Genetic studies have shown that ubiquitination and endocytosis of the Drosophila ligand Delta in signal-sending cells are required for activation of Notch signaling, but how these events promote Notch activation remains poorly understood. Here, we show that an ubiquitination-defective mutant of the murine Delta-homologue Dll1 is endocytosed but, in contrast to the wild-type Dll1, is unable to subsequently recycle back to the cell surface or to bind Notch1 efficiently. These results demonstrate that ubiquitination, although not required for endocytosis, is essential for Dll1 recycling and that recycling is required to acquire affinity for the receptor. On the other hand, a chimeric molecule encompassing the extracellular domain of Dll1 and the transmembrane/intracellular domain of Dll3, which contains no lysine, is endocytosed, recycled, and interacts with Notch1 but is unable to induce transendocytosis of the extracellular region of Notch1 or to signal. These observations suggest that the chimera uses an ubiquitination-independent signal to recycle, allowing it to acquire affinity for Notch1. Our results support the idea that ligand recycling determines its competence to bind efficiently to the receptor but that this is insufficient to allow it to perform transendocytosis, an event required for activation of Notch signaling. Finally, the present study indicates that Dll1 partially localizes to lipid microdomains, whereas both ubiquitination-defective Dll1 and the Dll1-3 chimera are excluded from these compartments, suggesting that these microdomains provide the environment necessary for Dll1 to activate Notch signaling.
Download full-text PDF |
Source |
---|---|
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2516222 | PMC |
http://dx.doi.org/10.1073/pnas.0800695105 | DOI Listing |
Parasitol Res
December 2024
Institute of Hygiene and Microbiology, University of Würzburg, Josef-Schneider-Strasse 2, 97080, Würzburg, Germany.
Pluripotent somatic stem cells are the drivers of unlimited growth of Echinococcus multilocularis metacestode tissue within the organs of the intermediate host. To understand the dynamics of parasite proliferation within the host, it is therefore important to delineate basic mechanisms of Echinococcus stem cell maintenance and differentiation. We herein undertake the first step towards characterizing the role of an evolutionarily old metazoan cell-cell communication system, delta/notch signalling, in Echinococcus cell fate decisions.
View Article and Find Full Text PDFAirway multiciliated cells (MCs) maintain respiratory health by clearing mucus and trapped particles through the beating of motile cilia. While it is known that ciliary lengths decrease along the proximal-distal (P-D) axis of the tracheobronchial tree, how this is regulated is unclear. Here, we demonstrate that canonical Notch signaling in MCs plays a critical role in stabilizing ciliary length.
View Article and Find Full Text PDFMicroPubl Biol
December 2024
Colby-Sawyer College, New London, New Hampshire, United States.
Polyfluoro-alkyl substances (PFAS) are widely distributed environmental contaminants linked to human toxicity and developmental delays, especially low birthweight (LBW). In this study, Human Umbilical Vein Endothelial Cells (HUVECs) were exposed to the PFAS perfluorooctanesulfonic acid (PFOS). After 48-hours, their proliferation, and differential gene expression were assessed.
View Article and Find Full Text PDFFront Immunol
December 2024
Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, ;China.
Background: Hepatocellular carcinoma (HCC) is a highly heterogeneous tumor, and the development of accurate predictive models for prognosis and drug sensitivity remains challenging.
Methods: We integrated laboratory data and public cohorts to conduct a multi-omics analysis of HCC, which included bulk RNA sequencing, proteomic analysis, single-cell RNA sequencing (scRNA-seq), spatial transcriptomics sequencing (ST-seq), and genome sequencing. We constructed a tumor purity (TP) and tumor microenvironment (TME) prognostic risk model.
J Dent Res
December 2024
Department of Oral Surgery, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, China.
As the supply source for gingival grafts, the palatal tissue possesses marked regenerative ability after repeated wounding over the buccal attached gingiva and skin. However, the intrinsic mechanisms are poorly understood. Schwann cells reportedly participate in wound repair of many tissues.
View Article and Find Full Text PDFEnter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!