Negative regulation of ASK1 by p21Cip1 involves a small domain that includes Serine 98 that is phosphorylated by ASK1 in vivo.
The cyclin-dependent kinase inhibitor p21(Cip1) regulates multiple cellular functions and protects cells from genotoxic and other cellular stresses. Activation of apoptosis signal-regulating kinase 1 (ASK1) induced by inhibition of mTOR signaling leads to sustained phospho-c-Jun that is suppressed in cells with functional p53 or by forced expression of p21(Cip1). Here we show that small deletions of p21(Cip1) around S98 abrogate its association with ASK1 but do not affect binding to Cdk1, hence distinguishing between the cell cycle-regulating functions of p21(Cip1) and its ability to suppress activation of the ASK1/Jun N-terminal protein kinase (JNK) pathway. p21(Cip1) is phosphorylated in vitro by both ASK1 and JNK1 at S98. In vivo phosphorylation of p21(Cip1), predominantly carried out by ASK1, is associated with binding to ASK1 and inactivation of ASK1 kinase function. Binding of p21(Cip1) to ASK1 requires ASK1 kinase function and may involve phosphorylation of S98.
Zhan
Jun
J
Department of Molecular Pharmacology, St. Jude Children's Research Hospital, Memphis, TN 38105-2794, USA.
Easton
John B
JB
Huang
Shile
S
Mishra
Ashutosh
A
Xiao
Limin
L
Lacy
Eilyn R
ER
Kriwacki
Richard W
RW
Houghton
Peter J
PJ
D000873:Anthracenes / Q000494:pharmacology; D002460:Cell Line; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D048848:MAP Kinase Kinase Kinase 5 / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D019913:Nuclear Localization Signals; D010768:Phosphoserine / Q000378:metabolism*; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D020123:Sirolimus / Q000494:pharmacology
D000873:Anthracenes; D050759:Cyclin-Dependent Kinase Inhibitor p21; D019913:Nuclear Localization Signals; D047428:Protein Kinase Inhibitors; D010768:Phosphoserine; C432165:pyrazolanthrone; D048031:JNK Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; D020123:Sirolimus