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J. Biol. Chem., Vol. 275, Issue 22, 16609-16617, June 2, 2000

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ERK2 Mitogen-activated Protein Kinase Binding, Phosphorylation, and Regulation of the PDE4D cAMP-specific Phosphodiesterases
THE INVOLVEMENT OF COOH-TERMINAL DOCKING SITES AND NH₂-TERMINAL UCR REGIONS^*

Simon J. MacKenzie, George S. Baillie, Ian McPhee, Graeme B. Bolger^§¶, and Miles D. Houslay^¶**

From the Molecular Pharmacology Group, Division of Biochemistry and Molecular Biology, Davidson Bldg., IBLS, University of Glasgow, Glasgow G12 8QQ, Scotland, United Kingdom and the ^§ Veterans Affairs Medical Center, Huntsman Cancer Institute, and Departments of Medicine and Oncologic Science, University of Utah, Salt Lake City, Utah 84132

The cAMP-specific phosphodiesterase family 4, subfamily D, isoform 3 (PDE4D3) is shown to have FQF and KIM docking sites for extracellular signal-regulated kinase 2 (ERK2) (p42^MAPK). These straddle the target residue, Ser⁵⁷⁹, for ERK2 phosphorylation of PDE4D3. Mutation of either or both of these docking sites prevented ERK2 from being co-immunoprecipitated with PDE4D3, ablated the ability of epidermal growth factor to inhibit PDE4D3 through ERK2 action in transfected COS cells, and attenuated the ability of ERK2 to phosphorylate PDE4D3 in vitro. The two conserved NH₂-terminal blocks of sequence, called upstream conserved regions 1 and 2 (UCR1 and UCR2), that characterize PDE4 long isoforms, are proposed to amplify the small, inherent inhibitory effect that ERK2 phosphorylation exerts on the PDE4D catalytic unit. In contrast to this, the lone intact UCR2 region found in PDE4D1 directs COOH-terminal ERK2 phosphorylation to cause the activation of this short isoform. From the analysis of PDE4D3 truncates, it is suggested that UCR1 and UCR2 provide a regulatory signal integration module that serves to orchestrate the functional consequences of ERK2 phosphorylation. The PDE4D gene thus encodes a series of isoenzymes that are either inhibited or activated by ERK2 phosphorylation and thereby offers the potential for ERK2 activation either to increase or decrease cAMP levels in cellular compartments.

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