Open AccessNegative Regulation of ASK1 by p21Cip1 Involves a Small Domain That Includes Serine 98 That Is Phosphorylated by ASK1 In Vivo
Author(s) -
Jun Zhan,
John Easton,
Shile Huang,
Ashutosh Mishra,
Limin Xiao,
Eilyn R. Lacy,
Richard W. Kriwacki,
Peter J. Houghton
Publication year - 2007
Publication title -
molecular and cellular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.14
H-Index - 327
eISSN - 1067-8824
pISSN - 0270-7306
DOI - 10.1128/mcb.00086-06
Subject(s) - ask1 , biology , microbiology and biotechnology , cyclin dependent kinase 1 , kinase , cyclin dependent kinase 2 , map kinase kinase kinase , mitogen activated protein kinase kinase , cyclin dependent kinase 9 , map2k7 , cyclin dependent kinase 3 , cancer research , protein kinase a , cell cycle , biochemistry , apoptosis
The cyclin-dependent kinase inhibitor p21Cip1 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 p21Cip1 . Here we show that small deletions of p21Cip1 around S98 abrogate its association with ASK1 but do not affect binding to Cdk1, hence distinguishing between the cell cycle-regulating functions of p21Cip1 and its ability to suppress activation of the ASK1/Jun N-terminal protein kinase (JNK) pathway. p21Cip1 is phosphorylated in vitro by both ASK1 and JNK1 at S98. In vivo phosphorylation of p21Cip1 , predominantly carried out by ASK1, is associated with binding to ASK1 and inactivation of ASK1 kinase function. Binding of p21Cip1 to ASK1 requires ASK1 kinase function and may involve phosphorylation of S98.