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Crosstalk between cAMP-dependent kinase and MAP kinase through a protein tyrosine phosphatase

Nature Cell Biology volume 1, pages 305–310 (1999)Cite this article

Abstract

The haematopoietic protein tyrosine phosphatase (HePTP) is a negative regulator of the MAP kinases Erk1, Erk2 and p38. HePTP binds to these kinases through a kinase-interaction motif (KIM) in its non-catalytic amino terminus and inactivates them by dephosphorylating the critical phosphorylated tyrosine residue in their activation loop. Here we show that cyclic-AMP-dependent protein kinase (PKA) phosphorylates serine residue 23 in the KIM of HePTP in vitro and in intact cells. This modification reduces binding of MAP kinases to the KIM, an effect that is prevented by mutation of serine 23 to alanine. The PKA-mediated release of MAP kinase from HePTP is sufficient to activate the kinase and to induce transcription from the c-fos promoter. Expression of a HePTP serine-23-to-alanine mutant inhibits MAP-kinase dissociation and activation and induction of transcription from the c-fos promoter. We conclude that HePTP not only controls the activity of MAP kinases, but also mediates crosstalk between the cAMP system and the MAP-kinase cascade.

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Figure 1: Mapping of Ser 23 as a phosphorylation site in HePTP in T cells.
Figure 2: Dissociation of MAP kinase from HePTP by phosphorylation of HePTP at Ser 23.
Figure 3: Inhibition of cAMP-induced activation of MAP kinase by HePTP(S23A).
Figure 4: cAMP-induced c-fos activation.
Figure 5: HePTP(S23A) blocks antigen-receptor-induced MAP-kinase and c-fos activation.
Figure 6: Model for signal integration by HePTP.

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Acknowledgements

We thank B. Zanke for HePTP cDNA and for discussions; J. Schnitzer for comments on the manuscript; and M. Pelimiano and D. Hammi for technical assistance. This work was supported by NIH grants AI35603, AI41481 and AI40552.

Correspondence and requests for materials should be addressed to T.M.

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Authors and Affiliations

  1. Laboratory of Signal Transduction, Sidney Kimmel Cancer Center,, 10835 Altman Row, San Diego, 92121, California, USA

    Manju Saxena, Scott Williams & Tomas Mustelin

  2. Institute of Medical Biochemistry, University of Oslo, Oslo, N-0317, Norway

    Kjetil Taskén

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Correspondence to Tomas Mustelin.

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Saxena, M., Williams, S., Taskén, K. et al. Crosstalk between cAMP-dependent kinase and MAP kinase through a protein tyrosine phosphatase. Nat Cell Biol 1, 305–310 (1999). https://doi.org/10.1038/13024

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