title: A concentration-dependent endocytic trap and sink mechanism converts Bmper from an activator to an inhibitor of Bmp signaling.
abstract: 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.
authors.affiliation: Department of Medicine, Carolina Cardiovascular Biology Center, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Rusty
authors.initials: R
authors.lastname: Kelley
authors.forename: Rongqin
authors.initials: R
authors.lastname: Ren
authors.forename: Xinchun
authors.initials: X
authors.lastname: Pi
authors.forename: Yaxu
authors.initials: Y
authors.lastname: Wu
authors.forename: Isabel
authors.initials: I
authors.lastname: Moreno
authors.forename: Monte
authors.initials: M
authors.lastname: Willis
authors.forename: Martin
authors.initials: M
authors.lastname: Moser
authors.forename: Malcolm
authors.initials: M
authors.lastname: Ross
authors.forename: Monika
authors.initials: M
authors.lastname: Podkowa
authors.forename: Liliana
authors.initials: L
authors.lastname: Attisano
authors.forename: Cam
authors.initials: C
authors.lastname: Patterson
mesh_terms: D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D002966:Clathrin / Q000378:metabolism; D004705:Endocytosis; D005347:Fibroblasts / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D015398:Signal Transduction
chemical_list: C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D002352:Carrier Proteins; D002966:Clathrin; C517553:crossveinless 2 protein, mouse