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Light-mediated Reversible Modulation of the Mitogen-activated Protein Kinase Pathway during Cell Differentiation and Xenopus Embryonic Development
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IFT20 modulates ciliary PDGFRα signaling by regulating the stability of Cbl E3 ubiquitin ligases

Fabian Marc Schmid1, Kenneth Bødtker Schou1, Martin Juel Vilhelm1

  • 1Department of Biology, Section of Cell Biology and Physiology, University of Copenhagen, Copenhagen, Denmark.

The Journal of Cell Biology
|December 15, 2017
PubMed

Insights

Intraflagellar transport protein 20 (IFT20) is crucial for regulating platelet-derived growth factor receptor α (PDGFRα) signaling. IFT20 ensures PDGFRα internalization, preventing overactivation linked to developmental disorders and cancer.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Signaling Pathways

Background:

  • Primary cilia organize signaling pathways, including PDGFRα signaling, critical for development.
  • Aberrant PDGFRα signaling is implicated in developmental disorders, tumorigenesis, and cancer.
  • Mechanisms for PDGFRα sorting and feedback inhibition at cilia remain unclear.

Purpose of the Study:

  • To investigate the role of IFT20 in regulating PDGFRα localization and signaling at primary cilia.
  • To elucidate the mechanisms of PDGFRα feedback inhibition within the cilium.

Main Methods:

  • Investigated the interaction between IFT20 and E3 ubiquitin ligases c-Cbl and Cbl-b.
  • Examined the ubiquitination and internalization of PDGFRα in wild-type and IFT20-depleted cells.
  • Analyzed PDGFRα localization and activation upon PDGF-AA stimulation.

Main Results:

  • IFT20 interacts with c-Cbl and Cbl-b, facilitating Cbl-mediated PDGFRα ubiquitination and internalization.
  • In wild-type cells, PDGF-AA stimulation leads to c-Cbl enrichment, PDGFRα ubiquitination, and internalization.
  • IFT20 depletion causes aberrant PDGFRα plasma membrane localization and overactivation due to c-Cbl/Cbl-b destabilization.

Conclusions:

  • IFT20 is essential for the feedback inhibition of PDGFRα signaling at primary cilia.
  • IFT20 regulates PDGFRα internalization via interaction with c-Cbl and Cbl-b.
  • Dysregulation of IFT20-mediated PDGFRα regulation may contribute to disease pathogenesis.

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