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

The cAMP-specific phosphodiesterase family 4, sub- family D, isoform 3 (PDE 4D3) is shown to have FQF and RIM docking sites for extracellular signal-re gulated kinase 2 (ERK2) (p42(MAPK)). These straddle the target residue, Ser (579), for ERK2 phosphorylation of PDE4D3. Mutation of either or both of th ese docking sites prevented ERK2 from being co-immunoprecipitated with PDE4 D3, ablated the ability of epidermal growth factor to inhibit PDE4D3 throug h 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 c haracterize 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 dire cts COOH-terminal ERK2 phosphorylation to cause the activation of this shor t isoform. From the analysis of PDE4D3 truncates, it is suggested that UCR1 and UCR2 provide a regulatory signal integration module that serves to orc hestrate the functional consequences of ERK2 phosphorylation. The PDE4D gen e thus encodes a series of isoenzymes that are either inhibited or activate d by ERK2 phosphorylation and thereby offers the potential for ERK2 activat ion either to increase or decrease cAMP levels in cellular compartments.