TGF-β Signaling Is Associated with Endocytosis at the Pocket Region of the Primary Cilium

• Published in: Cell reports (Cambridge) 2013-06, Vol.3 (6), p.1806-1814
• Main Authors: Clement, Christian Alexandro, Ajbro, Katrine Dalsgaard, Koefoed, Karen, Vestergaard, Maj Linea, Veland, Iben Rønn, Henriques de Jesus, Maria Perestrello Ramos, Pedersen, Lotte Bang, Benmerah, Alexandre, Andersen, Claus Yding, Larsen, Lars Allan, Christensen, Søren Tvorup
• Format: Article
• Language: English
• Subjects: Animals; Cell Differentiation - physiology; Cellular Biology; Cilia - metabolism; Development Biology; Endocytosis - physiology; Fibroblasts - cytology; Fibroblasts - metabolism; Genetics; Human health and pathology; Humans; Life Sciences; Mice; Myocytes, Cardiac - cytology; Myocytes, Cardiac - metabolism; Receptors, Transforming Growth Factor beta - metabolism; Signal Transduction; Up-Regulation; Urology and Nephrology
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2013.05.020

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. [Display omitted] [Display omitted] •The primary cilium is a site for coordination of TGF-β signaling•TGF-β signaling was observed in fibroblasts and in stem cells during cardiomyogenesis•TGF-β signaling at the ciliary base is associated with clathrin-dependent endocytosis•The ciliary base may comprise a site for crosstalk between different signaling pathways Primary cilia are microtubule-based antenna-like structures present on the surface of a wide range of animal cells. Christensen, Larsen, and colleagues show that primary cilia take part in the coordination of TGF-β signaling, which regulates cellular processes during development and in tissue homeostasis. Signaling is associated with clathrin-dependent endocytosis at the ciliary pocket, which surrounds the base and proximal part of the cilium. These findings may improve our understanding of developmental disorders and diseases linked to defects in primary cilia.