SIGNIFICANCE: Metazoans have evolved pathways that regulate the size of organs. One of the key pathways is known as the Hippo pathway. Research on the Hippo pathway has grown exponentially during the past 8 years, revealing a complex signaling network. When components of the network are affected by genetic lesions or are abnormally expressed, this leads to cancer. The main effectors of this pathway, YAP and TAZ, are transcriptional co-activators, which act as stemness factors and potent oncogenes. The applicants co-organized two Hippo workshops in Rome, Italy in 2009 & 2010, during which several paradoxes in the field emerged. We realized that the fast progress in this field is due to an active dialog between Drosophila geneticists and mammalian signalers. (See meeting reports in Science Signaling and CDD). The overwhelming interest of researchers in the function of the Hippo pathway in stem cells and cancer prompted us to seek a larger forum. At the proposed meeting we aim to: (i) Define why YAP and TAZ function as either oncogenes or tumor suppressors; (ii) Identify membrane complexes, which activate the Hippo pathway in mammals, as the orthology with the fly receptors is not clear; (iii) Define targets for small molecule inhibitors and activators within pathway components based on structured modules, including WW, PDZ and SARAH domains. INNOVATION: The meeting will bring together Drosophila geneticists, basic and clinical cancer researchers, and the stem cell research community. It should consolidate the emerging field and have an impact on development of new cancer therapies.