Regulation of YAP by mTOR and autophagy reveals a therapeutic target of tuberous sclerosis complex

Liang, Ning; Zhang, Chi; Dill, Patricia; Panasyuk, Ganna; Pion, Delphine; Koka, Vonda; Gallazzini, Morgan; Olson, Eric N.; Lam, Hilaire C.; Henske, Elizabeth P.; Dong, Zheng; Apte, Udayan; Pallet, Nicolas; Johnson, Randy L.; Terzi, Fabiola; Kwiatkowski, David J.; Scoazec, Jean Yves; Martignoni, Guido; Pende, Mario

doi:10.1084/jem.20140341

Cited by 175 publications

(177 citation statements)

References 43 publications

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“…Importantly, thrombin, a ligand for the G-protein-coupled receptor PAR1, activated YAP1 and inhibited PTEN expression (33). Additionally, in the context of TSC1 ((hamartin) tuberous sclerosis 1) loss, mTOR has been reported to regulate YAP degradation in an ATG7 (autophagy-related protein 7)-dependent manner (36). Our data are compatible with these mechanisms in that they support coordinated regulation of Hippo and mTOR signaling to promote cell growth.…”

Section: Discussionsupporting

confidence: 80%

Phosphorylation of the Hippo Pathway Component AMOTL2 by the mTORC2 Kinase Promotes YAP Signaling, Resulting in Enhanced Glioblastoma Growth and Invasiveness

Artinian

Cloninger

Holmes

et al. 2015

Journal of Biological Chemistry

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Section: Discussionsupporting

confidence: 80%

Phosphorylation of the Hippo Pathway Component AMOTL2 by the mTORC2 Kinase Promotes YAP Signaling, Resulting in Enhanced Glioblastoma Growth and Invasiveness

Artinian

Cloninger

Holmes

et al. 2015

Journal of Biological Chemistry

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“…Cells and organisms must adjust to fluctuating nutrient levels, especially during development and regeneration [2,47,48]. Crosstalk between potent cellular growth pathways, such as the Hippo and mTOR pathways, on multiple levels is crucial to maintain homeostasis [1,45,[49][50][51][52]. This report shows that cells with high YAP/TAZ activity gain an enhanced ability of acquiring nutrients to support biosynthesis and growth.…”

Section: Discussionmentioning

confidence: 89%

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

et al. 2015

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YAP and TAZ are transcriptional co-activators and function as the major effectors of the Hippo tumor suppressor pathway, which controls cell growth, tissue homeostasis, and organ size. Here we show that YAP/TAZ play an essential role in amino acid-induced mTORC1 activation, particularly under nutrient-limiting conditions. Mechanistically, YAP/TAZ act via the TEAD transcription factors to induce expression of the high-affinity leucine transporter LAT1, which is a heterodimeric complex of SLC7A5 and SLC3A2. Deletion of YAP/TAZ abolishes expression of LAT1 and reduces leucine uptake. Re-expression of SLC7A5 in YAP/TAZ knockout cells restores leucine uptake and mTORC1 activation. Moreover, SLC7A5 knockout cells phenocopies YAP/TAZ knockout cells which exhibit defective mTORC1 activation in response to amino acids. We further demonstrate that YAP/TAZ act through SLC7A5 to provide cells with a competitive growth advantage. Our study provides molecular insight into the mechanism of YAP/TAZ target genes in cell growth regulation.

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“…Active Wts phosphorylates and inactivates Yki, leading to 14-3-3-mediated Yki cytoplasmic retention. addition, YAP protein can also be degraded by autophagy (Liang et al 2014).…”

Section: Core Components Of the Mammalian Hippo Pathwaymentioning

confidence: 99%

“…For instance, the nutrient-sensing kinases salt-induced kinase 2 and kinase 3 phosphorylate Sav at Ser413 to promote Yki target gene expression (Wehr et al 2013). Both mTORC1 and mTORC2 are reported to positively regulate YAP in perivascular epithelioid cell tumors and glioblastomas (Liang et al 2014;Artinian et al 2015;Sciarretta et al 2015). It is worth noting that mTORC1 is highly sensitive to nutrient availability and cellular energy status.…”

Section: Stress Signalsmentioning

confidence: 99%

Mechanisms of Hippo pathway regulation

2016

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The Hippo pathway was initially identified in Drosophila melanogaster screens for tissue growth two decades ago and has been a subject extensively studied in both Drosophila and mammals in the last several years. The core of the Hippo pathway consists of a kinase cascade, transcription coactivators, and DNA-binding partners. Recent studies have expanded the Hippo pathway as a complex signaling network with >30 components. This pathway is regulated by intrinsic cell machineries, such as cell–cell contact, cell polarity, and actin cytoskeleton, as well as a wide range of signals, including cellular energy status, mechanical cues, and hormonal signals that act through G-protein-coupled receptors. The major functions of the Hippo pathway have been defined to restrict tissue growth in adults and modulate cell proliferation, differentiation, and migration in developing organs. Furthermore, dysregulation of the Hippo pathway leads to aberrant cell growth and neoplasia. In this review, we focus on recent developments in our understanding of the molecular actions of the core Hippo kinase cascade and discuss key open questions in the regulation and function of the Hippo pathway.

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Regulation of YAP by mTOR and autophagy reveals a therapeutic target of tuberous sclerosis complex

Cited by 175 publications

References 43 publications

Phosphorylation of the Hippo Pathway Component AMOTL2 by the mTORC2 Kinase Promotes YAP Signaling, Resulting in Enhanced Glioblastoma Growth and Invasiveness

Phosphorylation of the Hippo Pathway Component AMOTL2 by the mTORC2 Kinase Promotes YAP Signaling, Resulting in Enhanced Glioblastoma Growth and Invasiveness

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

Mechanisms of Hippo pathway regulation

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