Regulation of Notch Trafficking and Signaling by Abelson kinase

Development relies on molecular signaling pathways to coordinate complex cellular processes. Notch signaling during development coordinates processes such as proliferation, cell fate decision making, and morphogenesis. While the core molecular and cellular events of Notch signaling have been elucidated, a complete understanding of how Notch signaling is regulated remains elusive. Here I dissect the regulation of Notch trafficking and signaling by Abelson kinase (Abl). Using a combination of Drosophila genetics and cell biology, I show that Abl prevents the accumulation of Notch receptor in endosomal compartments. In addition, Abl promotes Notch signaling during retina and wing development. In cell culture, Abl prevents Notch accumulation and promotes Notch signaling in a kinase-dependent way. Mechanistically, Abl phosphorylates Notch in vitro. One of the Abl-target tyrosine residues in Notch is required for repression of Notch signaling, revealing that Abl may also have repressive activity on Notch. This work elucidates a novel mechanism to regulate Notch trafficking and signaling. Given that Notch and Abelson play important roles in human cancers, the findings of this work are of potential relevance to human health.