Document Detail

YAP-dependent induction of amphiregulin identifies a non-cell-autonomous component of the Hippo pathway.
MedLine Citation:
PMID:  19935651     Owner:  NLM     Status:  MEDLINE    
The Hippo signalling pathway regulates cellular proliferation and survival, thus has profound effects on normal cell fate and tumorigenesis. The pivotal effector of this pathway is YAP (yes-associated protein), a transcriptional co-activator amplified in mouse and human cancers, where it promotes epithelial to mesenchymal transition (EMT) and malignant transformation. So far, studies of YAP target genes have focused on cell-autonomous mediators; here we show that YAP-expressing MCF10A breast epithelial cells enhance the proliferation of neighbouring untransfected cells, implicating a non-cell-autonomous mechanism. We identify the gene for the epidermal growth factor receptor (EGFR) ligand amphiregulin (AREG) as a transcriptional target of YAP, whose induction contributes to YAP-mediated cell proliferation and migration, but not EMT. Knockdown of AREG or addition of an EGFR kinase inhibitor abrogates the proliferative effects of YAP expression. Suppression of the negative YAP regulators LATS1 and 2 (large tumour suppressor 1 and 2) is sufficient to induce AREG expression, consistent with physiological regulation of AREG by the Hippo pathway. Genetic interaction between the Drosophila YAP orthologue Yorkie and Egfr signalling components supports the link between these two highly conserved signalling pathways. Thus, YAP-dependent secretion of AREG indicates that activation of EGFR signalling is an important non-cell-autonomous effector of the Hippo pathway, which has implications for the regulation of both physiological and malignant cell proliferation.
Jianmin Zhang; Jun-Yuan Ji; Min Yu; Michael Overholtzer; Gromoslaw A Smolen; Rebecca Wang; Joan S Brugge; Nicholas J Dyson; Daniel A Haber
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2009-11-22
Journal Detail:
Title:  Nature cell biology     Volume:  11     ISSN:  1476-4679     ISO Abbreviation:  Nat. Cell Biol.     Publication Date:  2009 Dec 
Date Detail:
Created Date:  2009-12-01     Completed Date:  2009-12-21     Revised Date:  2014-09-17    
Medline Journal Info:
Nlm Unique ID:  100890575     Medline TA:  Nat Cell Biol     Country:  England    
Other Details:
Languages:  eng     Pagination:  1444-50     Citation Subset:  IM    
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MeSH Terms
Cell Line, Tumor
Drosophila Proteins / genetics,  metabolism*
Drosophila melanogaster / genetics,  metabolism*
Glycoproteins / genetics,  metabolism*
Intercellular Signaling Peptides and Proteins / genetics,  metabolism*
Intracellular Signaling Peptides and Proteins / genetics,  metabolism*
Nuclear Proteins / genetics,  metabolism*
Protein-Serine-Threonine Kinases / genetics,  metabolism*
Receptor, Epidermal Growth Factor / genetics,  metabolism
Receptors, Invertebrate Peptide / metabolism
Signal Transduction*
Trans-Activators / genetics,  metabolism*
Transcription Factors / genetics,  metabolism*
Grant Support
CA080111/CA/NCI NIH HHS; CA089393/CA/NCI NIH HHS; F32 CA117737/CA/NCI NIH HHS; GM053203/GM/NIGMS NIH HHS; GM81607/GM/NIGMS NIH HHS; R01 95281//PHS HHS; R01 GM081607/GM/NIGMS NIH HHS; R01 GM081607-02/GM/NIGMS NIH HHS; T32 CA09361/CA/NCI NIH HHS; T32 CA09361-27/CA/NCI NIH HHS; //Howard Hughes Medical Institute; //Howard Hughes Medical Institute
Reg. No./Substance:
0/Drosophila Proteins; 0/Glycoproteins; 0/Intercellular Signaling Peptides and Proteins; 0/Intracellular Signaling Peptides and Proteins; 0/Nuclear Proteins; 0/Receptors, Invertebrate Peptide; 0/Trans-Activators; 0/Transcription Factors; 0/YY1AP1 protein, human; 0/Yorkie protein, Drosophila; 117147-70-3/amphiregulin; EC protein, human; EC protein, Drosophila; EC, Epidermal Growth Factor; EC Kinases; EC protein, Drosophila

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