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

Transforming growth factor beta (TGF-beta) 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-beta receptors localize to the ciliary tip and endocytic vesicles at the ciliary base in fibroblasts and that TGF-beta stimulation increases receptor localization and activation of SMAD2/3 and ERK1/2 at the ciliary base. Inhibition of CDE reduced TGF-beta-mediated signaling at the cilium, and TGF-beta signaling and CDE activity are reduced at stunted primary cilia in Tg737(orpk) fibroblasts. Similarly, TGF-beta signaling during cardiomyogenesis correlated with accumulation of TGF-beta receptors and activation of SMAD2/3 at the ciliary base. Our results indicate that the primary cilium regulates TGF-beta signaling and that the ciliary pocket is a compartment for CDE-dependent regulation of signal transduction.