Transglutaminase-mediated cross-linking of WDR54 regulates EGF receptor-signaling

Akane Maeda, Tasuku Nishino, Ryota Matsuzaki, Atsushi Yokoyama, Hiroshi Suga, Toshiki Yagi, Hiroaki Konishi

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

WDR54 is a member of the WD40 repeat (WDR) domain-containing protein family that was recently identified as a novel oncogene in colorectal cancer. However, the molecular mechanism of WDR54 and its functional association with other molecules related to tumor cell growth are unknown. Here, we show that WDR54 can be cross-linked by the action of transglutaminase (TG) 2, which enhances the activation of EGF receptor-mediated signaling pathway. The most carboxyl-terminal WD domain was required for cross-linking. In addition, lysine 280 in WDR54, also in this WD domain, was an important residue for both cross-linking and ubiquitination. Cross-linked WDR54 was found in vesicles aggregated at the plasma membrane. The activated EGF receptor was co-localized with this vesicle, and the internalization of the EGF receptor into the cytosol was sustained. As a result, Erk activity in response to EGF stimulation was enhanced. Furthermore, the growth of the cells lacking WDR54 expression generated by genome editing was delayed compared with that in wild-type cells. Because TG2 is also has been proposed to activate the EGF receptor-signaling and proliferation of tumor cells, WDR54 might have a functional relationship with the EGF receptor and TG2. Our study on the mechanism of biological function of WDR54 may provide rationale for the design and development of a cancer drug based on inhibiting the post-translational modification of this oncogene product.

Original languageEnglish
Pages (from-to)285-295
Number of pages11
JournalBiochimica et Biophysica Acta - Molecular Cell Research
Volume1866
Issue number2
DOIs
Publication statusPublished - 2019 Feb

Keywords

  • Cross-linking
  • ERK
  • Epidermal growth factor receptor (egfr)
  • Ubiquitination
  • WD40 repeat

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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