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

  1. Author:
    Chen, A. J.
    Zhou, G. S.
    Juan, T.
    Colicos, S. M.
    Cannon, J. P.
    Cabriera-Hansen, M.
    Meyer, C. F.
    Jurecic, R.
    Copeland, N. G.
    Gilbert, D. J.
    Jenkins, N. A.
    Fletcher, F.
    Tan, T. H.
    Belmont, J. W.

  2. Author Address

    Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA Baylor Coll Med, Dept Immunol, Houston, TX 77030 USA Amgen Inc, Dept Expt Hematol, Newbury Pk, CA 91320 USA NCI, Frederick Canc Res & Dev Ctr, Mammalian Genet Lab, ABL Basic Res Program, Ft Detrick, MD 21702 USA Belmont JW Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA
    1. Year: 2002
  2. Journal: Journal of Biological Chemistry
    1. 277
    2. 39
    3. Pages: 36592-36601
  4. Type of Article: Article
  1. Abstract:

    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-a-induced JNK activation. Targeted gene disruption in murine embryonic stem cells abolished JNK activation by tumor necrosis factor-a and transforming growth factor-beta, 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.

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