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Transcriptional Output of the Salvador/Warts/Hippo Pathway Is Controlled in Distinct Fashions in Drosophila melanogaster and Mammalian Cell Lines

¹ Cell Growth and Proliferation Laboratory and ² Cell Cycle and Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia and ³ Department of Pathology, University of Melbourne, Parkville, Victoria, Australia

Requests for reprints: Kieran F. Harvey, Peter MacCallum Cancer Centre, 7 St. Andrews Place, East Melbourne, Victoria 3002, Australia. Phone: 61-3-9656-1291; Fax: 61-3-9656-1411; E-mail: kieran.harvey{at}petermac.org.

Key Words: tissue growth • oncogenic transformation • Hippo pathway • Yki/YAP • WW domain

The Salvador/Warts/Hippo (SWH) pathway is an important modulator of organ size, and deregulation of pathway activity can lead to cancer. Several SWH pathway components are mutated or expressed at altered levels in different human tumors including NF2, LATS1, LATS2, SAV1, and YAP. The SWH pathway regulates tissue growth by restricting the activity of the transcriptional coactivator protein known as Yorkie (Yki) in Drosophila melanogaster and Yes-associated protein (YAP) in mammals. Yki/YAP drives tissue growth in partnership with the Scalloped (Sd)/TEAD1-4 transcription factors. Yki/YAP also possesses two WW domains, which contact several proteins that have been suggested to either promote or inhibit the ability of Yki to induce transcription. To investigate the regulatory role of the Yki/YAP WW domains, we analyzed the functional consequence of mutating these domains. WW domain mutant YAP promoted transformation and migration of breast epithelial cells with increased potency, suggesting that WW domains mediate the inhibitory regulation of YAP in these cells. By contrast, the WW domains were required for YAP to promote NIH-3T3 cell transformation and for the ability of Yki to drive tissue growth in D. melanogaster and optimally activate Sd. This shows that Yki/YAP WW domains have distinct regulatory roles in different cell types and implies the existence of proteins that promote tissue growth in collaboration with Yki and Sd. [Cancer Res 2009;69(15):6033–41]

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