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

In this study, we describe a novel mechanism by which a protein kinase C (P KC)-mediated activation of the Raf-extracellular signal-regulated kinase ki nase (MEK)-extracellular signal-regulated kinase (ERK) cascade regulates th e activity and membrane targeting of members of the cyclic AMP-specific pho sphodiesterase 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 PDE4 D variants expressed in vascular smooth muscle cells, namely PDE4D3 and PDE 4D5. In addition, we show that stimulation of PKC via the associated activa tion of the Raf-MEK-ERK cascade results in the phosphorylation and activati on of PDE4D3 in these cells. Furthermore, our studies demonstrate that simu ltaneous activation of both the protein kinase A and PKC-Raf-MEK-ERK pathwa ys allows for a coordinated activation of PDE4D3 and for the translocation of the particulate PDE4D3 to the cytosolic fraction of these cells. These d ata are presented and discussed in the context of the activation of the Raf -MEK-ERK cascade acting to modulate the activation and subcellular targetin g of PDE4D gene products mediated by cAMP.