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J Biol Chem, Vol. 274, Issue 15, 10557-10565, April 9, 1999

Phosphorylation-mediated Activation and Translocation of the Cyclic AMP-specific Phosphodiesterase PDE4D3 by Cyclic AMP-dependent Protein Kinase and Mitogen-activated Protein Kinases
A POTENTIAL MECHANISM ALLOWING FOR THE COORDINATED REGULATION OF PDE4D ACTIVITY AND TARGETING

Hanguan Liu and Donald H. Maurice^§

From the Departments of ^§ Pathology and  Pharmacology & Toxicology, Queen's University, Kingston, Ontario K7L 3N6, Canada

In this study, we describe a novel mechanism by which a protein kinase C (PKC)-mediated activation of the Raf-extracellular signal-regulated kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) cascade regulates the activity and membrane targeting of members of the cyclic AMP-specific phosphodiesterase D family (PDE4D). Using a combination of pharmacological and biochemical approaches, we show that increases in intracellular cAMP cause a protein kinase A-mediated phosphorylation and activation of the two PDE4D variants expressed in vascular smooth muscle cells, namely PDE4D3 and PDE4D5. In addition, we show that stimulation of PKC via the associated activation of the Raf-MEK-ERK cascade results in the phosphorylation and activation of PDE4D3 in these cells. Furthermore, our studies demonstrate that simultaneous activation of both the protein kinase A and PKC-Raf-MEK-ERK pathways allows for a coordinated activation of PDE4D3 and for the translocation of the particulate PDE4D3 to the cytosolic fraction of these cells. These data are presented and discussed in the context of the activation of the Raf-MEK-ERK cascade acting to modulate the activation and subcellular targeting of PDE4D gene products mediated by cAMP.

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