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CDK2  -  cyclin-dependent kinase 2

Homo sapiens

 
 
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Disease relevance of CDK2

 

High impact information on CDK2

  • Y88 phosphorylation does not prevent p27 binding to cyclin A/Cdk2 [6].
  • Instead, it causes phosphorylated Y88 and the entire inhibitory 3(10)-helix of p27 to be ejected from the Cdk2 active site, thus restoring partial Cdk activity [6].
  • Paradoxically, under certain circumstances, CDKs such as cyclin E-cdk2 are also required to promote licensing [7].
  • The surprising redundancy amongst the classical cyclins (A, B, and E) and cyclin-dependent kinases (Cdk1 and Cdk2) show that the important differences between these proteins are when and where they are expressed rather than the proteins they phosphorylate [8].
  • Cell proliferation without cyclin E-CDK2 [9].
 

Chemical compound and disease context of CDK2

 

Biological context of CDK2

  • One face of the complex exposes the sequence-conserved phosphate-binding region on Cks and the ATP-binding site on CDK2, suggesting that CKs may target CDK2 to other phosphoproteins during the cell cycle [14].
  • This interface is biologically critical, based upon mutational analysis, but far from the CDK2 N-terminal lobe, cyclin, and regulatory phosphorylation sites [14].
  • In mammals, the members of the CDK family include CDK2 and CDC2, which are thought to be involved in the control of DNA replication and mitosis, respectively [15].
  • The major protein interface between the two molecules is formed by the C-terminal lobe of CDK2 and the C-terminal helix of KAP, regions remote from the kinase-activation segment and the KAP catalytic site [16].
  • Prolonged induction of p21Cip1/WAF1/CDK2/PCNA complex by epidermal growth factor receptor activation mediates ligand-induced A431 cell growth inhibition [17].
 

Anatomical context of CDK2

  • We find that CDK2/cyclin complexes in mouse fibroblasts associate tightly with a 20K protein (CAP20) [15].
  • We purified CAP20 from 3T3 cells and found that low concentrations of the protein completely inhibit the kinase activity of CDK2 in vitro [15].
  • However, E2F-1 was phosphorylated by cyclin A/CDK2 in vitro and was phosphorylated in vivo in HeLa cells [18].
  • It is thought that abnormal activation of CDK2 induces centrosome amplification that is frequently observed in a wide range of aggressive tumors [19].
  • Finally, kinase activity of CDK2 and CDK4 decreases as C2C12 cells differentiate, whereas the CDK6 kinase activity is low in both proliferating myoblasts and differentiated myotubes [20].
 

Associations of CDK2 with chemical compounds

  • E1A also bypasses G1 arrest by roscovitine, a chemical inhibitor of CDK2 [1].
  • Similarly, overexpression of activated mutant CDK2 increased PR transcriptional activity in the absence and presence of progestin [2].
  • The p12(DOC-1)-mediated decrease of CDK2 was prevented if the p12(DOC-1) transfectants were grown in the presence of the proteosome inhibitor clasto-lactacystin beta-lactone, suggesting that p12(DOC-1) may target CDK2 for proteolysis [21].
  • This increased immunoprecipitated kinase activity was dependent on the Flavopiridol concentration added to intact cells and was associated with a reduction of CDK2 tyrosine phosphorylation [22].
  • Immunoprecipitated CDK2 kinase activity from either MCF-7 or MDA-MB-468 cells exposed to Flavopiridol (300 nM) for increasing time showed an initial increased activity (approximately 1.5-fold at 3 h) compared with untreated cells, followed by a loss of kinase activity to immeasurable levels by 24 h [22].
 

Physical interactions of CDK2

  • Binding studies conducted both in vitro and in vivo demonstrated that the cyclin A/CDK2-binding region resided within the N-terminal 124 amino acids of E2F-1 [18].
  • Furthermore, UCN-01 induced the expression of the CDK inhibitor p21 protein and its complex formation with CDK2 after 24 h exposure at 260 and 520 nM, whereas the expression level was very low or undetectable in untreated or DNA-damaged cells [23].
  • Activation of CDK2 and binding to SKP2 or p27(KIP1) were not affected by the phosphorylation of Ser-154 [24].
  • The abundance of the cyclin E/Cdk2 complex increases to the extent that the binding capacity of Cip1 is exceeded about 8-12 h after serum stimulation [25].
  • The Cdk2 bound to cyclin D1 in human cells was also the inactive form that was slowly migrated [26].
 

Enzymatic interactions of CDK2

  • BRCA1 is phosphorylated at serine 1497 in vivo at a cyclin-dependent kinase 2 phosphorylation site [27].
  • KAP was unable to dephosphorylate Tyr15 and only dephosphorylated Thr160 in native monomeric Cdk2 [28].
  • Here, we report that CDK4 complexes from Nalm-6 extracts phosphorylated in vitro the CDK2-preferred serine 612, which was inhibited by p16INK4a, and fascaplysin [10].
  • We report that serum stimulation causes a gradual, sustained increase in the activity of CDK-activating kinase (CAK) that phosphorylates CDK2 at Thr160, which starts by 5 h after serum stimulation and reaches the maximal plateau level at around the G1/S boundary [29].
  • These data suggest that CDK2 phosphorylates histone H1 in vivo, resulting in a more open chromatin structure by destabilizing H1-chromatin interactions [30].
 

Regulatory relationships of CDK2

  • A peptide based on the Cy motif of p21 competitively disrupts the association of Cdc25A with cyclin-cdks and inhibits the dephosphorylation of the kinase. p21 inhibits Cdc25A-cyclin-cdk2 association and the dephosphorylation of cdk2 [31].
  • Here we show that the ubiquitin ligase activity of BRCA1-BARD1 is down-regulated by CDK2 [32].
  • These tumor-specific N-terminal deleted forms of cyclin E are able to activate CDK2 [33].
  • Potent inhibitors of cyclin-dependent kinase 2 induce nuclear accumulation of wild-type p53 and nucleolar fragmentation in human untransformed and tumor-derived cells [34].
  • Consistent with this result, kinase activity of CDK2 was significantly down-regulated in cells overexpressing APC although its synthesis remained unchanged, while CDK4 activity was barely affected [35].
 

Other interactions of CDK2

 

Analytical, diagnostic and therapeutic context of CDK2

References

  1. A novel function of adenovirus E1A is required to overcome growth arrest by the CDK2 inhibitor p27(Kip1). Alevizopoulos, K., Catarin, B., Vlach, J., Amati, B. EMBO J. (1998) [Pubmed]
  2. Phosphorylation of progesterone receptor serine 400 mediates ligand-independent transcriptional activity in response to activation of cyclin-dependent protein kinase 2. Pierson-Mullany, L.K., Lange, C.A. Mol. Cell. Biol. (2004) [Pubmed]
  3. Expression of cyclin E renders cyclin D-CDK4 dispensable for inactivation of the retinoblastoma tumor suppressor protein, activation of E2F, and G1-S phase progression. Keenan, S.M., Lents, N.H., Baldassare, J.J. J. Biol. Chem. (2004) [Pubmed]
  4. HIV-1 Tat interaction with RNA polymerase II C-terminal domain (CTD) and a dynamic association with CDK2 induce CTD phosphorylation and transcription from HIV-1 promoter. Deng, L., Ammosova, T., Pumfery, A., Kashanchi, F., Nekhai, S. J. Biol. Chem. (2002) [Pubmed]
  5. Active cyclin A-CDK2 complex, a possible critical factor for cell proliferation in human primary lung carcinomas. Dobashi, Y., Shoji, M., Jiang, S.X., Kobayashi, M., Kawakubo, Y., Kameya, T. Am. J. Pathol. (1998) [Pubmed]
  6. Cdk-Inhibitory Activity and Stability of p27(Kip1) Are Directly Regulated by Oncogenic Tyrosine Kinases. Grimmler, M., Wang, Y., Mund, T., Cilensek, Z., Keidel, E.M., Waddell, M.B., Jäkel, H., Kullmann, M., Kriwacki, R.W., Hengst, L. Cell (2007) [Pubmed]
  7. CDKs promote DNA replication origin licensing in human cells by protecting Cdc6 from APC/C-dependent proteolysis. Mailand, N., Diffley, J.F. Cell (2005) [Pubmed]
  8. Recycling the cell cycle: cyclins revisited. Murray, A.W. Cell (2004) [Pubmed]
  9. Cell proliferation without cyclin E-CDK2. Méndez, J. Cell (2003) [Pubmed]
  10. Limited redundancy in phosphorylation of retinoblastoma tumor suppressor protein by cyclin-dependent kinases in acute lymphoblastic leukemia. Schmitz, N.M., Hirt, A., Aebi, M., Leibundgut, K. Am. J. Pathol. (2006) [Pubmed]
  11. Indole-3-carbinol (I3C) inhibits cyclin-dependent kinase-2 function in human breast cancer cells by regulating the size distribution, associated cyclin E forms, and subcellular localization of the CDK2 protein complex. Garcia, H.H., Brar, G.A., Nguyen, D.H., Bjeldanes, L.F., Firestone, G.L. J. Biol. Chem. (2005) [Pubmed]
  12. CDK2 is a target for retinoic acid-mediated growth inhibition in MCF-7 human breast cancer cells. Teixeira, C., Pratt, M.A. Mol. Endocrinol. (1997) [Pubmed]
  13. Androgen and epidermal growth factor down-regulate cyclin-dependent kinase inhibitor p27Kip1 and costimulate proliferation of MDA PCa 2a and MDA PCa 2b prostate cancer cells. Ye, D., Mendelsohn, J., Fan, Z. Clin. Cancer Res. (1999) [Pubmed]
  14. Crystal structure and mutational analysis of the human CDK2 kinase complex with cell cycle-regulatory protein CksHs1. Bourne, Y., Watson, M.H., Hickey, M.J., Holmes, W., Rocque, W., Reed, S.I., Tainer, J.A. Cell (1996) [Pubmed]
  15. Inhibition of CDK2 activity in vivo by an associated 20K regulatory subunit. Gu, Y., Turck, C.W., Morgan, D.O. Nature (1993) [Pubmed]
  16. Phosphoprotein-protein interactions revealed by the crystal structure of kinase-associated phosphatase in complex with phosphoCDK2. Song, H., Hanlon, N., Brown, N.R., Noble, M.E., Johnson, L.N., Barford, D. Mol. Cell (2001) [Pubmed]
  17. Prolonged induction of p21Cip1/WAF1/CDK2/PCNA complex by epidermal growth factor receptor activation mediates ligand-induced A431 cell growth inhibition. Fan, Z., Lu, Y., Wu, X., DeBlasio, A., Koff, A., Mendelsohn, J. J. Cell Biol. (1995) [Pubmed]
  18. Cyclin A/CDK2 binds directly to E2F-1 and inhibits the DNA-binding activity of E2F-1/DP-1 by phosphorylation. Xu, M., Sheppard, K.A., Peng, C.Y., Yee, A.S., Piwnica-Worms, H. Mol. Cell. Biol. (1994) [Pubmed]
  19. Suppression of centrosome amplification after DNA damage depends on p27 accumulation. Sugihara, E., Kanai, M., Saito, S., Nitta, T., Toyoshima, H., Nakayama, K., Nakayama, K.I., Fukasawa, K., Schwab, M., Saya, H., Miwa, M. Cancer Res. (2006) [Pubmed]
  20. Induction of p18INK4c and its predominant association with CDK4 and CDK6 during myogenic differentiation. Franklin, D.S., Xiong, Y. Mol. Biol. Cell (1996) [Pubmed]
  21. p12(DOC-1) is a novel cyclin-dependent kinase 2-associated protein. Shintani, S., Ohyama, H., Zhang, X., McBride, J., Matsuo, K., Tsuji, T., Hu, M.G., Hu, G., Kohno, Y., Lerman, M., Todd, R., Wong, D.T. Mol. Cell. Biol. (2000) [Pubmed]
  22. Flavopiridol induces G1 arrest with inhibition of cyclin-dependent kinase (CDK) 2 and CDK4 in human breast carcinoma cells. Carlson, B.A., Dubay, M.M., Sausville, E.A., Brizuela, L., Worland, P.J. Cancer Res. (1996) [Pubmed]
  23. G1 phase accumulation induced by UCN-01 is associated with dephosphorylation of Rb and CDK2 proteins as well as induction of CDK inhibitor p21/Cip1/WAF1/Sdi1 in p53-mutated human epidermoid carcinoma A431 cells. Akiyama, T., Yoshida, T., Tsujita, T., Shimizu, M., Mizukami, T., Okabe, M., Akinaga, S. Cancer Res. (1997) [Pubmed]
  24. Degradation of cyclin A does not require its phosphorylation by CDC2 and cyclin-dependent kinase 2. Yam, C.H., Siu, W.Y., Lau, A., Poon, R.Y. J. Biol. Chem. (2000) [Pubmed]
  25. Cyclin E/Cdk2 activity is controlled by different mechanisms in the G0 and G1 phases of the cell cycle. Bresnahan, W.A., Boldogh, I., Ma, T., Albrecht, T., Thompson, E.A. Cell Growth Differ. (1996) [Pubmed]
  26. Cyclin-dependent kinase-2 (Cdk2) forms an inactive complex with cyclin D1 since Cdk2 associated with cyclin D1 is not phosphorylated by Cdk7-cyclin-H. Higashi, H., Suzuki-Takahashi, I., Saitoh, S., Segawa, K., Taya, Y., Okuyama, A., Nishimura, S., Kitagawa, M. Eur. J. Biochem. (1996) [Pubmed]
  27. BRCA1 is phosphorylated at serine 1497 in vivo at a cyclin-dependent kinase 2 phosphorylation site. Ruffner, H., Jiang, W., Craig, A.G., Hunter, T., Verma, I.M. Mol. Cell. Biol. (1999) [Pubmed]
  28. Dephosphorylation of Cdk2 Thr160 by the cyclin-dependent kinase-interacting phosphatase KAP in the absence of cyclin. Poon, R.Y., Hunter, T. Science (1995) [Pubmed]
  29. Protein kinase C inhibits the CAK-CDK2 cyclin-dependent kinase cascade and G1/S cell cycle progression in human diploid fibroblasts. Hamada, K., Takuwa, N., Zhou, W., Kumada, M., Takuwa, Y. Biochim. Biophys. Acta (1996) [Pubmed]
  30. The dynamic mobility of histone H1 is regulated by cyclin/CDK phosphorylation. Contreras, A., Hale, T.K., Stenoien, D.L., Rosen, J.M., Mancini, M.A., Herrera, R.E. Mol. Cell. Biol. (2003) [Pubmed]
  31. p21CIP1 and Cdc25A: competition between an inhibitor and an activator of cyclin-dependent kinases. Saha, P., Eichbaum, Q., Silberman, E.D., Mayer, B.J., Dutta, A. Mol. Cell. Biol. (1997) [Pubmed]
  32. Down-regulation of BRCA1-BARD1 ubiquitin ligase by CDK2. Hayami, R., Sato, K., Wu, W., Nishikawa, T., Hiroi, J., Ohtani-Kaneko, R., Fukuda, M., Ohta, T. Cancer Res. (2005) [Pubmed]
  33. Activation of cyclin-dependent kinase 2 by full length and low molecular weight forms of cyclin E in breast cancer cells. Harwell, R.M., Mull, B.B., Porter, D.C., Keyomarsi, K. J. Biol. Chem. (2004) [Pubmed]
  34. Potent inhibitors of cyclin-dependent kinase 2 induce nuclear accumulation of wild-type p53 and nucleolar fragmentation in human untransformed and tumor-derived cells. David-Pfeuty, T. Oncogene (1999) [Pubmed]
  35. The tumour suppressor gene product APC blocks cell cycle progression from G0/G1 to S phase. Baeg, G.H., Matsumine, A., Kuroda, T., Bhattacharjee, R.N., Miyashiro, I., Toyoshima, K., Akiyama, T. EMBO J. (1995) [Pubmed]
  36. Separate domains of p21 involved in the inhibition of Cdk kinase and PCNA. Chen, J., Jackson, P.K., Kirschner, M.W., Dutta, A. Nature (1995) [Pubmed]
  37. Requirements for cdk7 in the assembly of cdk1/cyclin B and activation of cdk2 revealed by chemical genetics in human cells. Larochelle, S., Merrick, K.A., Terret, M.E., Wohlbold, L., Barboza, N.M., Zhang, C., Shokat, K.M., Jallepalli, P.V., Fisher, R.P. Mol. Cell (2007) [Pubmed]
  38. Cleavage of p21Cip1/Waf1 and p27Kip1 mediates apoptosis in endothelial cells through activation of Cdk2: role of a caspase cascade. Levkau, B., Koyama, H., Raines, E.W., Clurman, B.E., Herren, B., Orth, K., Roberts, J.M., Ross, R. Mol. Cell (1998) [Pubmed]
  39. Structure and regulation of the CDK5-p25(nck5a) complex. Tarricone, C., Dhavan, R., Peng, J., Areces, L.B., Tsai, L.H., Musacchio, A. Mol. Cell (2001) [Pubmed]
  40. Phosphorylation of mammalian CDC6 by cyclin A/CDK2 regulates its subcellular localization. Petersen, B.O., Lukas, J., Sørensen, C.S., Bartek, J., Helin, K. EMBO J. (1999) [Pubmed]
  41. Human cyclin A is required for mitosis until mid prophase. Furuno, N., den Elzen, N., Pines, J. J. Cell Biol. (1999) [Pubmed]
  42. G1 arrest and down-regulation of cyclin E/cyclin-dependent kinase 2 by the protein kinase inhibitor staurosporine are dependent on the retinoblastoma protein in the bladder carcinoma cell line 5637. Schnier, J.B., Nishi, K., Goodrich, D.W., Bradbury, E.M. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  43. Up-regulation of cyclin-dependent kinase 4/cyclin D2 expression but down-regulation of cyclin-dependent kinase 2/cyclin E in testicular germ cell tumors. Schmidt, B.A., Rose, A., Steinhoff, C., Strohmeyer, T., Hartmann, M., Ackermann, R. Cancer Res. (2001) [Pubmed]
  44. Cyclin-Dependent Kinase 2 Functions in Normal DNA Repair and Is a Therapeutic Target in BRCA1-Deficient Cancers. Deans, A.J., Khanna, K.K., McNees, C.J., Mercurio, C., Heierhorst, J., McArthur, G.A. Cancer Res. (2006) [Pubmed]
 
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