SAPK/JNK regulates cdc2/cyclin B kinase through phosphorylation and inhibition of cdc25c.
Cells undergo M phase arrest in response to stresses like UV irradiation or DNA damage. Stress-activated protein kinase (SAPK, also known as c-Jun N-terminal kinase, JNK) is activated by such stress stimuli. We addressed the potential effects of SAPK activation on cell cycle regulatory proteins. Activation of SAPK strongly correlated with inhibition of cdc2/cyclin B kinase, an important regulator of G2/M phase. SAPK directly phosphorylated the cdc2 regulator, cdc25c, in vitro on serine 168 (S168). This residue was highly phosphorylated in vivo in response to stress stimuli. cdc25c phosphorylated on S168 in cells lacks phosphatase activity, and expression of a S168A mutant of cdc25c reversed the inhibition of cdc2/cyclin B kinase activity by cell stress. Antibodies directed against phosphorylated S168 detect increased phosphorylation of S168 after cell stress. We conclude that SAPK regulates cdc2/cyclin B kinase following stress events by a novel mechanism involving inhibitory phosphorylation of the cdc2-activating phosphatase cdc25c on S168.
Institute of Pathology, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA.
Valerie L
VL
Goss
Janet V
JV
Cross
Kaiwen
K
Ma
Yongyi
Y
Qian
Paul W
PW
Mola
Dennis J
DJ
Templeton
D000595:Amino Acid Sequence / Q000187:drug effects / Q000502:physiology; D000906:Antibodies / Q000494:pharmacology; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D016203:CDC2 Protein Kinase / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019926:Cyclin B / Q000378:metabolism*; D025461:Feedback, Physiological / Q000187:drug effects / Q000502:physiology; D016195:G2 Phase / Q000187:drug effects / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008938:Mitosis / Q000187:drug effects / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013312:Stress, Physiological / Q000201:enzymology*; D020687:cdc25 Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D000906:Antibodies; D018797:Cell Cycle Proteins; D019926:Cyclin B; D012694:Serine; D016203:CDC2 Protein Kinase; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; C517009:CDC25C protein, human; D020687:cdc25 Phosphatases