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Department of Hematology-Oncology, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105 [J-Y. A., C. E. C.], and Department of Cell Biology and Physiology [J. K. S., H. P-W.], Howard Hughes Medical Institute [H. P-W.], Washington University School of Medicine, St. Louis, Missouri 63110
Eukaryotic cells activate an evolutionarily conserved set of proteins that rapidly induce cell cycle arrest to prevent replication or segregation of damaged DNA before repair is completed. In response to ionizing radiation (IR), the cell cycle checkpoint kinase, Chk2 (hCds1), is phosphorylated and activated in an ataxia telangiectasia mutated (ATM)-dependent manner. Here we show that the ATM protein kinase directly phosphorylates T68 within the SQ/TQ-rich domain of Chk2 in vitro and that T68 is phosphorylated in vivo in response to IR in an ATM-dependent manner. Furthermore, phosphorylation of T68 was required for full activation of Chk2 after IR. Together, these data are consistent with the model that ATM directly phosphorylates Chk2 in vivo and that this event contributes to the activation of Chk2 in irradiated cells.
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M. T. Jack, R. A. Woo, N. Motoyama, H. Takai, and P. W. K. Lee DNA-dependent Protein Kinase and Checkpoint Kinase 2 Synergistically Activate a Latent Population of p53 upon DNA Damage J. Biol. Chem., April 9, 2004; 279(15): 15269 - 15273. [Abstract] [Full Text] [PDF]
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J. T. Powers, S. Hong, C. N. Mayhew, P. M. Rogers, E. S. Knudsen, and D. G. Johnson E2F1 Uses the ATM Signaling Pathway to Induce p53 and Chk2 Phosphorylation and Apoptosis Mol. Cancer Res., April 1, 2004; 2(4): 203 - 214. [Abstract] [Full Text] [PDF]
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C.-P. Ng, H. C. Lee, C. W. Ho, T. Arooz, W. Y. Siu, A. Lau, and R. Y. C. Poon Differential Mode of Regulation of the Checkpoint Kinases CHK1 and CHK2 by Their Regulatory Domains J. Biol. Chem., March 5, 2004; 279(10): 8808 - 8819. [Abstract] [Full Text] [PDF]
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L. Zannini, D. Lecis, S. Lisanti, R. Benetti, G. Buscemi, C. Schneider, and D. Delia Karyopherin-{alpha}2 Protein Interacts with Chk2 and Contributes to Its Nuclear Import J. Biol. Chem., October 24, 2003; 278(43): 42346 - 42351. [Abstract] [Full Text] [PDF]
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J. Yang, Y. Yu, H. E. Hamrick, and P. J. Duerksen-Hughes ATM, ATR and DNA-PK: initiators of the cellular genotoxic stress responses Carcinogenesis, October 1, 2003; 24(10): 1571 - 1580. [Abstract] [Full Text] [PDF]
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A. Haoudi, R. C. Daniels, E. Wong, G. Kupfer, and O. J. Semmes Human T-cell Leukemia Virus-I Tax Oncoprotein Functionally Targets a Subnuclear Complex Involved in Cellular DNA Damage-Response J. Biol. Chem., September 26, 2003; 278(39): 37736 - 37744. [Abstract] [Full Text] [PDF]
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S.-J. Lee, M. F. Schwartz, J. K. Duong, and D. F. Stern Rad53 Phosphorylation Site Clusters Are Important for Rad53 Regulation and Signaling Mol. Cell. Biol., September 1, 2003; 23(17): 6300 - 6314. [Abstract] [Full Text] [PDF]
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K. Yamane, J. Chen, and T. J. Kinsella Both DNA Topoisomerase II-binding Protein 1 and BRCA1 Regulate the G2-M Cell Cycle Checkpoint Cancer Res., June 15, 2003; 63(12): 3049 - 3053. [Abstract] [Full Text] [PDF]
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J. K. Schwarz, C. M. Lovly, and H. Piwnica-Worms Regulation of the Chk2 Protein Kinase by Oligomerization-Mediated cis- and trans-Phosphorylation Mol. Cancer Res., June 1, 2003; 1(8): 598 - 609. [Abstract] [Full Text] [PDF]
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P. V. Jallepalli, C. Lengauer, B. Vogelstein, and F. Bunz The Chk2 Tumor Suppressor Is Not Required for p53 Responses in Human Cancer Cells J. Biol. Chem., May 30, 2003; 278(23): 20475 - 20479. [Abstract] [Full Text] [PDF]
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J. Ahn, M. Urist, and C. Prives Questioning the Role of Checkpoint Kinase 2 in the p53 DNA Damage Response J. Biol. Chem., May 30, 2003; 278(23): 20480 - 20489. [Abstract] [Full Text] [PDF]
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L. Tsvetkov, X. Xu, J. Li, and D. F. Stern Polo-like Kinase 1 and Chk2 Interact and Co-localize to Centrosomes and the Midbody J. Biol. Chem., February 28, 2003; 278(10): 8468 - 8475. [Abstract] [Full Text] [PDF]
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X. Xu and D. F. Stern NFBD1/KIAA0170 Is a Chromatin-associated Protein Involved in DNA Damage Signaling Pathways J. Biol. Chem., February 28, 2003; 278(10): 8795 - 8803. [Abstract] [Full Text] [PDF]
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Y. L. Shang, A. J. Bodero, and P.-L. Chen NFBD1, a Novel Nuclear Protein with Signature Motifs of FHA and BRCT, and an Internal 41-Amino Acid Repeat Sequence, Is an Early Participant in DNA Damage Response J. Biol. Chem., February 14, 2003; 278(8): 6323 - 6329. [Abstract] [Full Text] [PDF]
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J. Ahn and C. Prives Checkpoint Kinase 2 (Chk2) Monomers or Dimers Phosphorylate Cdc25C after DNA Damage Regardless of Threonine 68 Phosphorylation J. Biol. Chem., December 6, 2002; 277(50): 48418 - 48426. [Abstract] [Full Text] [PDF]
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A. Hirao, A. Cheung, G. Duncan, P.-M. Girard, A. J. Elia, A. Wakeham, H. Okada, T. Sarkissian, J. A. Wong, T. Sakai, et al. Chk2 Is a Tumor Suppressor That Regulates Apoptosis in both an Ataxia Telangiectasia Mutated (ATM)-Dependent and an ATM-Independent Manner Mol. Cell. Biol., September 15, 2002; 22(18): 6521 - 6532. [Abstract] [Full Text] [PDF]
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B. Xu, A. H. O'Donnell, S.-T. Kim, and M. B. Kastan Phosphorylation of Serine 1387 in Brca1 Is Specifically Required for the Atm-mediated S-Phase Checkpoint after Ionizing Irradiation Cancer Res., August 15, 2002; 62(16): 4588 - 4591. [Abstract] [Full Text] [PDF]
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J.-Y. Ahn, X. Li, H. L. Davis, and C. E. Canman Phosphorylation of Threonine 68 Promotes Oligomerization and Autophosphorylation of the Chk2 Protein Kinase via the Forkhead-associated Domain J. Biol. Chem., May 24, 2002; 277(22): 19389 - 19395. [Abstract] [Full Text] [PDF]
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T. O'Neill, L. Giarratani, P. Chen, L. Iyer, C.-H. Lee, M. Bobiak, F. Kanai, B.-B. Zhou, J. H. Chung, and G. A. Rathbun Determination of Substrate Motifs for Human Chk1 and hCds1/Chk2 by the Oriented |
