Negative regulation of ASK1 by p21Cip1 involves a small domain that includes serine 98 that is phosphorylated by ASK1 in vivo

Jun Zhan, John B. Easton, Shile Huang, Ashutosh Mishra, Limin Xiao, Eilyn R. Lacy, Richard W. Kriwacki, Peter J. Houghton

Research output: Contribution to journalArticlepeer-review

43 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)3530-3541
Number of pages12
JournalMolecular and cellular biology
Issue number9
StatePublished - May 2007
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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