NEK11: linking CHK1 and CDC25A in DNA damage checkpoint signaling.
The DNA damage induced G(2)/M checkpoint is an important guardian of the genome that prevents cell division when DNA lesions are present. The checkpoint prevents cells from entering mitosis by degrading CDC25A, a key CDK activator. CDC25A proteolysis is controlled by direct phosphorylation events that lead to its recognition by the ubiquitin ligase beta-TrCP. Recently we have identified NEK11, a member of NIMA-related kinase family, as the critical kinase triggering CDC25A degradation. NEK11 controls degradation of CDC25A by directly phosphorylating CDC25A on residues whose phosphorylation is required for beta-TrCP mediated CDC25A polyubiquitylation and degradation. The activity of NEK11 is in turn controlled by CHK1 that activates NEK11 via phosphorylation on serine 273. Since inhibition of NEK11 activity forces checkpoint-arrested cells into mitosis and cell death, NEK11 is, like CHK1, a strong candidate target for the development of novel anticancer drugs. Here we further support this notion by showing results suggesting that NEK11 expression increases during colon cancer development.
Sørensen
Claus Storgaard
CS
Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark. claus.storgaard@bric.ku.dk
Melixetian
Marina
M
Klein
Ditte Kjaersgaard
DK
Helin
Kristian
K
D002453:Cell Cycle; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D004249:DNA Damage; D016195:G2 Phase; D006801:Humans; D008938:Mitosis; D008954:Models, Biological; D000072379:NIMA-Related Kinases; D009369:Neoplasms / Q000201:enzymology / Q000473:pathology / Q000628:therapy; D011230:Precancerous Conditions / Q000201:enzymology / Q000473:pathology; D011494:Protein Kinases / Q000378:metabolism*; D015398:Signal Transduction; D020687:cdc25 Phosphatases / Q000378:metabolism*
D000071877:Checkpoint Kinase 1; D000072379:NIMA-Related Kinases; D011494:Protein Kinases; D020687:cdc25 Phosphatases; C000605867:CHEK1 protein, human; C469355:NEK11 protein, human; C517004:CDC25A protein, human