title: YAP mediates crosstalk between the Hippo and PI(3)K–TOR pathways by suppressing PTEN via miR-29.
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.
authors.affiliation: Department of Pharmacology and Moores Cancer Center, School of Medicine, University of California at San Diego, La Jolla, California 92093, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Tumaneng
authors.forename: Karin
authors.initials: K
authors.lastname: Schlegelmilch
authors.forename: Ryan C
authors.initials: RC
authors.lastname: Russell
authors.forename: Dean
authors.initials: D
authors.lastname: Yimlamai
authors.forename: Harihar
authors.initials: H
authors.lastname: Basnet
authors.forename: Navin
authors.initials: N
authors.lastname: Mahadevan
authors.forename: Julien
authors.initials: J
authors.lastname: Fitamant
authors.forename: Nabeel
authors.initials: N
authors.lastname: Bardeesy
authors.forename: Fernando D
authors.initials: FD
authors.lastname: Camargo
authors.forename: Kun-Liang
authors.initials: KL
authors.lastname: Guan
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D018797:Cell Cycle Proteins; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D002867:Chromones / Q000494:pharmacology; D005434:Flow Cytometry; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D000090742:Serine-Threonine Kinase 3; D000091102:YAP-Signaling Proteins; D000099317:Hippo Kinases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D002867:Chromones; D017228:Hepatocyte Growth Factor; D035683:MicroRNAs; D009025:Morpholines; D051059:PTEN Phosphohydrolase; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000090742:Serine-Threonine Kinase 3; D000091102:YAP-Signaling Proteins; C547014:MIRN29 microRNA, mouse; C486223:Yap1 protein, mouse; C082332:macrophage stimulating protein; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C490818:Stk3 protein, mouse; D000099317:Hippo Kinases