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Regulation of HSPDE3B interaction with 14‐3‐3 proteins and cellular targeting

The phosphodiesterase 3 (PDE3) family of cyclic nucleotide phosphodiesterases are broadly expressed, hydrolyze cAMP in a wide variety of cell types, and are sensitive to inhibition by endogenous cGMP as well as selective pharmacological agents. While previous published reports have shown that PDE3 phosphorylation resultant from activation of either the cAMP‐dependent protein kinase A‐ (PKA) or protein kinase B‐ (PKB) can activate these enzymes, and that their expression is regulated transcriptionally in cells, there is currently little information describing the mechanisms coordinating subcellular targeting of these enzymes. In these studies, we demonstrate that human PDE3B (Homo Sapien PDE3B, HSPDE3B) associates with 14‐3‐3 proteins in cells and that this interaction is coordinated by phosphorylation. Indeed, we report that PKA‐catalyzed phosphorylation of HSPDE3B at S73, S296 and S318 each promote HSPDE3B interaction with 14‐3‐3 proteins in cells. We demonstrate that these PKA‐dependent phosphorylation events coordinate the formation of a HSPDE3B stable complex with cAMP‐effector proteins. In marked contrast to previous work with rat PDE3B, our data is entirely inconsistent with a role for PKB‐mediated phosphorylation of S295 in coordinating HSPDE3B interactions with 14‐3‐3 proteins in cells. Our data are presented in the context of HSPDE3B expression within a multi‐protein cellular complex and defines a central role for PKA in regulating this association and the sensitivity of anchored HSPDE3B to PDE3‐selective inhibitors.