EGF receptor kinase suppresses ciliogenesis through activation of USP8 deubiquitinase

Kousuke Kasahara, Hiromasa Aoki, Tohru Kiyono, Shujie Wang, Harumi Kagiwada, Mizuki Yuge, Toshio Tanaka, Yuhei Nishimura, Akira Mizoguchi, Naoki Goshima and Masaki Inagaki ()
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Kousuke Kasahara: Mie University Graduate School of Medicine
Hiromasa Aoki: Nagoya City University
Tohru Kiyono: National Cancer Center Research Institute
Shujie Wang: Mie University Graduate School of Medicine
Harumi Kagiwada: National Institute of Advanced Industrial Science and Technology
Mizuki Yuge: Mie University Graduate School of Medicine
Toshio Tanaka: Mie University Graduate School of Medicine
Yuhei Nishimura: Mie University Graduate School of Medicine
Akira Mizoguchi: Mie University Graduate School of Medicine
Naoki Goshima: National Institute of Advanced Industrial Science and Technology
Masaki Inagaki: Mie University Graduate School of Medicine

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-03117-y

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