%0 Journal Article
%T SNX17 regulates Notch pathway and pancreas development through the retromer-dependent recycling of Jag1
%A Wenguang Yin
%A Dapeng Liu
%A Nian Liu
%A Liangliang Xu
%A Song Li
%A Shuo Lin
%A Xiaodong Shu
%A Duanqing Pei
%J Cell Regeneration
%D 2012
%I BioMed Central
%R 10.1186/2045-9769-1-4
%X Here we identified SNX17 as a novel regulator of the Notch pathway. SNX17 is a sorting nexin family protein implicated in vesicular trafficking and we find it is specifically required in the ligand-expressing cells for Notch signaling. Mechanistically, SNX17 regulates the protein level of Jag1a on plasma membrane by binding to Jag1a and facilitating the retromer-dependent recycling of the ligand. In zebrafish, inhibition of this SNX17-mediated Notch signaling pathway results in defects in neurogenesis as well as pancreas development.Our results reveal that SNX17, by acting as a cargo-specific adaptor, promotes the retromer dependent recycling of Jag1a and Notch signaling and this pathway is involved in cell fate determination during zebrafish neurogenesis and pancreas development.In the canonical Notch pathway, membrane-bound ligand binds to the Notch (receptor) in the target cells and induces a series of proteolytic cleavages to release the Notch intracellular domain (NICD) from the plasma membrane. The NICD then translocates into the nucleus and activates the expression of Notch target genes [1,2]. Studies during the past decade have revealed that ubiquitylation by the Neur or Mib family E3 ubiquitin ligases and subsequent endocytosis of Notch ligands are essential for the activation of this pathway [3,4]. It has been proposed that endocytosis generates a pulling force on the Notch receptor and promotes the cleavage and the activation of the receptor. Otherwise, the internalized ligand can be recycled back to specific micro-domains on the plasma membrane conducive for Notch signaling. It has also been suggested that ligands can be activated by certain modifications during the recycling process [3-6]. However, the molecular nature of the modification remains elusive.Sorting nexin (SNX) family proteins play diverse roles in processes such as endocytosis, intracellular protein sorting and endosomal signaling [7]. The PX-BAR subfamily members of SNXs are able to induc
%U http://www.cellregenerationjournal.com/content/1/1/4