The dual specificity JKAP specifically activates the c-Jun N-terminal kinase pathway

Alice J. Chen, Guisheng Zhou, Todd Juan, Suzanne M. Colicos, John P. Cannon, Maria Cabriera-Hansen, Christian F. Meyer, Roland Jurecic, Neal G. Copeland, Debra J. Gilbert, Nancy A. Jenkins, Fred Fletcher, Tse Hua Tan, John W. Belmont

Research output: Contribution to journalArticlepeer-review

88 Scopus citations


The involvement of dual specificity phosphatases (DSPs) in the mitogen-activated protein kinase (MAPK) signaling has been mostly limited to the inactivation of MAPKs by the direct dephosphorylation of the TXY motif within their activation loop. We report the cloning and characterization of a murine DSP, called JNK pathway-associated phosphatase (JKAP), which lacks the regulatory region present in most other MAP kinase phosphatases (MKPs) and is preferentially expressed in murine Lin-Sca-1+ stem cells. Overexpression of JKAP in human embryonic kidney 293T cells specifically activated c-Jun N-terminal kinase (JNK) but not p38 and extracellular signal-regulated kinase 2. Overexpression of a mutant JKAP, JKAP-C88S, blocked tumor necrosis factor-α-induced JNK activation. Targeted gene disruption in murine embryonic stem cells abolished JNK activation by tumor necrosis factor-a and transforming growth factor-β, but not by ultraviolet-C irradiation, indicating that JKAP is necessary for optimal JNK activation. JKAP associated with JNK and MKK7, but not SEK1, in vivo. However, JKAP did not interact with JNK in vitro, suggesting that JKAP exerts its effect on JNK in an indirect manner. Taken together, these studies identify a positive regulator for the JNK pathway and suggest a novel role for DSP in mitogen-activated protein kinase regulation.

Original languageEnglish (US)
Pages (from-to)36592-36601
Number of pages10
JournalJournal of Biological Chemistry
Issue number39
StatePublished - Sep 27 2002

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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