Biology subjects

Sanchez-Luege, N.

Publications and source records attributed to Sanchez-Luege, N..

3 recordsLinked to original sources

bioRxiv2024

The Abelson kinase and the Nedd4-family E3 ligases co-regulate Notch trafficking to limit signaling

Precise output from the conserved Notch signaling pathway governs a plethora of cellular processes and developmental transitions. Unlike other pathways that use a cytoplasmic relay, the Notch cell surface receptor transduces signaling directly to the nucleus, with endocytic trafficking providing critical regulatory nodes. Here we report that the cytoplasmic tyrosine kinase Abelson (Abl) facilitates Notch internalization into late endosomes/multivesicular bodies (LEs), thereby limiting signaling output in both ligand-dependent and -independent contexts. Abl phosphorylates the PPxY motif within Notch, a molecular target for its degradation via Nedd4-family ubiquitin ligases. We show that Su(dx), a family member, mediates the Abl-directed LE regulation of Notch via the PPxY, while another family member, Nedd4Lo, contributes to Notch internalization into LEs through both PPxY-dependent and independent mechanisms. Our findings demonstrate how a network of post-translational modifiers converging at LEs cooperatively modulate Notch signaling to ensure the precision and robustness of its cellular and developmental functions.

developmental biology↗

bioRxiv2023

Orthogonal coupling of a 3D cytoskeletal scaffold coordinates cell morphogenesis and maintains tissue organization in the Drosophila pupal retina

How complex three-dimensional (3D) organs coordinate cellular morphogenetic events to achieve the correct final form is a central question in development. The question is uniquely tractable in the late Drosophila pupal retina where cells maintain stereotyped contacts as they elaborate the specialized cytoskeletal structures that pattern the apical, basal and longitudinal planes of the epithelium. In this study, we combined cell type-specific genetic manipulation of the cytoskeletal regulator Abelson (Abl) with 3D imaging to explore how the distinct cellular morphogenetic programs of photoreceptors and interommatidial pigment cells coordinately organize tissue pattern to support retinal integrity. Our experiments revealed an unanticipated intercellular feedback mechanism whereby correct cellular differentiation of either cell type can non-autonomously induce cytoskeletal remodeling in the other Abl mutant cell type, restoring retinal pattern and integrity. We propose that genetic regulation of specialized cellular differentiation programs combined with inter-plane mechanical feedback confers spatial coordination to achieve robust 3D tissue morphogenesis.

developmental biology↗

bioRxiv2020

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

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.

developmental biology↗