Primary cilia and coordination of receptor tyrosine kinase (RTK) signaling

Primary cilia are microtubule-based sensory organelles that coordinate signalling pathways in cell-cycle control, migration, differentiation and other cellular processes critical during development and for tissue homeostasis. Accordingly, defects in assembly or function of primary cilia lead to a plethora of developmental disorders and pathological conditions now known as ciliopathies. In this review, we summarize the current status of the role of primary cilia in coordinating receptor tyrosine kinase (RTK) signalling pathways. Further, we present potential mechanisms of signalling crosstalk and networking in the primary cilium and discuss how defects in ciliary RTK signalling are linked to human diseases and disorders

PDGFRaa Signaling Is Regulated through the Primary Cilium in Fibroblasts

SummaryRecent findings show that cilia are sensory organelles that display specific receptors and ion channels, which transmit signals from the extracellular environment via the cilium to the cell to control tissue homeostasis and function [1–6]. Agenesis of primary cilia or mislocation of ciliary signal components affects human pathologies, such as polycystic kidney disease [7] and disorders associated with Bardet-Biedl syndrome [8]. Primary cilia are essential for hedgehog ligand-induced signaling cascade regulating growth and patterning [9,10]. Here, we show that the primary cilium in fibroblasts [11] plays a critical role in growth control via platelet-derived growth factor receptor α (PDGFRα), which localizes to the primary cilium during growth arrest in NIH3T3 cells and primary cultures of mouse embryonic fibroblasts. Ligand-dependent activation of PDGFRαα is followed by activation of Akt and the Mek1/2-Erk1/2 pathways, with Mek1/2 being phosphorylated within the cilium and at the basal body. Fibroblasts derived from Tg737orpk mutants fail to form normal cilia and to upregulate the level of PDGFRα; PDGF-AA fails to activate PDGFRαα and the Mek1/2-Erk1/2 pathway. Signaling through PDGFRβ, which localizes to the plasma membrane, is maintained at comparable levels in wild-type and mutant cells. We propose that ciliary PDGFRαα signaling is linked to tissue homeostasis and to mitogenic signaling pathways

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

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