RT Journal Article
SR Electronic
T1 The Abelson tyrosine kinase and the Nedd4-family ubiquitin ligase Suppressor of Deltex converge at the Notch PPxY motif to regulate endosomal trafficking and signaling
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.10.20.347468
DO 10.1101/2020.10.20.347468
A1 Nicelio Sanchez-Luege
A1 Julio Miranda-Alban
A1 Xiao Sun
A1 Fernando M. Valbuena
A1 Benjamin S. Glick
A1 Ilaria Rebay
YR 2020
UL http://biorxiv.org/content/early/2020/10/20/2020.10.20.347468.abstract
AB The conserved Notch signaling pathway coordinates diverse cellular processes during animal development. Unlike most cell surface receptors that use a cytoplasmic cascade to amplify and diversify signaling dynamics, Notch itself transduces external cues directly to the nucleus. How appropriate signaling dynamics and transcriptional responses are achieved with this pathway architecture remains unclear. Here, we report that the cytoplasmic tyrosine kinase Abelson (Abl) fine-tunes Notch signaling by regulating Notch endocytic trafficking. We show that Abl can directly phosphorylate a PPxY motif important for Nedd4-family ubiquitin-ligase-mediated transfer of Notch into degradative endosomal compartments. Consistent with this, loss of Abl or inhibition of its kinase activity results in aberrant endosomal accumulation of Notch, while mutation of the PPxY tyrosine renders Notch insensitive to such regulation. Phenotypic and genetic interaction studies in the wing, together with parallel assays in cultured cells, show that loss or gain of Abl activity can respectively increase or decrease Notch output. We propose that the Notch PPxY motif operates as a molecular hub that integrates multiple post-translational modifications to regulate Notch trafficking and fine-tune signaling output.Competing Interest StatementThe authors have declared no competing interest.