EGF receptor kinase suppresses ciliogenesis through activation of USP8 deubiquitinase

Nat Commun. 2018 Feb 22;9(1):758. doi: 10.1038/s41467-018-03117-y.


Ciliogenesis is generally inhibited in dividing cells, however, it has been unclear which signaling cascades regulate the phenomenon. Here, we report that epidermal growth factor receptor (EGFR) kinase suppresses ciliogenesis by directly phosphorylating the deubiquitinase USP8 on Tyr-717 and Tyr-810 in RPE1 cells. These phosphorylations elevate the deubiquitinase activity, which then stabilizes the trichoplein-Aurora A pathway, an inhibitory mechanism of ciliogenesis. EGFR knockdown and serum starvation result in ciliogenesis through downregulation of the USP8-trichoplein-Aurora A signal. Moreover, primary cilia abrogation, which is induced upon IFT20 or Cep164 depletion, ameliorates the cell cycle arrest of EGFR knockdown cells. The present data reveal that the EGFR-USP8-trichoplein-Aurora A axis is a critical signaling cascade that restricts ciliogenesis in dividing cells, and functions to facilitate cell proliferation. We further show that usp8 knockout zebrafish develops ciliopathy-related phenotypes including cystic kidney, suggesting that USP8 is a regulator of ciliogenesis in vertebrates.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Aurora Kinase A / metabolism
  • Carrier Proteins / metabolism
  • Cell Cycle Checkpoints
  • Cell Line
  • Cilia / metabolism*
  • Cilia / ultrastructure*
  • Ciliopathies / genetics
  • Ciliopathies / metabolism
  • Ciliopathies / pathology
  • Culture Media, Serum-Free
  • Deubiquitinating Enzymes / deficiency
  • Deubiquitinating Enzymes / genetics
  • Deubiquitinating Enzymes / metabolism
  • Disease Models, Animal
  • Endopeptidases / chemistry
  • Endopeptidases / metabolism*
  • Endosomal Sorting Complexes Required for Transport / chemistry
  • Endosomal Sorting Complexes Required for Transport / metabolism*
  • ErbB Receptors / metabolism*
  • Gene Knockout Techniques
  • Humans
  • Phosphorylation
  • Proteolysis
  • Retinal Pigment Epithelium / metabolism
  • Retinal Pigment Epithelium / ultrastructure
  • Signal Transduction
  • Ubiquitin Thiolesterase / chemistry
  • Ubiquitin Thiolesterase / metabolism*
  • Zebrafish
  • Zebrafish Proteins / deficiency
  • Zebrafish Proteins / genetics
  • Zebrafish Proteins / metabolism


  • Carrier Proteins
  • Culture Media, Serum-Free
  • Endosomal Sorting Complexes Required for Transport
  • TCHP protein, human
  • Zebrafish Proteins
  • EGFR protein, human
  • ErbB Receptors
  • AURKA protein, human
  • Aurora Kinase A
  • Endopeptidases
  • Deubiquitinating Enzymes
  • USP8 protein, human
  • Ubiquitin Thiolesterase