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PMID: 12444918 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Review

PDE4 cAMP phosphodiesterases: modular enzymes that orchestrate signalling cross-talk, desensitization and compartmentalization.

The Biochemical journal ·Vol. 370 ·No. Pt 1 ·2003-02-15 ·Pages 1-18

Houslay MD, Adams DR

Abstract

cAMP is a second messenger that controls many key cellular functions. The only way to inactivate cAMP is to degrade it through the action of cAMP phosphodiesterases (PDEs). PDEs are thus poised to play a key regulatory role. PDE4 cAMP-specific phosphodiesterases appear to have specific functions with selective inhibitors serving as potent anti-inflammatory agents. The recent elucidation of the structure of the PDE4 catalytic unit allows for molecular insight into the mode of catalysis as well as substrate and inhibitor selectivity. The four PDE4 genes encode over 16 isoforms, each of which is characterized by a unique N-terminal region. PDE4 isoforms play a pivotal role in controlling functionally and spatially distinct pools of cAMP by virtue of their unique intracellular targeting. Targeting occurs by association with proteins, such as arrestins, SRC family tyrosyl kinases, A-kinase anchoring proteins ('AKAPs') and receptor for activated C kinase 1 ('RACK1'), and, in the case of isoform PDE4A1, by a specific interaction (TAPAS-1) with phosphatidic acid. PDE4 isoforms are 'designed' to be regulated by extracellular-signal-related protein kinase (ERK), which binds to anchor sites on the PDE4 catalytic domain that it phosphorylates. The upstream conserved region 1 (UCR1) and 2 (UCR2) modules that abut the PDE4 catalytic unit confer regulatory functions by orchestrating the functional outcome of phosphorylation by cAMP-dependent protein kinase ('PKA') and ERK. PDE4 enzymes stand at a crossroads that allows them to integrate various signalling pathways with that of cAMP in spatially distinct compartments.

MeSH Terms
3',5'-Cyclic-AMP Phosphodiesterases/chemistry,metabolism Catalytic Domain Cell Compartmentation Cyclic Nucleotide Phosphodiesterases, Type 4 Humans Models, Molecular Protein Conformation Pulmonary Disease, Chronic Obstructive/enzymology Signal Transduction
Chemicals
3',5'-Cyclic-AMP Phosphodiesterases Cyclic Nucleotide Phosphodiesterases, Type 4
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Houslay Miles D
Molecular Pharmacology Group, Division of Biochemistry and Molecular Biology, Davidson Building, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow G12 8QQ, Scotland, UK. [email protected]
Adams David R
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Article Info
Journal
The Biochemical journal
Abbr.
Biochem J
ISSN
0264-6021
DOI
10.1042/BJ20021698
Email
[email protected]
Published
2003-02-15
Pages
1-18
Language
English
Region
England
NLM ID
2984726R
PMCID
PMC1223165
Subset
IM
External Links
PubMed source DOI: 10.1042/BJ20021698 PMC Full Text View journal details
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