Commun. 2018; 9: 1338Crossref PubMed Scopus (23) Google Scholar, Mani et al., 2011Mani T. Hennigan R.F. Foster L.A. Conrady D.G. Herr A.B. Ip W. FERM domain phosphoinositide binding targets merlin to the membrane and is essential for its growth-suppressive function.Mol. Cell. Biol. 2011; 31: 1983-1996Crossref PubMed Scopus (34) Google Scholar). 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. Several studies have indicated that PLD-regulated PA signaling intersects with Rho-mediated cytoskeletal remodeling to drive mesenchymal-like cellular features, and it is known that Rho signaling has the potential to induce YAP/TAZ nuclear activity. Accordingly, Han et al., 2018Han H. Qi R. Zhou J.J. Ta A.P. Yang B. Nakaoka H.J. Guan K.L. Luo R. Wang W. Regulation of the Hippo pathway by phosphatidic acid-mediated lipid-protein interaction.Mol. Cell. 2018; 72 (this issue): 328-340Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar provide evidence that PA can impact YAP regulation downstream of Rho activation. However, they did not directly test whether stiffness-mediated cytoskeletal remodeling impacts PLD-PA-directed inhibition of LATS activity. This is relevant given that recent evidence from a study by Meng et al., 2018Meng Z. Qiu Y. Lin K.C. Kumar A. Placone J.K. Fang C. Wang K.C. Lu S. Pan M. Hong A.W. et al.RAP2 mediates mechanoresponses of the Hippo pathway.Nature. 2018; 560: 655-660Crossref PubMed Scopus (184) Google Scholar suggests that inhibition of PDL1/2 in cells grown under condition of low stiffness results in the nuclear accumulation of YAP. This study proposes that at low stiffness, a collective increase in PIP2, PLD1 activity, and PA at the plasma membrane activates the RAP2 GTPase, which consequently inhibits nuclear YAP localization through upstream Hippo pathway signaling activation. This apparent contradictory finding that PA inhibits nuclear YAP localization can be reconciled by potential altered roles for PA in microenvironments of different stiffness. Meng et al., 2018Meng Z. Qiu Y. Lin K.C. Kumar A. Placone J.K. Fang C. Wang K.C. Lu S. Pan M. Hong A.W. et al.RAP2 mediates mechanoresponses of the Hippo pathway.Nature. 2018; 560: 655-660Crossref PubMed Scopus (184) Google Scholar show that RAP2 is activated by low matrix stiffness and at endogenous levels promotes Hippo pathway signaling to restrict nuclear YAP accumulation. Therefore, PA function or localization may differ in response to mechanical signals or cytoskeletal alterations. In support of this idea, PA has been shown to distribute as a gradient under different polarizing conditions. In the case of the intestinal epithelium, PA accumulates at the apical domain of polarized intestinal epithelial cells and locally activates RAP2 via apical recruitment of the guanine nucleotide exchange factor PDZGEF (Gloerich et al., 2012Gloerich M. ten Klooster J.P. Vliem M.J. Koorman T. Zwartkruis F.J. Clevers H. Bos J.L. Rap2A links intestinal cell polarity to brush border formation.Nat. Cell Biol. 2012; 14: 793-801Crossref PubMed Scopus (83) Google Scholar). A similar gradient at the cell membrane may occur upon cortical actin remodeling under low stiffness conditions. Meng et al., 2018Meng Z. Qiu Y. Lin K.C. Kumar A. Placone J.K. Fang C. Wang K.C. Lu S. Pan M. Hong A.W. et al.RAP2 mediates mechanoresponses of the Hippo pathway.Nature. 2018; 560: 655-660Crossref PubMed Scopus (184) Google Scholar indeed argue that PA-mediated recruitment of PDZGEFs to the cell membrane activates RAP2 in low stiffness environments, leading to RAP2-induced activation of the Hippo pathway. Given that most experiments performed by Han et al., 2018Han H. Qi R. Zhou J.J. Ta A.P. Yang B. Nakaoka H.J. Guan K.L. Luo R. Wang W. Regulation of the Hippo pathway by phosphatidic acid-mediated lipid-protein interaction.Mol. Cell. 2018; 72 (this issue): 328-340Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar were under the stiff conditions of tissue culture plastic, a minimal PA gradient may have existed in their studies, which might alter PA localization or function to facilitate binding to LATS kinases and NF2 (see model in Figure 1). Stiff microenvironment conditions likely exist in YAP/TAZ-driven cancers, and therefore, the loss of PA gradient under those conditions may be relevant for driving PA-mediated LATS kinase inhibition. The mechanisms uncovered by Han et al., 2018Han H. Qi R. Zhou J.J. Ta A.P. Yang B. Nakaoka H.J. Guan K.L. Luo R. Wang W. Regulation of the Hippo pathway by phosphatidic acid-mediated lipid-protein interaction.Mol. Cell. 2018; 72 (this issue): 328-340Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar therefore advance our understanding of Hippo pathway signaling and like any important study raise interesting new questions and avenues for future research. Regulation of the Hippo Pathway by Phosphatidic Acid-Mediated Lipid-Protein InteractionHan et al.Molecular CellOctober 4, 2018In BriefHan et al. report that phosphatidic acid (PA)-related lipid signaling is a key regulator of the Hippo pathway. PA directly binds Hippo pathway components LATS and NF2 and inhibits LATS-MOB1 complex formation and NF2-mediated LATS membrane translocation and activation, respectively, thereby inhibiting Hippo signaling. Full-Text PDF Open Archive" @default.
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• W2897615854 title "Phosphatidic Acid Signals via the Hippo Pathway" @default.
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