The role of ERK2 docking and phosphorylation of PDE4 cAMP phosphodiesterase isoforms in mediating cross-talk between the cAMP and ERK signalling pathways.
PDE4 cAMP phosphodiesterases are widely expressed enzymes that serve as major regulators of cAMP signalling in cells. They provide targets for therapeutics having anti-inflammatory and cognitive-enhancing properties. ERK2 (extracellular-signal-regulated kinase 2) interacts with the PDE4 catalytic unit by binding to a KIM (kinase interaction motif) docking site located on an exposed beta-hairpin loop and an FQF (Phe-Gln-Phe) specificity site located on an exposed alpha-helix. These flank a site that allows phosphorylation by ERK, the functional outcome of which is orchestrated by the N-terminal UCR1/2 (upstream conserved region 1 and 2) modules. The three classes of PDE4 isoforms differ in these regulatory modules, allowing phosphorylation by ERK to lead to either inhibition or activation. ERK inhibition of long isoforms is regulated by a unique feedback control whereby elevated cAMP levels cause PKA (protein kinase A) to phosphorylate UCR1 and ablate the inhibitory action of ERK. PDE4 isoforms can also be found in complex with beta-arrestins where they provide a novel part of the cellular desensitization mechanism to receptor-mediated cAMP signalling. Stimulation of the beta(2)-adrenoceptor recruits beta-arrestins with bound PDE4, delivering an enzyme capable of degrading cAMP at its site of synthesis at the plasma membrane. Use of dominant negative PDE4 isoforms identifies that a major role of recruited PDE4 is to regulate plasma membrane PKA activity involved in phosphorylating the beta(2)-adrenoceptor. Recruited PDE4 thus desensitizes the ability of the beta(2)-adrenoceptor to activate ERK via G(i).
Houslay
M D
MD
Molecular Pharmacology Group, Division of Biochemistry & Molecular Biology, Wolfson Building, Institute of Biomedical & Life Sciences, University of Glasgow, Glasgow G12 8QQ, Scotland, U.K. M.Houslay@bio.gla.ac.uk
Baillie
G S
GS
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism*; D019390:Arrestins / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D007527:Isoenzymes / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D010766:Phosphorylation; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism; D015398:Signal Transduction; D000071557:beta-Arrestins
D019390:Arrestins; D007527:Isoenzymes; D018343:Receptors, Adrenergic, beta-2; D000071557:beta-Arrestins; D000242:Cyclic AMP; D019950:Mitogen-Activated Protein Kinase 1; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4