title: TGF-β signaling is associated with endocytosis at the pocket region of the primary cilium.
abstract: Transforming growth factor β (TGF-β) signaling is regulated by clathrin-dependent endocytosis (CDE) for the control of cellular processes during development and in tissue homeostasis. The primary cilium coordinates several signaling pathways, and the pocket surrounding the base and proximal part of the cilium is a site for CDE. We report here that TGF-β receptors localize to the ciliary tip and endocytic vesicles at the ciliary base in fibroblasts and that TGF-β stimulation increases receptor localization and activation of SMAD2/3 and ERK1/2 at the ciliary base. Inhibition of CDE reduced TGF-β-mediated signaling at the cilium, and TGF-β signaling and CDE activity are reduced at stunted primary cilia in Tg737orpk fibroblasts. Similarly, TGF-β signaling during cardiomyogenesis correlated with accumulation of TGF-β receptors and activation of SMAD2/3 at the ciliary base. Our results indicate that the primary cilium regulates TGF-β signaling and that the ciliary pocket is a compartment for CDE-dependent regulation of signal transduction.
authors.affiliation: Department of Biology, University of Copenhagen, DK-1165 Copenhagen, Denmark.
authors.forename: Christian Alexandro
authors.initials: CA
authors.lastname: Clement
authors.forename: Katrine Dalsgaard
authors.initials: KD
authors.lastname: Ajbro
authors.forename: Karen
authors.initials: K
authors.lastname: Koefoed
authors.forename: Maj Linea
authors.initials: ML
authors.lastname: Vestergaard
authors.forename: Iben Rønn
authors.initials: IR
authors.lastname: Veland
authors.forename: Maria Perestrello Ramos
authors.initials: MP
authors.lastname: Henriques de Jesus
authors.forename: Lotte Bang
authors.initials: LB
authors.lastname: Pedersen
authors.forename: Alexandre
authors.initials: A
authors.lastname: Benmerah
authors.forename: Claus Yding
authors.initials: CY
authors.lastname: Andersen
authors.forename: Lars Allan
authors.initials: LA
authors.lastname: Larsen
authors.forename: Søren Tvorup
authors.initials: ST
authors.lastname: Christensen
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002923:Cilia / Q000378:metabolism*; D004705:Endocytosis / Q000502:physiology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006801:Humans; D051379:Mice; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D018125:Receptors, Transforming Growth Factor beta