Abstract
Phosphodiesterases (PDEs) shape local cAMP gradients to underpin the specificity of receptor function. Key to this process is the highly defined nature of the intra-cellular location of PDEs in the cell. PDE4A5 is a PDE isoform that specifically degrades cAMP and is known to associate with the p75 neurotrophin receptor (p75NTR) where it modulates cAMP signalling cascades that regulate extracellular matrix remodelling in the lungs. Here we map and validate novel protein-protein interaction sites that are important for formation of the PDE4A5-p75NTR complex and show, for the first time, that phosphorylation of PDE4A5 by MAPKAPK2 enhances PDE4A5 interaction with p75NTR and that this, in turn, serves to attenuate fibrin degradation.
Highlights
Cyclic-AMP signalling via p75 neurotrophin receptor (p75NTR) can inhibit scar formation and suppress extracellular matrix remodelling and these positive outcomes are opposed by recruitment of PDE4A to the receptor [13, 14]
We report that that this process is fine-tuned by phosphorylation of PDE4A5 by MAPKAPK2, the downstream kinase of the p38 Mitogen-activated protein kinase (MAPK) inflammatory signalling cascade
P38MAPK has been linked to the production of a variety of pro-inflammatory mediators such as IL-12, IL-1b, tumour necrosis factor a (TNF-a), prostaglandin E2 (PGE2) and IL-12 as well as cyclooxygenase 2 (COX-2), IL-8, IL-6, IL-3, IL-2 and IL-1 (reviewed in [24])
Summary
Compartmentalized degradation of cAMP in cells is made possible by the ability of PDE4s to integrate into macromolecular complexes, or signalosomes, via interactions with different cellular scaffold proteins, such as A-kinase anchoring proteins (AKAPs) and other signalosome components [4, 7]. This paradigm provides a cellular desensitization mechanism, whereby compartmentalized increases in cAMP activate PKA (protein kinase A) pools localized in the vicinity of the PDE4 in order to phosphorylate and activate long PDE4 isoforms [8].
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