Figure 2. Signaling of the cilium influencing ECM interaction and planar cell polarity.

The specialized ciliary membrane displays receptors for proteins that influence the ECM interactions, epithelial-mesencymal transition (EMT), and planar cell polarity (PCP). The polycystin PC1/PC2 heterodimer is a mechanosensor that responses to fluid flow by changing activity of the PC2 Ca²⁺ channel, controlling intracellular Ca²⁺, and regulating signaling important for the integrity of renal architecture [15]. During epidermal development, the commitment of progenitor cells to differentiate relies on Notch signaling, with a pool of Notch functioning at the cilium [22]. In quiescent fibroblasts, basal body-localized PDGFRα mediates signals for directional cell migration and chemotaxis through activation of Akt [19,20]. In chondrocytes, integrins (αβ) and NG2 chondroitin sulfate proteoglycan (NG2) interact with ECM at the ciliary membrane [8,10,110] with integrins shown to potentiate fibronectin-induced Ca²⁺ response [21]. Hedgehog (Hh) signaling relies on the primary cilium; the Hh receptor Patched (Ptc) is removed from the cilia membrane following Hh binding, allowing Smoothened (Smo) to enter the ciliary membrane, which in turn activates the Gli transcription factor family, promoting EMT and ECM invasion [111]. The Wnt receptor Frizzled (Fz) is present in the cilium, and accumulated in cystic epithelia [112]; downstream of Wnt, cilia-based suppression of canonical β-catenin versus activation of non-canonic PCP signaling are influenced by the nephrocystin NPHP2 [28]. Other nephrocystins localized to the transition zone (NPHP1, NPHP4) can interact with adhesion-associated proteins including BCAR1/p130Cas and PYK2 and PCP effectors [23–27]. Knockdown of the ciliary protein NPHP7 leads to severe renal fibrosis. NEDD9/HEF1 and Aurora A (AURKA) are localized at the basal body initiating ciliary disassembly [35], but also influence focal adhesion signaling and secretion of MMPs via interactions with SRC and FAK [95–97].