YAP-dependent induction of amphiregulin identifies a non-cell-autonomous component of the Hippo pathway.
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.
Zhang
Jianmin
J
Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.
Ji
Jun-Yuan
JY
Yu
Min
M
Overholtzer
Michael
M
Smolen
Gromoslaw A
GA
Wang
Rebecca
R
Brugge
Joan S
JS
Dyson
Nicholas J
NJ
Haber
Daniel A
DA
D066258:Amphiregulin; D000818:Animals; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism*; D066255:EGF Family of Proteins; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005260:Female; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D018010:Receptors, Invertebrate Peptide / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000091102:YAP-Signaling Proteins; D000099317:Hippo Kinases
D066258:Amphiregulin; D018797:Cell Cycle Proteins; D029721:Drosophila Proteins; D066255:EGF Family of Proteins; D066246:ErbB Receptors; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D018010:Receptors, Invertebrate Peptide; D015534:Trans-Activators; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C587848:AREG protein, human; C587849:Areg protein, mouse; C456659:YY1AP1 protein, human; C503814:Yki protein, Drosophila; C512478:EGFR protein, human; C066532:Egfr protein, Drosophila; C499474:hpo protein, Drosophila; D000099317:Hippo Kinases