EGF receptor kinase suppresses ciliogenesis through activation of USP8 deubiquitinase

Area of Science:

• Cell Biology
• Molecular Biology
• Signaling Pathways

Background:

• Ciliogenesis, the formation of primary cilia, is typically inhibited in dividing cells.
• The specific signaling cascades regulating this inhibition have remained largely unknown.

Purpose of the Study:

• To elucidate the molecular mechanisms by which epidermal growth factor receptor (EGFR) signaling suppresses ciliogenesis in dividing cells.
• To identify key proteins and pathways involved in regulating ciliogenesis during the cell cycle.

Main Methods:

• Utilized RPE1 cells to investigate the role of EGFR and USP8 in ciliogenesis.
• Employed techniques such as EGFR knockdown, serum starvation, and depletion of IFT20 or Cep164.
• Analyzed the phosphorylation status and deubiquitinase activity of USP8.
• Examined the trichoplein-Aurora A pathway.
• Investigated usp8 knockout zebrafish models for ciliopathy-related phenotypes.

Main Results:

• EGFR kinase directly phosphorylates USP8 at Tyr-717 and Tyr-810, enhancing its deubiquitinase activity.
• This activation stabilizes the trichoplein-Aurora A pathway, a known inhibitor of ciliogenesis.
• EGFR knockdown or serum starvation leads to ciliogenesis via downregulation of the USP8-trichoplein-Aurora A signal.
• Abrogation of primary cilia formation by IFT20 or Cep164 depletion ameliorates cell cycle arrest in EGFR knockdown cells.
• Usp8 knockout zebrafish exhibit ciliopathy phenotypes, including cystic kidney.

Conclusions:

• The EGFR-USP8-trichoplein-Aurora A axis is a critical signaling cascade that restricts ciliogenesis in dividing cells, promoting cell proliferation.
• USP8 is a key regulator of ciliogenesis with conserved functions in vertebrates, as evidenced by zebrafish studies.