Volume 272, Number 26, Issue of June 27, 1997 pp. 16073-16076
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

COMMUNICATION:
Inhibitory Cross-talk by cAMP Kinase on the Calmodulin-dependent Protein Kinase Cascade

(Received for publication, March 12, 1997, and in revised form, April 22, 1997)

From the Vollum Institute, Oregon Health Sciences University, Portland, Oregon 97201

The calmodulin-dependent kinase (CaM-K) cascade, a Ca²⁺-triggered system involving phosphorylation and activation of CaM-KI and CaM-KIV by CaM kinase kinase (CaM-KK), regulates transcription through direct phosphorylation of transcription factors such as cAMP response element-binding protein. We have shown previously that activated CaM-KIV can activate the mitogen-activated protein kinases (Enslen, H., Tokumitsu, H., Stork, P. J. S., Davis, R. J., and Soderling, T. R. (1996) Proc. Natl. Acad. Sci. U. S. A. 93, 10803-10808), and the present paper describes a novel regulatory cross-talk between cAMP kinase (PKA) and CaM-KK. PKA gave rapid phosphorylation in vitro and in cells of recombinant CaM-KK, resulting in 50-75% inhibition of CaM-KK activity, part of which was due to suppression of CaM-binding by phosphorylation of Ser⁴⁵⁸ in the CaM-binding domain. However, the Ser⁴⁵⁸  Ala mutant, or a truncation mutant in which the CaM-binding and autoinhibitory domains were deleted, was still partially suppressed by PKA-mediated phosphorylation. The second inhibitory site was identified as Thr¹⁰⁸ by site-specific mutagenesis. Treatments of COS-7, PC12, hippocampal, or Jurkat cells with the PKA activators forskolin or isoproterenol gave 30-90% inhibition of either endogenous or transfected CaM-KK and/or CaM-KIV activities. These results demonstrate that the CaM kinase cascade is negatively regulated in cells by the cAMP/PKA pathway.

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