title: The extracellular signal-regulated kinase-mitogen-activated protein kinase pathway phosphorylates and targets Cdc25A for SCF beta-TrCP-dependent degradation for cell cycle arrest.
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, Chk1 hyperphosphorylates Cdc25A, a positive cell cycle regulator, and targets it for Skp1/Cullin1/F-box protein (SCF)(beta-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 SCF(beta-TrCP)-dependent degradation. When strongly activated in Xenopus eggs, the ERK pathway induces prominent phosphorylation and SCF(beta-TrCP)-dependent degradation of Cdc25A. p90rsk, the kinase downstream of ERK, directly phosphorylates Cdc25A on multiple sites, which, interestingly, overlap with Chk1 phosphorylation sites. Furthermore, ERK itself phosphorylates Cdc25A on multiple sites, a major site of which apparently is phosphorylated by cyclin-dependent kinase (Cdk) in Chk1-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, Chk1 for cell cycle arrest.
authors.affiliation: Department of Biology, Kyushu University, Hakozaki, Fukuoka, Japan.
authors.forename: Michitaka
authors.initials: M
authors.lastname: Isoda
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Kanemori
authors.forename: Nobushige
authors.initials: N
authors.lastname: Nakajo
authors.forename: Sanae
authors.initials: S
authors.lastname: Uchida
authors.forename: Katsumi
authors.initials: K
authors.lastname: Yamashita
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ueno
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Sagata
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D055162:Biocatalysis; D002453:Cell Cycle; D002454:Cell Differentiation; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000201:enzymology; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D010063:Ovum / Q000166:cytology / Q000201:enzymology; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism*; D014981:Xenopus / Q000196:embryology / Q000378:metabolism*; D029867:Xenopus Proteins / Q000737:chemistry / Q000378:metabolism*; D044844:beta-Transducin Repeat-Containing Proteins / Q000378:metabolism*; D020687:cdc25 Phosphatases / Q000737:chemistry / Q000378:metabolism*
chemical_list: D029867:Xenopus Proteins; D044844:beta-Transducin Repeat-Containing Proteins; D044843:SKP Cullin F-Box Protein Ligases; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D048049:Extracellular Signal-Regulated MAP Kinases; C102266:Cdc25A protein, Xenopus; D020687:cdc25 Phosphatases