Document Detail


YAP mediates crosstalk between the Hippo and PI(3)K–TOR pathways by suppressing PTEN via miR-29.
MedLine Citation:
PMID:  23143395     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Karen Tumaneng; Karin Schlegelmilch; Ryan C Russell; Dean Yimlamai; Harihar Basnet; Navin Mahadevan; Julien Fitamant; Nabeel Bardeesy; Fernando D Camargo; Kun-Liang Guan
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Nature cell biology     Volume:  14     ISSN:  1476-4679     ISO Abbreviation:  Nat. Cell Biol.     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2013-01-17     Completed Date:  2013-01-28     Revised Date:  2013-03-08    
Medline Journal Info:
Nlm Unique ID:  100890575     Medline TA:  Nat Cell Biol     Country:  England    
Other Details:
Languages:  eng     Pagination:  1322-9     Citation Subset:  IM    
Affiliation:
Department of Pharmacology and Moores Cancer Center, School of Medicine, University of California at San Diego, La Jolla, California 92093, USA.
Data Bank Information
Bank Name/Acc. No.:
GEO/GSE41124
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MeSH Terms
Descriptor/Qualifier:
Adaptor Proteins, Signal Transducing / genetics,  metabolism*
Animals
Cell Line
Chromatin Immunoprecipitation
Chromones / pharmacology
Flow Cytometry
Hepatocyte Growth Factor / genetics,  metabolism*
High-Throughput Nucleotide Sequencing
Humans
Liver / drug effects,  metabolism
Male
Mice
Mice, Knockout
Mice, Transgenic
MicroRNAs / genetics,  metabolism*
Morpholines / pharmacology
PTEN Phosphohydrolase / genetics,  metabolism
Phosphoproteins / genetics,  metabolism*
Protein-Serine-Threonine Kinases / genetics,  metabolism*
Proto-Oncogene Proteins / genetics,  metabolism*
Real-Time Polymerase Chain Reaction
Grant Support
ID/Acronym/Agency:
R01 CA136567/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Adaptor Proteins, Signal Transducing; 0/Chromones; 0/MIRN29 microRNA, mouse; 0/MicroRNAs; 0/Morpholines; 0/Phosphoproteins; 0/Proto-Oncogene Proteins; 0/Yap protein, mouse; 0/macrophage stimulating protein; 154447-36-6/2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; 67256-21-7/Hepatocyte Growth Factor; EC 2.7.11.1/Mst2 protein, mouse; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 3.1.3.67/PTEN Phosphohydrolase
Comments/Corrections
Comment In:
Nat Cell Biol. 2012 Dec;14(12):1244-5   [PMID:  23196842 ]
Nat Rev Cancer. 2013 Jan;13(1):4-5   [PMID:  23192230 ]

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