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XB-ART-39224
Mol Biol Cell 2009 Apr 01;208:2186-95. doi: 10.1091/mbc.e09-01-0008.
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The extracellular signal-regulated kinase-mitogen-activated protein kinase pathway phosphorylates and targets Cdc25A for SCF beta-TrCP-dependent degradation for cell cycle arrest.

Isoda M , Kanemori Y , Nakajo N , Uchida S , Yamashita K , Ueno H , Sagata N .


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.

PubMed ID: 19244340
PMC ID: PMC2669026
Article link: Mol Biol Cell


Species referenced: Xenopus
Genes referenced: btrc cdc25a chek1 dusp6 fbxo43 grap2 map2k6 map2k7 mapk1 mapk8 myc
GO keywords: cell cycle arrest
Morpholinos: fbxo43 MO1


Article Images: [+] show captions
References [+] :
Alonso, Differential activation of p38 mitogen-activated protein kinase isoforms depending on signal strength. 2000, Pubmed, Xenbase