title: The Notch-mediated hyperplasia circuitry in Drosophila reveals a Src-JNK signaling axis.
abstract: Notch 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.
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, United States.
authors.forename: Diana M
authors.initials: DM
authors.lastname: Ho
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, United States.
authors.forename: S K
authors.initials: SK
authors.lastname: Pallavi
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, United States.
authors.forename: Spyros
authors.initials: S
authors.lastname: Artavanis-Tsakonas
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D004330:Drosophila; D029721:Drosophila Proteins / Q000378:metabolism*; D006965:Hyperplasia; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism*; D051880:Receptors, Notch / Q000378:metabolism*
chemical_list: D029721:Drosophila Proteins; C497759:N protein, Drosophila; D011518:Proto-Oncogene Proteins; D051880:Receptors, Notch; D011505:Protein-Tyrosine Kinases; D016392:Proto-Oncogene Proteins pp60(c-src); C100382:Src42A protein, Drosophila; C075699:Src64B protein, Drosophila; D048670:MAP Kinase Kinase 4
keywords: D. melanogaster; JNK; Notch; Src; cell biology; developmental biology; hyperplasia; proliferation; stem cells