Negative feedback regulation of ErbB4 tyrosine kinase activity by ERK-mediated non-canonical phosphorylation

Ratna Dini Haryuni, Satoko Watabe, Asako Yamaguchi, Yayoi Fukushi, Tomohiro Tanaka, Yuki Kawasaki, Yue Zhou, Satoru Yokoyama, Hiroaki Sakurai*

*この論文の責任著者

研究成果: ジャーナルへの寄稿学術論文査読

4 被引用数 (Scopus)

抄録

ErbB4 receptor tyrosine kinase has four different isoforms that are classified based on variants in the extracellular juxtamembrane domain (JM-a and JM-b)and the C-terminal region (CYT-1 and CYT-2). Here, we used the JM-b/CYT-1 isoform to investigate the roles of serine/threonine phosphorylation in MEK-ERK-dependent feedback inhibition. TPA as an activator of the ERK pathway markedly induced ErbB4 phosphorylation at Thr-674, the conserved common feedback site in the intracellular JM domain, which resulted in the downregulation of tyrosine autophosphorylation. We also identified Ser-1026 as an ErbB4-specific ERK target site in the CYT-1 region. Moreover, double mutations (Thr-674/Ser-1026 to Ala)significantly upregulated ErbB4 activation, indicating that Thr-674 and Ser-1026 are cooperatively involved in negative feedback regulation. Given the fact that ErbB4 mutation is one of the most common genetic alterations in melanoma cells, we demonstrated that a typical oncogenic ErbB4 mutant was resistant to the negative feedback regulation to maintain a highly active status of tyrosine kinase activity. Together, these findings indicate that feedback mechanisms are key switches determining oncogenic potentials of ErbB receptor kinases.

本文言語英語
ページ(範囲)456-461
ページ数6
ジャーナルBiochemical and Biophysical Research Communications
514
2
DOI
出版ステータス出版済み - 2019/06/25

ASJC Scopus 主題領域

  • 生物理学
  • 生化学
  • 分子生物学
  • 細胞生物学

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