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Control of MAP kinase activation by the mitogen-induced threonine/tyrosine phosphatase PAC1

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Abstract

INTRACELLULAR signalling following mitogenic stimulation of quiescent cells involves the initiation of a phosphorylation cascade that leads to the rapid and reversible activation of the mitogen-activated protein (MAP) kinases ERK1 and ERK2 (refs 1,2). MAP kinase activation is mediated by dual phosphorylation within the motif Thr-Glu-Tyr by MAP kinase kinase (MEK)3. Following activation, the MAP kinases translocate into the nucleus where they phosphorylate several transduction targets, including transcription factors4–7. We have previously identified PAC1 as an immediate-early mitogen-inducible tyrosine phosphatase in nuclei of T cells8. Here we present several lines of evidence indicating that PAC1 is a physiologically relevant MAP kinase phosphatase. Recombinant PAC1 in vitro is a dual-specific Thr/Tyr phosphatase with stringent substrate specificity for MAP kinase. Constitutive expression of PAC1 in vivo leads to inhibition of MAP kinase activity normally stimulated by epidermal growth factor, phorbol myristyl acetate, or T-cell receptor crosslinking. The inactivation of MAP kinase by PAC1 results in inhibition of MAP kinase-regulated reporter gene expression.

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Author notes

  1. Shashi Gupta, Markus Wartmann and Roger J. Davis: Howard Hughes Medical Institute, Program in Molecular Medicine, Department of Biochemistry and Molecular Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA

Authors and Affiliations

  1. Laboratory of Pathology, National Cancer Institute, Building 10, Room 2A-33, Bethesda, Maryland, 20892, USA

    Yvona Ward, Shashi Gupta, Peter Jensen, Markus Wartmann, Roger J. Davis & Kathleen Kelly

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  1. Yvona Ward
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  2. Shashi Gupta
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  3. Peter Jensen
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  4. Markus Wartmann
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  5. Roger J. Davis
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  6. Kathleen Kelly
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Ward, Y., Gupta, S., Jensen, P. et al. Control of MAP kinase activation by the mitogen-induced threonine/tyrosine phosphatase PAC1. Nature 367, 651–654 (1994). https://doi.org/10.1038/367651a0

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