IFT20 modulates ciliary PDGFRα signaling by regulating the stability of Cbl E3 ubiquitin ligases.
Autor: | Schmid FM; Department of Biology, Section of Cell Biology and Physiology, University of Copenhagen, Copenhagen, Denmark., Schou KB; Department of Biology, Section of Cell Biology and Physiology, University of Copenhagen, Copenhagen, Denmark., Vilhelm MJ; Department of Biology, Section of Cell Biology and Physiology, University of Copenhagen, Copenhagen, Denmark., Holm MS; Department of Biology, Section of Cell Biology and Physiology, University of Copenhagen, Copenhagen, Denmark., Breslin L; Department of Biology, Section of Cell Biology and Physiology, University of Copenhagen, Copenhagen, Denmark.; Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark., Farinelli P; Department of Biology, Section of Cell Biology and Physiology, University of Copenhagen, Copenhagen, Denmark., Larsen LA; Wilhelm Johannsen Centre for Functional Genome Research, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark., Andersen JS; Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark., Pedersen LB; Department of Biology, Section of Cell Biology and Physiology, University of Copenhagen, Copenhagen, Denmark., Christensen ST; Department of Biology, Section of Cell Biology and Physiology, University of Copenhagen, Copenhagen, Denmark stchristensen@bio.ku.dk. |
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Jazyk: | angličtina |
Zdroj: | The Journal of cell biology [J Cell Biol] 2018 Jan 02; Vol. 217 (1), pp. 151-161. Date of Electronic Publication: 2017 Dec 13. |
DOI: | 10.1083/jcb.201611050 |
Abstrakt: | 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. (© 2018 Schmid et al.) |
Databáze: | MEDLINE |
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