IFT20 modulates ciliary PDGFRα signaling by regulating the stability of Cbl E3 ubiquitin ligases

Abstract

PDGFRα signals from cilia to control development and tumorigenesis. Schmid et al. now show that intraflagellar transport protein 20 (IFT20) interacts with and stabilizes the E3 ubiquitin ligases c-Cbl and Cbl-b to promote feedback inhibition of PDGFRα signaling at the primary cilium.

Mixed signals from the cell's antennae: primary cilia in cancer

“…PDGFRalpha, but not the beta isoform, was shown to be localized to PC in quiescent cells . Studies on ciliary mutants revealed that PDGFRalpha localizes to the plasma membrane in the absence of PC, where it is over‐activated upon ligand binding . Notably, aberrant PDGFRalpha signaling has been associated with pathologies such as gastrointestinal stromal tumors .…”

Primary cilia control cell alignment and patterning in bone development via ceramide-PKCζ-β-catenin signaling

“…Intraflagellar transport (IFT) proteins mediate the transport of cargoes along cilia 4,5 and are essential for cilia formation and function. IFT20 is one of the components of IFT-B complexes that mediates the anterograde transport of structural and signaling molecules from the bases to the tips of cilia [6][7][8] . The mutation of IFT-B proteins leads to skeletal ciliopathies such as Joubert syndrome and ciliary skeletal dysplasias 9,10 .…”

Regulation of ciliary membrane protein trafficking and signalling by kinesin motor proteins

“…Subsequent work confirmed the involvement of IFT20 in ciliogenesis and ciliary membrane protein trafficking, e.g. opsin trafficking in photoreceptors , fibrocystin trafficking in kidney epithelial cells , and PDGFRα trafficking in osteoblasts and fibroblasts . Consistently, a growing number of IFT20‐interacting proteins have also been implicated in ciliogenesis and ciliary membrane protein trafficking in various systems .…”

“…Recent work in NIH3T3 cells showed that IFT20 interacts with and stabilizes the tumour suppressors and E3 ubiquitin ligases c‐CBL and CBL‐b, which upon receptor activation accumulate in the cilium and mediate the internalization of PDGFRα for feedback inhibition of receptor signalling. In IFT20‐depleted cells with defective ciliogenesis, PDGFRα mislocalizes to the plasma membrane from where the receptor is overactivated because of autoubiquitination‐induced degradation of the CBL proteins . Additional mechanisms that contribute to the balanced output of ciliary PDGFRα signalling include dephosphorylation of AKT by PP2A, which localizes to the ciliary base and is under the control of IFT and mTORC1 signalling.…”

“…This leads to receptor dimerization and autophosphorylation, followed by activation of downstream signalling via the MEK 1/2‐ ERK 1/2‐ RSK and PI 3K‐ AKT pathways. Feedback inhibition of signalling is controlled by receptor ubiquitination by the Cbl E3 ubiquitin ligases that in turn are stabilized by IFT 20 . During TGF ‐β signalling, TGF ‐β receptors I and II ( RI / II ) are activated in the cilium upon ligand binding, and subsequent clathrin‐mediated receptor internalization at the CiPo leads to recruitment and activation of SMAD 2/3 in early endosomes, and activated SMAD 2/3 then interacts with SMAD 4 and translocate to the nucleus to promote target gene transcription.…”