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

J Cell Biol. 2018 Jan 2;217(1):151-161. doi: 10.1083/jcb.201611050. Epub 2017 Dec 13.


Primary cilia have pivotal roles as organizers of many different signaling pathways, including platelet-derived growth factor receptor α (PDGFRα) signaling, which, when aberrantly regulated, is associated with developmental disorders, tumorigenesis, and cancer. PDGFRα is up-regulated during ciliogenesis, and ciliary localization of the receptor is required for its appropriate ligand-mediated activation by PDGF-AA. However, the mechanisms regulating sorting of PDGFRα and feedback inhibition of PDGFRα signaling at the cilium are unknown. Here, we provide evidence that intraflagellar transport protein 20 (IFT20) interacts with E3 ubiquitin ligases c-Cbl and Cbl-b and is required for Cbl-mediated ubiquitination and internalization of PDGFRα for feedback inhibition of receptor signaling. In wild-type cells treated with PDGF-AA, c-Cbl becomes enriched in the cilium, and the receptor is subsequently ubiquitinated and internalized. In contrast, in IFT20-depleted cells, PDGFRα localizes aberrantly to the plasma membrane and is overactivated after ligand stimulation because of destabilization and degradation of c-Cbl and Cbl-b.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Carrier Proteins / metabolism*
  • Cell Line
  • Cilia / metabolism
  • HEK293 Cells
  • Humans
  • Mice
  • Platelet-Derived Growth Factor / pharmacology
  • Proto-Oncogene Proteins c-cbl / metabolism*
  • RNA Interference
  • Receptor, Platelet-Derived Growth Factor alpha / metabolism*
  • Signal Transduction / genetics
  • Ubiquitination / physiology


  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • Cblb protein, mouse
  • IFT20 protein, human
  • Ift20 protein, mouse
  • Platelet-Derived Growth Factor
  • platelet-derived growth factor A
  • Proto-Oncogene Proteins c-cbl
  • Receptor, Platelet-Derived Growth Factor alpha
  • CBL protein, human