CDC25A

M-phase inducer phosphatase 1 also known as dual specificity phosphatase Cdc25A is a protein that in humans is encoded by the cell division cycle 25 homolog A (CDC25A) gene.

Function

CDC25A is a member of the CDC25 family of dual-specificity phosphatases.

Dual-specificity protein phosphatases remove phosphate groups from phosphorylated tyrosine and serine / threonine residues. They represent a subgroup of the tyrosine phosphatase family (as opposed to the serine/threonine phosphatase family).

All mammals examined to date have three homologues of the ancestral Cdc25 gene (found e.g. in the fungus species S. pombe), designated Cdc25A, Cdc25B, and Cdc25C. In contrast, some invertebrates harbour two (e.g., the Drosophila proteins String and Twine) or four (e.g., C. elegans Cdc-25.1 - Cdc-25.4) homologues.

CDC25A is required for progression from G1 to the S phase of the cell cycle, but also plays roles in later cell cycle events. In particular, it is stabilized in metaphase cells and is degraded upon metaphase exit akin to Cyclin B. It is competent to activate the G1/S cyclin-dependent kinases CDK4 and CDK2 by removing inhibitory phosphate groups from adjacent tyrosine and threonine residues; it can also activate Cdc2 (Cdk1), the principal mitotic Cdk.

Involvement in cancer

CDC25A is specifically degraded in response to DNA damage, resulting in cell cycle arrest. Thus, this degradation represents one axis of a DNA damage checkpoint, complementing induction of p53 and p21 in the inhibition of CDKs.

CDC25A is considered an oncogene, as it can cooperate with oncogenic RAS to transform rodent fibroblasts, and it is overexpressed in tumours from a variety of tissues, including breast and head & neck tumours. It is a target of the E2F family of transcription factors. Therefore, its overexpression is a common consequence of dysregulation of the p53-p21-Cdk axis in carcinogenesis.{{cite web | title = Entrez Gene: CDC25A cell division cycle 25 homolog A (S. pombe)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=993}}

Interactions

CDC25A has been shown to interact with:

ASK1,{{cite journal | vauthors = Zou X, Tsutsui T, Ray D, Blomquist JF, Ichijo H, Ucker DS, Kiyokawa H | title = The cell cycle-regulatory CDC25A phosphatase inhibits apoptosis signal-regulating kinase 1 | journal = Mol. Cell. Biol. | volume = 21 | issue = 14 | pages = 4818–28 | date = Jul 2001 | pmid = 11416155 | pmc = 87174 | doi = 10.1128/MCB.21.14.4818-4828.2001 }}
C-Raf,{{cite journal | vauthors = Galaktionov K, Jessus C, Beach D | title = Raf1 interaction with Cdc25 phosphatase ties mitogenic signal transduction to cell cycle activation | journal = Genes Dev. | volume = 9 | issue = 9 | pages = 1046–58 | date = May 1995 | pmid = 7744247 | doi = 10.1101/gad.9.9.1046| url = http://repository.cshl.edu/30592/1/Genes%20Dev.-1995-Galaktionov-1046-58.pdf | doi-access = free }}{{cite journal | vauthors = Huang TS, Shu CH, Yang WK, Whang-Peng J | title = Activation of CDC 25 phosphatase and CDC 2 kinase involved in GL331-induced apoptosis | journal = Cancer Res. | volume = 57 | issue = 14 | pages = 2974–8 | date = Jul 1997 | pmid = 9230211 }}
CHEK1,{{cite journal | vauthors = Goloudina A, Yamaguchi H, Chervyakova DB, Appella E, Fornace AJ, Bulavin DV | title = Regulation of human Cdc25A stability by Serine 75 phosphorylation is not sufficient to activate a S phase checkpoint | journal = Cell Cycle | volume = 2 | issue = 5 | pages = 473–8 | pmid = 12963847 | doi = 10.4161/cc.2.5.482 | year=2003| doi-access = free }}{{cite journal | vauthors = Sanchez Y, Wong C, Thoma RS, Richman R, Wu Z, Piwnica-Worms H, Elledge SJ | title = Conservation of the Chk1 checkpoint pathway in mammals: linkage of DNA damage to Cdk regulation through Cdc25 | journal = Science | volume = 277 | issue = 5331 | pages = 1497–501 | date = Sep 1997 | pmid = 9278511 | doi = 10.1126/science.277.5331.1497}}{{cite journal | vauthors = Zhao H, Watkins JL, Piwnica-Worms H | title = Disruption of the checkpoint kinase 1/cell division cycle 25A pathway abrogates ionizing radiation-induced S and G2 checkpoints | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 99 | issue = 23 | pages = 14795–800 | date = Nov 2002 | pmid = 12399544 | pmc = 137498 | doi = 10.1073/pnas.182557299 | bibcode = 2002PNAS...9914795Z | doi-access = free }}{{cite journal | vauthors = Jin J, Ang XL, Ye X, Livingstone M, Harper JW | title = Differential roles for checkpoint kinases in DNA damage-dependent degradation of the Cdc25A protein phosphatase | journal = J. Biol. Chem. | volume = 283 | issue = 28 | pages = 19322–8 | date = Jul 2008 | pmid = 18480045 | pmc = 2443656 | doi = 10.1074/jbc.M802474200 | doi-access = free }}
CCNE1,{{cite journal | vauthors = Shanahan F, Seghezzi W, Parry D, Mahony D, Lees E | title = Cyclin E associates with BAF155 and BRG1, components of the mammalian SWI-SNF complex, and alters the ability of BRG1 to induce growth arrest | journal = Mol. Cell. Biol. | volume = 19 | issue = 2 | pages = 1460–9 | date = Feb 1999 | pmid = 9891079 | pmc = 116074 | doi = 10.1128/mcb.19.2.1460}}{{cite journal | vauthors = Xu X, Burke SP | title = Roles of active site residues and the NH2-terminal domain in the catalysis and substrate binding of human Cdc25 | journal = J. Biol. Chem. | volume = 271 | issue = 9 | pages = 5118–24 | date = Mar 1996 | pmid = 8617791 | doi = 10.1074/jbc.271.9.5118| doi-access = free }}
EGFR,{{cite journal | vauthors = Wang Z, Wang M, Lazo JS, Carr BI | title = Identification of epidermal growth factor receptor as a target of Cdc25A protein phosphatase | journal = J. Biol. Chem. | volume = 277 | issue = 22 | pages = 19470–5 | date = May 2002 | pmid = 11912208 | doi = 10.1074/jbc.M201097200 | doi-access = free }}
PIM1{{cite journal | vauthors = Mochizuki T, Kitanaka C, Noguchi K, Muramatsu T, Asai A, Kuchino Y | title = Physical and functional interactions between Pim-1 kinase and Cdc25A phosphatase. Implications for the Pim-1-mediated activation of the c-Myc signaling pathway | journal = J. Biol. Chem. | volume = 274 | issue = 26 | pages = 18659–66 | date = Jun 1999 | pmid = 10373478 | doi = 10.1074/jbc.274.26.18659| doi-access = free }} and
YWHAB.{{cite journal | vauthors = Conklin DS, Galaktionov K, Beach D | title = 14-3-3 proteins associate with cdc25 phosphatases | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 92 | issue = 17 | pages = 7892–6 | date = Aug 1995 | pmid = 7644510 | pmc = 41252 | doi = 10.1073/pnas.92.17.7892| bibcode = 1995PNAS...92.7892C | doi-access = free }}

References

External links

{{UCSC gene info|CDC25A}}