Journal Article

YAP-dependent induction of amphiregulin identifies a non-cell-autonomous component of the Hippo pathway

Haber, Daniel A., Brugge, Joan S., Zhang, Jianmin, Dyson, Nicholas J., Wang, Rebecca, Ji, Jun-Yuan, Overholtzer, Michael, Smolen, Gromoslaw A., Yu, Min

2009

Overview

The Hippo pathway regulates proliferation and survival in Drosophila and mammals, although shared transcriptional targets of their effectors have not been identified. Mammalian YAP controls expression of the EGFR ligand amphiregulin to regulate epithelial-to-mesenchymal transition in mammary epithelial cells, and the EGFR pathway genetically interacts with Yorkie in Drosophila. The Hippo signalling pathway regulates cellular proliferation and survival, thus has profound effects on normal cell fate and tumorigenesis 1 , 2 , 3 . 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 4 , 5 , 6 , 7 , 8 , 9 , 10 . 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: Amphiregulin / Animals / Biomedical and Life Sciences / Cancer cells / Cancer Research / Carcinogenesis / Causes of / Cell Biology / Cell Cycle Proteins / Cell growth / Cell Line, Tumor / Cellular signal transduction / Developmental Biology / Drosophila melanogaster - genetics / Drosophila melanogaster - metabolism / Drosophila Proteins - genetics / Drosophila Proteins - metabolism / EGF Family of Proteins / Epidermal growth factor / ErbB Receptors - genetics / ErbB Receptors - metabolism / Female / Genetic aspects / Glycoproteins - genetics / Glycoproteins - metabolism / Health aspects / Humans / Intercellular Signaling Peptides and Proteins - genetics / Intercellular Signaling Peptides and Proteins - metabolism / Intracellular Signaling Peptides and Proteins - genetics / Intracellular Signaling Peptides and Proteins - metabolism / Kinases / letter / Life Sciences / Nuclear Proteins - genetics / Nuclear Proteins - metabolism / Physiological aspects / Physiology / Protein Serine-Threonine Kinases - genetics / Protein Serine-Threonine Kinases - metabolism / Proteins / Receptors, Invertebrate Peptide - metabolism / Signal Transduction / Stem Cells / Trans-Activators - genetics / Trans-Activators - metabolism / Transcription Factors - genetics / Transcription Factors - metabolism / YAP-Signaling Proteins