Department of Biology, University of Copenhagen, DK-1165 Copenhagen, Denmark.
Cell Rep. 2013 Jun 27;3(6):1806-14. doi: 10.1016/j.celrep.2013.05.020. Epub 2013 Jun 6.
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.
转化生长因子 β（TGF-β）信号受网格蛋白依赖的内吞作用（CDE）调控，以控制发育过程和组织稳态中的细胞过程。初级纤毛协调几种信号通路，纤毛基部和近端周围的口袋是 CDE 的部位。我们在这里报告，TGF-β 受体定位于成纤维细胞的纤毛尖端和纤毛基部的内吞小泡，并且 TGF-β 刺激增加了 SMAD2/3 和 ERK1/2 在纤毛基部的受体定位和激活。CDE 的抑制减少了纤毛中的 TGF-β 介导的信号转导，并且在 Tg737orpk 成纤维细胞中发育不良的初级纤毛中，TGF-β 信号转导和 CDE 活性降低。同样，心脏发生过程中的 TGF-β 信号转导与纤毛基部 TGF-β 受体的积累和 SMAD2/3 的激活相关。我们的结果表明，初级纤毛调节 TGF-β 信号转导，并且纤毛口袋是 CDE 依赖性调节信号转导的隔室。
