The Hippo pathway effectors YAP and TAZ promote cell growth by modulating amino acid signaling to mTORC1

Hansen, Carsten Gram; Ng, Yuen Lam Dora; Lam, Wai-Ling Macrina; Plouffe, Steven W.; Guan, Kun‐Liang

doi:10.1038/cr.2015.140

Cited by 169 publications

(182 citation statements)

References 62 publications

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“…As a central effector of cell growth and proliferation, mTOR signaling has also been shown to mediate YAP function elsewhere (Hansen et al, 2015; Tumaneng et al, 2012), and our data add to the growing evidence that YAP is able to induce mTOR signaling through several different pathways.…”

Section: Discussionsupporting

confidence: 70%

An FAK-YAP-mTOR Signaling Axis Regulates Stem Cell-Based Tissue Renewal in Mice

et al. 2017

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Summary Tissue homeostasis requires production of newly differentiated cells from resident adult stem cells. Central to this process is the expansion of undifferentiated intermediates known as transit-amplifying (TA) cells, but how stem cells are triggered to enter this proliferative TA state remains an important open question. Using the continuously growing mouse incisor as a model of stem cell-based tissue renewal, we found that the transcriptional cofactors YAP and TAZ are required both to maintain TA cell proliferation and to inhibit differentiation. Specifically, we identified a pathway involving activation of Integrin α3 in TA cells that signals through a LATS-independent FAK/CDC42/PP1A cascade to control YAP-S397 phosphorylation and nuclear localization. This leads to Rheb expression and potentiates mTOR signaling to drive proliferation of TA cells. These findings thus reveal a YAP/TAZ signaling mechanism that coordinates stem cell expansion and differentiation during organ renewal.

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Section: Discussionsupporting

confidence: 70%

An FAK-YAP-mTOR Signaling Axis Regulates Stem Cell-Based Tissue Renewal in Mice

et al. 2017

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“…This inverse relationship is also clearly evidenced in PC tissues of TCGA dataset. It has been reported that YAP is a transcriptional coactivator and functions as the major effector of the Hippo tumor suppressor pathway, which controls cell growth, tissue homeostasis, and organ size [24]. Inhibition of YAP1 expression greatly reduces detachment-induced apoptosis [25].…”

Section: Discussionmentioning

confidence: 99%

miR-375 induces docetaxel resistance in prostate cancer by targeting SEC23A and YAP1

et al. 2016

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BackgroundTreatment options for metastatic castrate-resistant prostate cancer (mCRPC) are limited and typically are centered on docetaxel-based chemotherapy. We previously reported that elevated miR-375 levels were significantly associated with poor overall survival of mCRPC patients. In this study, we evaluated if miR-375 induced chemo-resistance to docetaxel through regulating target genes associated with drug resistance.MethodsWe first compared miR-375 expression level between prostate cancer tissues and normal prostate tissues using data from The Cancer Genome Atlas (TCGA). To examine the role of miR-375 in docetaxel resistance, we transfected miR-375 using a pre-miRNA lentiviral vector and examined the effects of exogenously overexpressed miR-375 on cell growth in two prostate cancer cell lines, DU145 and PC-3. To determine the effect of overexpressed miR-375 on tumor growth and chemo-resistance in vivo, we injected prostate cancer cells overexpressing miR-375 into nude mice subcutaneously and evaluated tumor growth rate during docetaxel treatment. Lastly, we utilized qRT-PCR and Western blot assay to examine two miR-375 target genes, SEC23A and YAP1, for their expression changes after miR-375 transfection.ResultsBy examining 495 tumor tissues and 52 normal tissues from TCGA data, we found that compared to normal prostate, miR-375 was significantly overexpressed in prostate cancer tissues (8.45-fold increase, p value = 1.98E-23). Docetaxel treatment induced higher expression of miR-375 with 5.83- and 3.02-fold increases in DU145 and PC-3 cells, respectively. Interestingly, miR-375 appeared to play a dual role in prostate cancer proliferation. While miR-375 overexpression caused cell growth inhibition and cell apoptosis, elevated miR-375 also significantly reduced cell sensitivity to docetaxel treatment in vitro, as evidenced by decreased apoptotic cells. In vivo xenograft mouse study showed that tumors with increased miR-375 expression were more tolerant to docetaxel treatment, demonstrated by greater tumor weight and less apoptotic cells in miR-375 transfected group when compared to empty vector control group. In addition, we examined expression levels of the two miR-375 target genes (SEC23A and YAP1) and observed significant reduction in the expression at both protein and mRNA levels in miR-375 transfected prostate cancer cell lines. TCGA dataset analysis further confirmed the negative correlations between miR-375 and the two target genes (r = −0.62 and −0.56 for SEC23A and YAP1, respectively; p < 0.0001).ConclusionsmiR-375 is involved in development of chemo-resistance to docetaxel through regulating SEC23A and YAP1 expression. Our results suggest that miR-375 or its target genes, SEC23A or YAP1, might serve as potential predictive biomarkers to docetaxel-based chemotherapy and/or therapeutic targets to overcome chemo-resistance in mCRPC stage.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-016-0556-9) contains supplementary material, which is available to authorize...

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“…Moreover, WNT signaling can stabilize YAP to potentiate its downstream effects, through upregulation of TRIB2, which downregulates a ubiquitin ligase that normally targets YAP for degradation 116 . Additionally, in certain subtypes of HCC, loss of Hippo signaling correlates with mTOR pathway activation 117, 118 , which is thought to proceed through activation of the PI3K pathway via a YAP-induced microRNA that reduces expression of PTEN 119 . YAP has also been shown to activate the mTOR pathway through the upregulation of amino acid transporters, SLC38A1 and SLC7A5 118 .…”

Section: Liver Cancer Developmentmentioning

confidence: 99%

Hippo Signaling in the Liver Regulates Organ Size, Cell Fate, and Carcinogenesis

2017

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The Hippo signaling pathway, also known as the Salvador–Warts–Hippo pathway, is a regulator of organ size. The pathway takes its name from the Drosophila protein kinase, Hippo (STK4/MST1 and STK3/MST2 in mammals), which, when inactivated, leads to considerable tissue overgrowth. In mammals, MST1 and MST2 negatively regulate the transcriptional co-activators yes-associated protein 1 (YAP) and WW domain containing transcription regulator 1 (WWTR1/TAZ), which together regulate the expression of genes that control proliferation, survival, and differentiation. YAP and TAZ activation have been associated with liver development, regeneration, and tumorigenesis. How their activity is dynamically regulated in these contexts, however, is just beginning to be elucidated. We review the mechanisms of Hippo signaling in the liver and explore outstanding questions for future research.

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The Hippo pathway effectors YAP and TAZ promote cell growth by modulating amino acid signaling to mTORC1

Cited by 169 publications

References 62 publications

An FAK-YAP-mTOR Signaling Axis Regulates Stem Cell-Based Tissue Renewal in Mice

An FAK-YAP-mTOR Signaling Axis Regulates Stem Cell-Based Tissue Renewal in Mice

miR-375 induces docetaxel resistance in prostate cancer by targeting SEC23A and YAP1

Hippo Signaling in the Liver Regulates Organ Size, Cell Fate, and Carcinogenesis

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