A concentration-dependent endocytic trap and sink mechanism converts Bmper from an activator to an inhibitor of Bmp signaling
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Cell-biology study of Bmper endocytic regulation of Bmp signaling; the object is a molecular mechanism.
The study investigates molecular signaling mechanisms rather than how research is conducted or communicated.
Molecular cell-biology study of Bmper and Bmp signaling mechanisms.
Résumé
Bmper, which is orthologous to Drosophila melanogaster crossveinless 2, is a secreted factor that regulates Bmp activity in a tissue- and stage-dependent manner. Both pro- and anti-Bmp activities have been postulated for Bmper, although the molecular mechanisms through which Bmper affects Bmp signaling are unclear. In this paper, we demonstrate that as molar concentrations of Bmper exceed Bmp4, Bmper dynamically switches from an activator to an inhibitor of Bmp4 signaling. Inhibition of Bmp4 through a novel endocytic trap-and-sink mechanism leads to the efficient degradation of Bmper and Bmp4 by the lysosome. Bmper-mediated internalization of Bmp4 reduces the duration and magnitude of Bmp4-dependent Smad signaling. We also determined that Noggin and Gremlin, but not Chordin, trigger endocytosis of Bmps. This endocytic transport pathway expands the extracellular roles of selective Bmp modulators to include intracellular regulation. This dosage-dependent molecular switch resolves discordances among studies that examine how Bmper regulates Bmp activity and has broad implications for Bmp signal regulation by secreted mediators.
Conservé avec la notice de tri, où il sert de preuve aux étiquettes ci-dessus.
La notice
- Revue
- The Journal of Cell Biology
- Thématique
- Cellular transport and secretion
- Domaine
- Biochemistry, Genetics and Molecular Biology
- Établissements canadiens
- University of Toronto
- Organismes subventionnaires
- National Heart, Lung, and Blood Institute
- Mots-clés
- Endocytic cycleBiologyCell biologyBone morphogenetic proteinBMPR2Signal transductionEndocytosisNogginSMADInternalizationCrosstalkActivator (genetics)BiochemistryCellReceptor
- Résumé présent dans OpenAlex
- oui