The extracellular signal-regulated kinase-mitogen-activated protein kinase pathway phosphorylates and targets Cdc25A for SCFβ-TrCP- dependent degradation for cell cycle arrest

Michitaka Isoda, Yoshinori Kanemori, Nobushige Nakajo, Sanae Uchida, Katsumi Yamashita, Hiroyuki Ueno, Noriyuki Sagata

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

The extracellular signal-regulated kinase (ERK) pathway is generally mitogenic, but, upon strong activation, it causes cell cycle arrest by a not-yet fully understood mechanism. In response to genotoxic stress, Chkl hyperphosphorylates Cdc25A, a positive cell cycle regulator, and targets it for Skpl/Cullinl/F-box protein (SCF)β-TrCP ubiquitin ligase-dependent degradation, thereby leading to cell cycle arrest. Here, we show that strong ERK activation can also phosphorylate and target Cdc25A for SCFβ-TrCP-dependent degradation. When strongly activated in Xenopus eggs, the ERK pathway induces prominent phosphorylation and SCF β-TrCP-dependent degradation of Cdc25A. p90rsk, the kinase downstream of ERK, directly phosphorylates Cdc25A on multiple sites, which, interestingly, overlap with Chkl phosphorylation sites. Furthermore, ERK itself phosphorylates Cdc25A on multiple sites, a major site of which apparently is phosphorylated by cyclin-dependent kinase (Cdk) in Chkl-induced degradation. p90rsk phosphorylation and ERK phosphorylation contribute, roughly equally and additively, to the degradation of Cdc25A, and such Cdc25A degradation occurs during oocyte maturation in which the endogenous ERK pathway is fully activated. Finally, and importantly, ERK-induced Cdc25A degradation can elicit cell cycle arrest in early embryos. These results suggest that strong ERK activation can target Cdc25A for degradation in a manner similar to, but independent of, Chkl for cell cycle arrest.

Original languageEnglish
Pages (from-to)2186-2195
Number of pages10
JournalMolecular biology of the cell
Volume20
Issue number8
DOIs
Publication statusPublished - Apr 15 2009

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'The extracellular signal-regulated kinase-mitogen-activated protein kinase pathway phosphorylates and targets Cdc25A for SCF<sup>β-TrCP</sup>- dependent degradation for cell cycle arrest'. Together they form a unique fingerprint.

  • Cite this