RRC ID 50463
Author Kasahara K, Aoki H, Kiyono T, Wang S, Kagiwada H, Yuge M, Tanaka T, Nishimura Y, Mizoguchi A, Goshima N, Inagaki M.
Title EGF receptor kinase suppresses ciliogenesis through activation of USP8 deubiquitinase.
Journal Nat Commun
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.
Volume 9(1)
Pages 758
Published 2018-2-22
DOI 10.1038/s41467-018-03117-y
PII 10.1038/s41467-018-03117-y
PMID 29472535
PMC PMC5823934
MeSH 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* Gene Knockout Techniques Humans Phosphorylation Proteolysis Receptor, Epidermal Growth Factor / metabolism* 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
IF 12.353
DNA material CSII-EF-MCS (RDB04378).