Reactome | Ubiquitin-Mediated Degradation of Phosphorylated Cdc25A

Ubiquitin-Mediated Degradation of Phosphorylated Cdc25A

Stable Identifier

R-HSA-69601

Type

Pathway

Species

Homo sapiens

ReviewStatus

4/5

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Ubiquitin-Mediated Degradation of Phosphorylated Cdc25A

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CDC25A protein, a phosphatase required for progression from G1 to S phase of the cell cycle, is degraded by the ubiquitin-proteasome machinery in both terminally differentiating and cycling cells (Bernardi et al. 2000).

In response to UV light or ionizing radiation (IR), CDC25A in human cells undergoes a rapid ubiquitin- and proteasome-dependent degradation that depends on CHEK1 but not TP53, inducing G1/S arrest that can be bypassed by overexpression of CDC25A (Mailand et al. 2000, reviewed in Teixera and Reed 2013). CHEK2 (Chk2) contributes to CDC25A destruction in response to IR (Falck et al. 2000, reviewed in Bartek and Lukas 2001). For details, please refer to events "Phosphorylation of CDC25A by CHEK1", "Phosphorylation of CDC25A by CHEK2", and "CHEK1 phosphorylates CHEK2-phosphorylated CDC25A". Treatment with hydroxyurea, which induces DNA replication stress and can indirectly lead to DNA damage, leads to a marked decrease in CDC25A protein levels in many human cell lines in a ubiquitin- and proteasome-dependent manner and persistent phosphorylation of CDK2 on tyrosine residue Y15 (Molinari et al. 2000). Besides CHEK1 and CHEK2, other kinases that may contribute to phosphorylation of CDC25A that targets it for ubiquitin-mediated degradation in response to DNA damage or replicative stress are PLK3 and GSK3B (Kang et al. 2008). Osmotic stress can also lead to p38 MAPK phosphorylation-dependent ubiquitination and degradation of CDC25A (Goloudina et al. 2003). Phosphorylation of CDC25A by CHEK1 and likely p38 MAPK and GSK3B primes it for additional phosphorylation by kinases such as NEK11 (Melixetian et al. 2009) or Casein kinases I (Honaker and Piwnica-Worms 2010, Piao et al. 2011), which creates a phosphodegron needed for binding to the SCF-BTrCP E3 ubiquitin ligase complex, leading to ubiquitin-mediated degradation of CDC25A (Busino et al. 2003, Jin et al. 2003, reviewed in Teixeira and Reed 2013).

Literature References

PubMed ID	Title	Journal	Year
12963847	Regulation of human Cdc25A stability by Serine 75 phosphorylation is not sufficient to activate a S phase checkpoint Goloudina, A, Yamaguchi, H, Chervyakova, DB, Appella, E, Fornace, AJ, Bulavin, DV	Cell Cycle	2003
20348946	Casein kinase 1 functions as both penultimate and ultimate kinase in regulating Cdc25A destruction Honaker, Y, Piwnica-Worms, H	Oncogene	2010
21252624	CK1ε targets Cdc25A for ubiquitin-mediated proteolysis under normal conditions and in response to checkpoint activation Piao, S, Lee, SJ, Xu, Y, Gwak, J, Oh, S, Park, BJ, Ha, NC	Cell Cycle	2011
23495935	Ubiquitin ligases and cell cycle control Teixeira, LK, Reed, SI	Annu Rev Biochem	2013
14681206	SCFbeta-TRCP links Chk1 signaling to degradation of the Cdc25A protein phosphatase Jin, J, Shirogane, T, Xu, L, Nalepa, G, Qin, J, Elledge, SJ, Harper, JW	Genes Dev	2003
18167338	GSK-3 beta targets Cdc25A for ubiquitin-mediated proteolysis, and GSK-3 beta inactivation correlates with Cdc25A overproduction in human cancers Kang, T, Wei, Y, Honaker, Y, Yamaguchi, H, Appella, E, Hung, MC, Piwnica-Worms, H	Cancer Cell	2008
11698191	Mammalian G1- and S-phase checkpoints in response to DNA damage Bartek, J, Lukas, J	Curr Opin Cell Biol	2001
11298456	The ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant DNA synthesis Falck, J, Mailand, N, Syljuâsen, RG, Bartek, J, Lukas, J	Nature	2001
10828887	Cdc25A stability is controlled by the ubiquitin-proteasome pathway during cell cycle progression and terminal differentiation Bernardi, R, Liebermann, DA, Hoffman, B	Oncogene	2000
10827953	Rapid destruction of human Cdc25A in response to DNA damage. Mailand, N, Lukas, C, Syljuâsen, RG, Welcker, M, Lukas, J	Science	2000
19734889	NEK11 regulates CDC25A degradation and the IR-induced G2/M checkpoint Melixetian, M, Klein, DK, Sørensen, CS, Helin, K	Nat Cell Biol	2009
14603323	Degradation of Cdc25A by beta-TrCP during S phase and in response to DNA damage Busino, L, Donzelli, M, Chiesa, M, Guardavaccaro, D, Ganoth, D, Dorrello, NV, Hershko, A, Pagano, M, Draetta, GF	Nature	2003
11256629	Human Cdc25 A inactivation in response to S phase inhibition and its role in preventing premature mitosis Molinari, M, Mercurio, C, Dominguez, J, Goubin, F, Draetta, GF	EMBO Rep	2000