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General Comment |
The Hippo signaling pathway interactome. Kwon Y 2013 et al.
The Hippo pathway controls metazoan organ growth by regulating cell proliferation and apoptosis. Many components have been identified, but our knowledge of the composition and structure of this pathway is still incomplete. Using existing pathway components as baits, we generated by mass spectrometry a high-confidence Drosophila Hippo protein-protein interaction network (Hippo-PPIN) consisting of 153 proteins and 204 interactions. Depletion of 67% of the proteins by RNA interference regulated the transcriptional coactivator Yorkie (Yki) either positively or negatively. We selected for further characterization a new member of the alpha-arrestin family, Leash, and show that it promotes degradation of Yki through the lysosomal pathway. Given the importance of the Hippo pathway in tumor development, the Hippo-PPIN will contribute to our understanding of this network in both normal growth and cancer.
///ARRDC1 and 3 are orthologs for LEASH.
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The report of the Drosophila Hippo pathway interactome by Kwon et al. includes the discovery of a negative regulator of Yki, a previously uncharacterized alpha arrestin protein now aptly named "Leash" in flies. This protein interacts with and recruits Yki to endosomes, which is the first step in lysosomal degradation of Yki. Genetic analysis shows that this system works in parallel to Warts inhibition of Yki. Ubiquitination of Leash is crucial for inhibition of Yki, and Leash interacts with Nedd4, a ubiquitin ligase involved in endosomal-lysosomal?mediated destruction of proteins (10). Overall, these findings unveil a mechanism for attenuation of Yki activity that is associated with the endomembrane system. Although it is not clear whether human cells have a similar mechanism, mammalian alpha arrestin proteins related to Leash can modulate Yki when expressed in Drosophila cells (5), which suggests functional conservation.
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