Ho, DianaPallavi, SKArtavanis-Tsakonas, Spyridon2015-08-032015Ho, Diana M, SK Pallavi, and Spyros Artavanis-Tsakonas. 2015. “The Notch-mediated hyperplasia circuitry in Drosophila reveals a Src-JNK signaling axis.” eLife 4 (1): e05996. doi:10.7554/eLife.05996. http://dx.doi.org/10.7554/eLife.05996.2050-084Xhttp://nrs.harvard.edu/urn-3:HUL.InstRepos:17820869Notch signaling controls a wide range of cell fate decisions during development and disease via synergistic interactions with other signaling pathways. Here, through a genome-wide genetic screen in Drosophila, we uncover a highly complex Notch-dependent genetic circuitry that profoundly affects proliferation and consequently hyperplasia. We report a novel synergistic relationship between Notch and either of the non-receptor tyrosine kinases Src42A and Src64B to promote hyperplasia and tissue disorganization, which results in cell cycle perturbation, JAK/STAT signal activation, and differential regulation of Notch targets. Significantly, the JNK pathway is responsible for the majority of the phenotypes and transcriptional changes downstream of Notch-Src synergy. We previously reported that Notch-Mef2 also activates JNK, indicating that there are commonalities within the Notch-dependent proliferation circuitry; however, the current data indicate that Notch-Src accesses JNK in a significantly different fashion than Notch-Mef2. DOI: http://dx.doi.org/10.7554/eLife.05996.001en-USNotchSrcJNKhyperplasiaproliferationJournal Article2015-08-0310.7554/eLife.05996