Abstract
Organ development is a complex process governed by the interplay of several signalling pathways that have critical functions in the regulation of cell growth and proliferation. Over the past years, the Hippo pathway has emerged as a key regulator of organ size. Perturbation of this pathway has been shown to play important roles in tumorigenesis. YAP, the main downstream target of the mammalian Hippo pathway, promotes organ growth, yet the underlying molecular mechanism of this regulation remains unclear. Here we provide evidence that YAP activates the mammalian target of rapamycin (mTOR), a major regulator of cell growth. We have identified the tumour suppressor PTEN, an upstream negative regulator of mTOR, as a critical mediator of YAP in mTOR regulation. We demonstrate that YAP downregulates PTEN by inducing miR-29 to inhibit PTEN translation. Last, we show that PI(3)K–mTOR is a pathway modulated by YAP to regulate cell size, tissue growth and hyperplasia. Our studies reveal a functional link between Hippo and PI(3)K–mTOR, providing a molecular basis for the coordination of these two pathways in organ size regulation.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism*
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Animals
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Cell Cycle Proteins
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Cell Line
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Chromatin Immunoprecipitation
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Chromones / pharmacology
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Flow Cytometry
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Hepatocyte Growth Factor / genetics
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Hepatocyte Growth Factor / metabolism*
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High-Throughput Nucleotide Sequencing
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Humans
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Liver / drug effects
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Liver / metabolism
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Male
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Mice
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Mice, Knockout
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Mice, Transgenic
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MicroRNAs / genetics
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MicroRNAs / metabolism*
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Morpholines / pharmacology
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PTEN Phosphohydrolase / genetics
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PTEN Phosphohydrolase / metabolism
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Phosphoproteins / genetics
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Phosphoproteins / metabolism*
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Real-Time Polymerase Chain Reaction
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Serine-Threonine Kinase 3
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YAP-Signaling Proteins
Substances
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Adaptor Proteins, Signal Transducing
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Cell Cycle Proteins
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Chromones
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MIRN29 microRNA, mouse
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MicroRNAs
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Morpholines
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Phosphoproteins
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Proto-Oncogene Proteins
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YAP-Signaling Proteins
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Yap1 protein, mouse
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macrophage stimulating protein
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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Hepatocyte Growth Factor
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Protein Serine-Threonine Kinases
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Serine-Threonine Kinase 3
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Stk3 protein, mouse
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PTEN Phosphohydrolase