Affinage

PDE4D

3',5'-cyclic-AMP phosphodiesterase 4D · UniProt Q08499

Length
809 aa
Mass
91.1 kDa
Annotated
2026-06-10
100 papers in source corpus 36 papers cited in narrative 34 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PDE4D is a cAMP-specific phosphodiesterase that serves as a dominant terminator of cAMP signaling across diverse tissues, with its multiple alternatively spliced variants (PDE4D1–7) differentially compartmentalized through unique N-terminal regions that confer cytosolic, particulate, or nuclear targeting (PMID:9371713, PMID:18006274). Catalytic output is governed allosterically by a regulatory domain (UCR2/CR3) that closes over the active site, the conformation small-molecule modulators exploit to achieve partial inhibition (PMID:20037581). The enzyme is integrated into multiple feedback and signaling networks: PKA phosphorylates and activates long PDE4D isoforms to terminate cAMP signals (PMID:9677395, PMID:18508768), ERK2 phosphorylation at Ser579 inhibits long isoforms (via UCR1/UCR2) but activates short isoforms bearing UCR2 alone (PMID:10828059), and CaMKII activates PDE4D in cardiomyocytes to constrain beta-adrenergic cAMP (PMID:25646485). Conversely, integrin α5 binds PDE4D5 on fibronectin matrix and recruits PP2A via its B55α subunit to dephosphorylate the inhibitory Ser651 site, activating the enzyme, suppressing cAMP, and driving endothelial inflammation in atherosclerosis (PMID:27595237, PMID:31408443). Through these compartmentalized circuits PDE4D controls beta2-adrenergic cAMP and CREB-dependent transcription in fibroblasts (PMID:18508768, PMID:21288894), muscarinic cholinergic airway contraction (PMID:10841571, PMID:14519662), and GLP-1 secretion and beta-cell function (PMID:19371330, PMID:37729023). Loss-of-function missense mutations in PDE4D cause acrodysostosis, a skeletal dysplasia with brachydactyly and intellectual disability arising from disrupted cAMP-PKA signaling in bone and CNS (PMID:24203977, PMID:22464252, PMID:22464250, PMID:25064455), whereas elevated PDE4D drives pathological remodeling in heart, liver, and cancer, in part through PKA-dependent control of YAP phosphorylation and degradation (PMID:35597479, PMID:40015131).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1997 High

    Established that PDE4D's multiple splice variants are not redundant but are addressed to distinct subcellular compartments by their unique N-termini, explaining how one gene tunes cAMP in different locations.

    Evidence Transient expression in COS-7 cells with subcellular fractionation and rolipram IC50 determination across five isoforms

    PMID:9371713

    Open questions at the time
    • Did not define the molecular anchors binding each particulate isoform
    • Functional consequence of compartmentalization for cAMP gradients not measured
  2. 1998 High

    Showed that isoform targeting involves distinct anchoring mechanisms and that hormone-driven PKA phosphorylation activates PDE4D3, linking localization to regulated catalytic control.

    Evidence Subcellular fractionation, differential detergent extraction, immunofluorescence and TSH stimulation in FRTL-5 thyroid cells

    PMID:9677395

    Open questions at the time
    • Identity of the ionic-detergent-resistant anchor for PDE4D4 not determined
    • PKA phosphosites not mapped in this study
  3. 2000 High

    Resolved how a single gene produces both ERK2-inhibited and ERK2-activated isoenzymes by mapping ERK2 docking sites and the role of the UCR1/UCR2 module, establishing isoform-dependent kinase regulation.

    Evidence Docking-site mutagenesis, reciprocal Co-IP, in vitro ERK2 kinase assay and cellular cAMP readouts in COS cells

    PMID:10828059

    Open questions at the time
    • Physiological contexts where ERK2 inhibition versus activation dominates not defined
    • Crosstalk with PKA phosphorylation on the same isoform not resolved
  4. 1999 High

    Genetic ablation demonstrated PDE4D is required in vivo for gonadotropin signaling, growth, and fertility, moving the gene from a biochemical entity to an essential physiological cAMP regulator.

    Evidence PDE4D-/- knockout mouse with PDE4 activity assays and ovulation/fertility phenotyping

    PMID:10518565

    Open questions at the time
    • Which isoforms mediate the granulosa cell phenotype not dissected
    • Cell-autonomous versus systemic contributions not separated
  5. 2003 High

    Defined PDE4D as essential for muscarinic cholinergic airway contraction and traced the knockout phenotype to elevated cAMP driving prostanoid accumulation, providing a mechanistic pathway for airway tone.

    Evidence PDE4D-/- trachea contractility, cAMP and prostanoid measurements with prostanoid-synthesis-blockade rescue, in vivo airway assays

    PMID:10841571 PMID:14519662

    Open questions at the time
    • Specific cell type generating PGE2 not pinpointed
    • Isoform responsible for airway smooth muscle cAMP control not identified
  6. 2003 High

    Crystal structures of the catalytic domain with rolipram explained inhibitor selectivity at the residue level, including a key role for Gln369 conformation, informing selective inhibitor design.

    Evidence X-ray crystallography of PDE4D2 catalytic domain–rolipram complexes with comparison to PDE5/PDE7

    PMID:12834813 PMID:12842049

    Open questions at the time
    • Catalytic domain alone does not capture regulatory-domain allostery
    • Isoform-specific kinetic differences not structurally explained
  7. 2009 High

    Co-crystal structures revealed the regulatory UCR2/CR3 domain closes over the active site, establishing the structural basis of allosteric, partial inhibition exploitable for safer therapeutics.

    Evidence Seven X-ray co-crystal structures with mutagenesis, enzyme kinetics, cellular cAMP assays and in vivo emesis models

    PMID:20037581

    Open questions at the time
    • Dynamics of the open/closed equilibrium in full-length enzyme not captured
    • How post-translational modifications shift this equilibrium not resolved
  8. 2011 High

    Isoform-selective knockouts with spatially resolved cAMP sensors showed PDE4D and PDE4B operate in distinct subcellular cAMP pools, with PDE4D uniquely controlling bulk-cytosol cAMP and CREB transcription, establishing compartmentalized signaling.

    Evidence PDE4B and PDE4D knockout MEFs with FRET cAMP sensors, CREB reporters and isoproterenol stimulation; PKA feedback dissected with H89/PKI

    PMID:18508768 PMID:21288894

    Open questions at the time
    • Molecular determinants restricting each enzyme to its pool not defined
    • How distinct pools couple to specific downstream effectors not mapped
  9. 2010 High

    Identified a defined signaling complex of PDE4D with EPAC1 at VE-cadherin junctions that controls endothelial barrier function, linking PDE4D scaffolding to vascular permeability.

    Evidence Reciprocal Co-IP, fractionation, cell-permeable EPAC1 peptide disruption and permeability assays in human arterial endothelial cells

    PMID:20732872

    Open questions at the time
    • PDE4D isoform within the complex not specified
    • Whether catalytic activity or scaffolding drives the permeability effect not separated
  10. 2016 High

    Demonstrated that integrin α5 directly binds PDE4D5 and recruits PP2A-B55α to dephosphorylate inhibitory Ser651, activating the enzyme and driving atherosclerotic endothelial inflammation, linking matrix sensing to cAMP suppression.

    Evidence Integrin α5/α2 chimera knock-in mice, siRNA, Co-IP, Ser651 phospho-specific antibodies, cAMP measurement and in vivo inflammation assays; B55α confirmed by proteomics and in vitro phosphatase assay

    PMID:27595237 PMID:31408443

    Open questions at the time
    • Whether other integrins use this PDE4D5 axis not tested
    • Stoichiometry and assembly order of the integrin-PDE4D5-PP2A complex not resolved
  11. 2015 Medium

    Extended the kinase regulation network by showing CaMKII activates PDE4D in cardiomyocytes, integrating Ca2+ and cAMP signaling as a negative feedback constraining beta-adrenergic cAMP.

    Evidence CaMKII inhibitor pharmacology, PDE4D activity assays and cAMP measurements in cardiomyocytes

    PMID:25646485

    Open questions at the time
    • CaMKII phosphosite on PDE4D not mapped
    • Single-lab pharmacological approach without genetic confirmation
  12. 2012 Medium

    Human genetics established that heterozygous PDE4D loss-of-function mutations cause acrodysostosis without hormone resistance, defining a Mendelian disease arising from disrupted cAMP homeostasis in bone and CNS.

    Evidence Exome/Sanger sequencing of patients with zebrafish overexpression and morpholino knockdown producing mirror skeletal phenotypes; KO rat radiographic phenotyping and HEK293 catalytic assays

    PMID:22464250 PMID:22464252 PMID:24203977 PMID:25064455

    Open questions at the time
    • Paradoxical low cAMP in patient cells from PDE4A/PDE4B compensation complicates genotype-phenotype interpretation
    • Affected bone/CNS cell types and developmental windows not defined
  13. 2025 Medium

    Established PDE4D as a driver of pathological remodeling in heart, liver, and cancer, acting through PKA-controlled YAP phosphorylation/degradation and CREB-SIRT1-mitophagy axes, defining therapeutic rationale for PDE4D inhibition.

    Evidence Gain/loss-of-function mouse models (cardiac haploinsufficiency, hepatic and AAV9 overexpression), Co-IP, YAP-S127A rescue, roflumilast treatment and pathway readouts across HCC, NAFLD/hypertension and heart failure models

    PMID:29386221 PMID:34826603 PMID:35597479 PMID:40015131

    Open questions at the time
    • Whether the same isoform mediates effects across organs not resolved
    • Single-lab models for each disease context without independent replication

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how the full repertoire of PDE4D isoforms, their distinct compartmental anchors, and the competing kinase/phosphatase inputs are integrated to shape tissue-specific cAMP microdomains in vivo.
  • No unified model linking specific isoforms to specific cAMP pools across tissues
  • Anchor proteins for most particulate isoforms remain unidentified
  • In vivo dynamics of opposing PKA/ERK2/CaMKII/PP2A regulation not measured directly

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140098 catalytic activity, acting on RNA 4 GO:0016787 hydrolase activity 2
Localization
GO:0005829 cytosol 3 GO:0005886 plasma membrane 3 GO:0005856 cytoskeleton 2 GO:0005634 nucleus 1
Pathway
R-HSA-1643685 Disease 5 R-HSA-162582 Signal Transduction 3
Partners
EPAC1HSPB6ITGA5MAPK1PPP2R2APTK2RACK1YAP1
Complex memberships
EPAC1-PDE4D-VE-cadherinPDE4D5-RACK1-FAKPDE4D5-integrin α5-PP2A(B55α)

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 Co-crystal structures of PDE4D with inhibitors reveal that the regulatory domain (UCR2/CR3) closes across the active site, establishing the structural basis of allosteric regulation. Mutagenesis and kinetic studies confirmed that small-molecule allosteric modulators binding this closed conformation partially inhibit enzymatic activity (Imax ~80-90%) without fully blocking cAMP hydrolysis. X-ray co-crystallography (7 structures), site-directed mutagenesis, enzyme kinetics, cellular cAMP assays, in vivo emesis models Nature biotechnology High 20037581
2000 ERK2 phosphorylates PDE4D3 at Ser579 using FQF and KIM docking sites flanking the target residue; mutation of either docking site prevents ERK2 co-immunoprecipitation with PDE4D3, ablates EGF-mediated inhibition of PDE4D3 in transfected cells, and attenuates in vitro phosphorylation. The long-isoform UCR1/UCR2 regulatory module amplifies the inhibitory effect of ERK2 phosphorylation on the catalytic unit, whereas in the short isoform PDE4D1 (containing only UCR2), ERK2 phosphorylation activates the enzyme. Thus PDE4D encodes isoenzymes that are either inhibited or activated by ERK2. Site-directed mutagenesis of docking sites, co-immunoprecipitation, in vitro ERK2 kinase assay, transfected COS cell cAMP assay, truncation analysis The Journal of biological chemistry High 10828059
1997 The N-terminal unique regions of PDE4D3, PDE4D4, and PDE4D5 (derived from alternatively spliced exons) determine their subcellular localization: PDE4D1 and PDE4D2 are cytosolic only, while PDE4D3/4/5 partition between cytosolic and particulate fractions. Particulate forms of PDE4D3 and PDE4D5 show 2-7-fold higher IC50 for rolipram than their cytosolic counterparts. Transient expression in COS-7 cells, subcellular fractionation, immunoblotting of human cell lines and rat brain, rolipram IC50 determination The Biochemical journal High 9371713
1998 PDE4D splice variants are targeted to discrete subcellular compartments in thyroid FRTL-5 cells: PDE4D3 is recovered in both soluble and particulate fractions and is solubilized by nonionic detergent, whereas PDE4D4 requires ionic detergent, indicating different anchoring mechanisms. TSH stimulation causes PKA-dependent electrophoretic mobility shift (phosphorylation) and activation of PDE4D3, and long-term TSH induces PDE4D2 expression in the soluble fraction. Immunofluorescence localizes PDE4D signal to plasma-membrane-adjacent cytoskeletal structures and a perinuclear region. Subcellular fractionation, differential detergent extraction, immunoblotting, immunofluorescence microscopy, TSH/cAMP stimulation The Journal of biological chemistry High 9677395
1999 PKA phosphorylates and activates PDE4D3 and PDE4D5 in vascular smooth muscle cells (VSMCs) in response to elevated cAMP. PKC-Raf-MEK-ERK activation also phosphorylates and activates PDE4D3 in VSMCs. Simultaneous activation of both PKA and PKC-Raf-MEK-ERK causes coordinated activation of PDE4D3 and translocation of particulate PDE4D3 to the cytosolic fraction. Pharmacological inhibitors (PKA, MEK), biochemical fractionation, in-cell phosphorylation assays in VSMCs The Journal of biological chemistry Medium 10187850
2000 PKA-dependent elevation of cAMP induces expression of PDE4D1 and PDE4D2 in VSMCs (feedback induction). Simultaneous activation of PKC-Raf-MEK-ERK blunts this cAMP-mediated induction of PDE4D through a mechanism involving decreased PDE4D mRNA stability, thereby attenuating cAMP desensitization. mRNA stability assays, pharmacological inhibitors (PKA, MEK, PKC), quantitative RT-PCR, immunoblotting in VSMCs The Journal of biological chemistry Medium 10851231
2003 Crystal structures of the PDE4D2 catalytic domain complexed with (R)- or (R,S)-rolipram reveal that inhibitor selectivity is determined by the chemical nature of active-site residues and subtle conformational changes of the binding pocket; Gln369 conformation plays a key role in inhibitor recognition. X-ray crystallography of PDE4D2 catalytic domain–rolipram complexes, structural comparison with PDE5/PDE7 Structure High 12842049
1999 Genetic inactivation of PDE4D in mice (PDE4D−/−) reduces total PDE4 activity and causes impaired ovulation and diminished gonadotropin sensitivity of granulosa cells, delayed growth, and reduced viability, demonstrating that PDE4D-mediated cAMP hydrolysis is required for normal gonadotropin signaling, growth, and fertility. Gene knockout mouse model, immunoblotting, PDE4 activity assay, ovulation and fertility phenotyping Proceedings of the National Academy of Sciences of the United States of America High 10518565
2000 PDE4D−/− mouse airways are refractory to muscarinic cholinergic stimulation; muscarinic receptor-mediated decrease of cAMP is absent, and antigen-induced airway hyperreactivity is abolished despite normal inflammatory infiltration. The loss of response is airway-specific (not observed in heart), establishing PDE4D as essential for cAMP homeostasis and cholinergic signaling in airway. PDE4D−/− mouse model, airway resistance measurements, cAMP accumulation assays, antigen challenge model Proceedings of the National Academy of Sciences of the United States of America High 10841571
2003 PDE4D−/− tracheas show 60% reduction in maximal cholinergic-evoked tension and five-fold decreased sensitivity to muscarinic agonists, with preserved responses to KCl and arginine vasopressin, identifying a specific role for PDE4D in muscarinic smooth muscle contraction. Elevated cAMP in PDE4D−/− airway leads to increased prostanoid (PGE2) accumulation; blockade of prostanoid synthesis restores muscarinic responses in vitro and in vivo. Isolated trachea contractility assays (PDE4D−/− vs WT), cAMP accumulation, prostanoid inhibition rescue experiments, in vivo airway measurements FASEB journal High 14519662
2008 Ablation of PDE4D (but not PDE4A or PDE4B) in mouse embryonic fibroblasts markedly enhances beta2-adrenergic receptor (beta2AR)-induced PDE activation, prolongs cAMP accumulation and CREB phosphorylation, and delays return to basal cAMP levels. This effect is largely due to loss of a PKA-mediated negative feedback loop (PKA activates PDE4D to terminate the cAMP signal). PDE4D ablation also alters beta2AR desensitization kinetics and the receptor's interaction with Gαi. PDE4D/4A/4B knockout MEFs, cAMP accumulation assays, CREB phosphorylation, PKA inhibitors (H89/PKI), beta2AR desensitization and Gαi co-immunoprecipitation The Journal of biological chemistry High 18508768
2011 PDE4D ablation in mouse embryonic fibroblasts enhances agonist-induced cAMP in the bulk cytosol and at the plasma membrane, whereas PDE4B ablation specifically elevates cAMP in a near-membrane pool without affecting bulk cytosol cAMP. PDE4D (but not PDE4B) ablation significantly prolongs CREB-mediated transcription. These results establish that PDE4D and PDE4B function in distinct subcellular cAMP compartments. PDE4B and PDE4D knockout MEFs, FRET-based cAMP sensors (cytosol and near-membrane), CREB-reporter assays, isoproterenol stimulation The Journal of biological chemistry High 21288894
2010 PDE4D enzymes form a complex with EPAC1 at vascular endothelial cadherin (VE-Cad)-based intercellular junctions in human arterial endothelial cells. Protein–protein interactions between EPAC1 and PDE4D are required for their integration into VE-Cad complexes. Disruption of this interaction with a cell-permeable EPAC1 peptide antagonizes EPAC1–PDE4D binding and directly alters vascular permeability. Co-immunoprecipitation, biochemical fractionation, peptide competition assay, VE-cadherin complex isolation, permeability assay The Journal of biological chemistry High 20732872
2016 On fibronectin matrix, integrin α5 directly binds PDE4D5 and recruits PP2A (via B55α regulatory subunit) to dephosphorylate PDE4D5 at the inhibitory site Ser651, thereby activating the phosphodiesterase, suppressing cAMP, and promoting endothelial inflammatory signaling. In vivo knockdown of PDE4D5 inhibits inflammation at atherosclerosis-prone arterial sites. Integrin α5/α2 chimera knock-in mice, siRNA knockdown, Co-IP, phospho-specific antibodies (Ser651), cAMP measurement, in vivo endothelial inflammation assay Nature cell biology High 27595237
2019 The PP2A regulatory subunit B55α recruits PP2A to PDE4D5, directly dephosphorylating PDE4D5 at Ser651 (activating it) at focal adhesions. This PDE4D5-B55α-PP2A complex also dephosphorylates and activates YAP. Mutation of the integrin α5 binding site in PDE4D5 reduces endothelial inflammatory activation and atherosclerotic plaque size in a hyperlipidemic mouse model. Proteomics (mass spectrometry identification of B55α), Co-IP, in vitro phosphatase assay, PDE4D5 integrin-binding site knock-in mouse, atherosclerosis plaque quantification The Journal of clinical investigation High 31408443
2015 CaMKII phosphorylates and activates PDE4D in cardiomyocytes in response to beta-adrenergic receptor stimulation, establishing a negative feedback loop that constrains basal and beta-AR-stimulated cAMP levels. This CaMKII→PDE4D axis integrates cAMP/PKA and Ca2+/CaMKII signaling pathways. CaMKII inhibitor pharmacology, PDE4D activity assays, cAMP measurements in cardiomyocytes, CaMKII activation/inhibition experiments Proceedings of the National Academy of Sciences of the United States of America Medium 25646485
2014 Phosphorylated HSP20 forms a complex with PDE4D in cardiomyocytes; peptide disruption of the HSP20–PDE4D interaction in human iPSC-derived cardiomyocytes attenuates action potential prolongation, and in a mouse pressure-overload model protects against adverse cardiac remodeling (improved contractility, reduced hypertrophy and fibrosis). Peptide disruption, human iPSC-cardiomyocytes electrophysiology, mouse pressure-overload hypertrophy model, cardiac histology and contractility FEBS open bio Medium 25426411
2017 PDE4D5 isoform interacts with focal adhesion kinase (FAK) through the scaffolding protein RACK1 in BRAF-mutated melanoma cells; inhibition of PDE4D enzymatic activity or disruption of the PDE4D–FAK interaction reduces melanoma cell invasion in vitro. Co-immunoprecipitation (PDE4D5–RACK1–FAK), PDE4 pharmacological inhibitors, invasion assays, patient tissue detection by proximity ligation Oncogene Medium 28092671
2003 PDE4D6 (supershort) and PDE4D7 (long) isoforms hydrolyze cAMP with high affinity and are inhibited by rolipram. PDE4D7 activity is elevated by PKA-dependent phosphorylation at the conserved UCR1 site, whereas PDE4D6 (lacking UCR1) is not activated by PKA. Baculovirus expression of recombinant PDE4D6/7, enzyme kinetics, PKA phosphorylation assay Cellular signalling Medium 12834813
2007 In mouse embryonic fibroblasts, short PDE4D1 isoforms localize to the nucleus via a nuclear localization signal in the unique N-terminal region, while supershort isoforms (PDE4D2, PDE4D6, PDE4D10) are restricted to the cytoplasm. Deletion of the N-terminus of PDE4D1 abolishes nuclear targeting. Subcellular fractionation, deletion mutagenesis, immunofluorescence microscopy Cellular signalling Medium 18006274
2009 PDE4D controls GLP-1 release in GLUTag cells: rolipram enhances GLP-1 release in vivo (rats) and in vitro. Stable overexpression of catalytically-inactive D556A-PDE4D5 mutant elevates cAMP and increases basal and glucose-induced GLP-1 release; PKA inhibitor H89 partially blocks this increase, establishing that PDE4D4/5 regulates GLP-1 secretion via cAMP/PKA. PDE4 inhibitor (rolipram) in vivo and in vitro, stable overexpression of catalytically inactive PDE4D5 mutant, PKA inhibitor H89, GLP-1 ELISA British journal of pharmacology Medium 19371330
2009 Transposon insertional mutagenesis in mouse prostate identified PDE4D as a proliferation-promoting factor; knockdown of PDE4D reduced growth and migration of human prostate cancer cells in vitro and reduced tumor xenograft growth in vivo. Sleeping Beauty transposon somatic mutagenesis screen, siRNA knockdown, in vitro proliferation/migration assays, xenograft tumor growth assay Cancer research Medium 19401450
2014 Acrodysostosis-associated PDE4D missense mutations (Gly673Asp and Ile678Thr) reduce catalytic activity in vitro; ectopic expression in HEK293 cells confirms reduced PDE4D activity by elevated cAMP. However, patient-derived cells paradoxically show low cAMP due to compensatory upregulation of PDE4A and PDE4B. PDE4D-knockout rats have shorter metacarpals and phalanges consistent with acrodysostosis. 3D structural modeling, in vitro cAMP accumulation assay in HEK293 cells, patient-derived cell cAMP measurement, immunoblotting, PDE4D-KO rat radiographic phenotyping Cellular signalling Medium 25064455
2012 Heterozygous de novo missense mutations in PDE4D cause acrodysostosis (skeletal dysplasia, brachydactyly, nasal hypoplasia, intellectual disability) without hormone resistance, establishing that PDE4D loss-of-function disrupts cAMP homeostasis in bone and CNS. Functional assay confirmed by zebrafish: overexpression of mutated PDE4D mRNA and morpholino-based pde4d knockdown produce mirror skeletal phenotypes, validating the pathogenicity of point mutations. Exome sequencing, Sanger sequencing, zebrafish overexpression and morpholino knockdown, array CGH Journal of medical genetics Medium 22464250 22464252 24203977
2021 Hepatic overexpression of PDE4D in mice induces NAFLD and hypertension via activation of fatty acid translocase CD36 signaling, leading to hepatocyte TGF-β1 production and vascular TGF-β1 signaling. siRNA silencing of TGF-β1 in hepatocytes normalizes the hypertension caused by PDE4D overexpression, placing PDE4D upstream of CD36–TGF-β1 in a liver-to-vessel axis. Hepatic PDE4D overexpression (adenovirus), liver-targeted TGF-β1 siRNA nanoparticles, hepatic steatosis histology, blood pressure measurement, CD36 signaling assays Pharmacological research Medium 34826603
2022 PDE4D physically binds YAP in hepatocellular carcinoma cells; PDE4D overexpression increases YAP dephosphorylation and transcriptional activity to promote HCC growth. Roflumilast-mediated PDE4D inhibition activates cAMP-PKA, causing PKA-dependent YAP phosphorylation at Ser127 and YAP degradation. YAP-S127A mutant reverses roflumilast-mediated suppression, confirming PDE4D acts via PKA→YAP-S127. Co-immunoprecipitation (PDE4D–YAP), overexpression and knockdown, phospho-YAP(S127) immunoblotting, YAP-S127A rescue, roflumilast treatment, in vivo xenograft Cancer letters Medium 35597479
2023 In pancreatic β cells, endoplasmic reticulum stress activates the PERK-ATF4 pathway, which transcriptionally induces PDE4D expression, reducing cAMP signaling and impairing incretin-stimulated insulin secretion. Pharmacological inhibition of ATF4 reduces PDE4D expression and restores β-cell function in db/db mice; PDE4D inhibition similarly rescues β-cell function in ATF4-transgenic and db/db mice. ATF4 transgenic mice, db/db mice, ATF4 pathway inhibitor, PDE4 inhibitor, cAMP measurement, glucose tolerance and insulin secretion assays, nuclear localization studies American journal of physiology. Endocrinology and metabolism Medium 37729023
2025 PDE4D is upregulated in failing hearts via isoproterenol-stimulated cAMP-PKA signaling. PDE4D overexpression suppresses CREB-SIRT1 signaling and PINK1/Parkin-mediated mitophagy, causing oxidative stress and cardiomyocyte hypertrophy; PDE4D knockdown or roflumilast reverses these effects. Cardiac-specific PDE4D haploinsufficiency protects against TAC-induced cardiac hypertrophy and heart failure in vivo; PDE4D overexpression abolishes this protection. Global and cardiac-specific PDE4D heterozygous KO mice, AAV9-PDE4D overexpression, TAC and isoproterenol mouse models, mitophagy assays (PINK1/Parkin), CREB-SIRT1 pathway immunoblotting, roflumilast treatment Redox biology Medium 40015131
2015 Arctigenin binds PDK1 (identified by chemical proteomics capture) and inhibits PDK1 kinase activity, leading to reduced Akt-mediated phosphorylation of PDE4D in human bronchial smooth muscle cells, thereby attenuating PDE4D activity and increasing cAMP accumulation. This PDK1/Akt/PDE4D axis was identified as a novel mechanism controlling airway smooth muscle relaxation. Chemical proteomics (drug-protein capture), molecular dynamics simulation, in vitro PDK1 kinase assay, PDE4D phosphorylation Western blot, cAMP measurement, tracheal smooth muscle contractility assay Allergy Medium 26335809
2018 PDE4D overexpression in tamoxifen-resistant ER+ breast cancer cells suppresses cAMP/ER-stress/p38-JNK signaling and apoptosis. Inhibition of PDE4D (siRNA or pharmacological inhibitors) restores tamoxifen sensitivity by reactivating cAMP-mediated unfolded protein response/ER stress pathway and p38/JNK-dependent apoptosis. siRNA knockdown, pharmacological inhibitors (dipyridamole, GEBR-7b), cAMP measurement, UPR/p38/JNK pathway immunoblotting, apoptosis assays, in vivo xenograft tumor growth Clinical cancer research Medium 29386221
2011 PDE4D expression and activity are approximately 2-fold elevated in asthmatic airway smooth muscle cells, accounting for reduced beta2-agonist-induced cAMP accumulation; specific PDE4 inhibition normalizes cAMP production and reduces asthmatic ASM proliferation but not non-asthmatic ASM proliferation. Primary cultured ASM from asthmatic vs. non-asthmatic subjects, cAMP accumulation assay with/without PDE inhibitors, PDE4D protein quantification, proliferation assay PloS one Medium 21611147
2020 PDE4D protein localizes to dendrites associated with microtubules, mitochondria, and smooth endoplasmic reticulum, with postsynaptic labeling in dendritic spines near glutamatergic synapses and in perisynaptic astroglial leaflets in macaque dlPFC layer III pyramidal cell circuits, as determined by immunoelectron microscopy. Laser-capture microdissection transcriptomics, high-resolution immunoelectron microscopy in rhesus macaque dlPFC Frontiers in neuroanatomy Medium 33328902
2014 A co-crystal structure of PDE4B (catalytic domain) with triazine inhibitors shows the compounds interact with both the catalytic pocket and the C-terminal regulatory helix (CR3), locking the enzyme in an inactive 'closed' conformation; structure-activity relationships define CR3 contacts as the basis for PDE4B vs. PDE4D subtype selectivity. X-ray co-crystallography of PDE4B–triazine complex, structure-activity relationship analysis of selective inhibitors Bioorganic & medicinal chemistry letters Medium 24998378
2023 In the PDE4D/cAMP/IL-23 axis in lung adenocarcinoma, PDE4D activity in tumor cells suppresses cAMP, reducing IL-23 production; PDE4D inhibition elevates cAMP and IL-23, which activates CTL NF-κB signaling to induce an IL-9 autocrine loop, enhancing CTL effector function and immunotherapy efficacy. Co-culture system (LUAD cells + tumor-specific CD8+ T cells), fluorescent multiplex IHC, transcriptome sequencing, functional validation with PDE4D manipulation and IL-23/IL-9/NF-κB pathway assays, in vivo mouse xenograft Cancer letters Medium 37196909

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Design of phosphodiesterase 4D (PDE4D) allosteric modulators for enhancing cognition with improved safety. Nature biotechnology 319 20037581
2000 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 Journal of biological chemistry 203 10828059
2002 Antidepressant-like profile and reduced sensitivity to rolipram in mice deficient in the PDE4D phosphodiesterase enzyme. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 194 12377395
1999 Impaired growth and fertility of cAMP-specific phosphodiesterase PDE4D-deficient mice. Proceedings of the National Academy of Sciences of the United States of America 180 10518565
2005 ALOX5AP gene and the PDE4D gene in a central European population of stroke patients. Stroke 164 15731479
1997 Characterization of five different proteins produced by alternatively spliced mRNAs from the human cAMP-specific phosphodiesterase PDE4D gene. The Biochemical journal 161 9371713
2000 Absence of muscarinic cholinergic airway responses in mice deficient in the cyclic nucleotide phosphodiesterase PDE4D. Proceedings of the National Academy of Sciences of the United States of America 136 10841571
2005 Splice variants of the cyclic nucleotide phosphodiesterase PDE4D are differentially expressed and regulated in rat tissue. The Biochemical journal 118 15717866
2003 PDE4D plays a critical role in the control of airway smooth muscle contraction. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 113 14519662
2012 Exome sequencing identifies PDE4D mutations in acrodysostosis. American journal of human genetics 110 22464252
2012 Exome sequencing identifies PDE4D mutations as another cause of acrodysostosis. American journal of human genetics 104 22464250
2008 Enhanced long-term potentiation and impaired learning in phosphodiesterase 4D-knockout (PDE4D) mice. The European journal of neuroscience 103 18702734
2007 Differential expression and function of phosphodiesterase 4 (PDE4) subtypes in human primary CD4+ T cells: predominant role of PDE4D. Journal of immunology (Baltimore, Md. : 1950) 102 17404263
2003 Three-dimensional structures of PDE4D in complex with roliprams and implication on inhibitor selectivity. Structure (London, England : 1993) 95 12842049
2012 PRKAR1A and PDE4D mutations cause acrodysostosis but two distinct syndromes with or without GPCR-signaling hormone resistance. The Journal of clinical endocrinology and metabolism 83 23043190
2010 Cyclic AMP phosphodiesterase 4D (PDE4D) Tethers EPAC1 in a vascular endothelial cadherin (VE-Cad)-based signaling complex and controls cAMP-mediated vascular permeability. The Journal of biological chemistry 82 20732872
2016 Interaction between integrin α5 and PDE4D regulates endothelial inflammatory signalling. Nature cell biology 81 27595237
2009 Identification of PDE4D as a proliferation promoting factor in prostate cancer using a Sleeping Beauty transposon-based somatic mutagenesis screen. Cancer research 81 19401450
1998 Subcellular localization of rolipram-sensitive, cAMP-specific phosphodiesterases. Differential targeting and activation of the splicing variants derived from the PDE4D gene. The Journal of biological chemistry 77 9677395
2011 β2-Agonist induced cAMP is decreased in asthmatic airway smooth muscle due to increased PDE4D. PloS one 75 21611147
1999 Phosphorylation-mediated activation and translocation of the cyclic AMP-specific phosphodiesterase PDE4D3 by cyclic AMP-dependent protein kinase and mitogen-activated protein kinases. A potential mechanism allowing for the coordinated regulation of PDE4D activity and targeting. The Journal of biological chemistry 74 10187850
2014 RNA interference-mediated knockdown of long-form phosphodiesterase-4D (PDE4D) enzyme reverses amyloid-β42-induced memory deficits in mice. Journal of Alzheimer's disease : JAD 71 23948935
2018 miR-203a-3p promotes colorectal cancer proliferation and migration by targeting PDE4D. American journal of cancer research 70 30662799
2000 Expression of phosphodiesterase 4D (PDE4D) is regulated by both the cyclic AMP-dependent protein kinase and mitogen-activated protein kinase signaling pathways. A potential mechanism allowing for the coordinated regulation of PDE4D activity and expression in cells. The Journal of biological chemistry 68 10851231
2017 Comparison of the Pharmacological Profiles of Selective PDE4B and PDE4D Inhibitors in the Central Nervous System. Scientific reports 63 28054669
2017 Multiple Behavior Phenotypes of the Fragile-X Syndrome Mouse Model Respond to Chronic Inhibition of Phosphodiesterase-4D (PDE4D). Scientific reports 57 29116166
2015 A CaMKII/PDE4D negative feedback regulates cAMP signaling. Proceedings of the National Academy of Sciences of the United States of America 57 25646485
2008 Variation in the PDE4D gene and ischemic stroke risk: a systematic review and meta-analysis on 5200 cases and 6600 controls. Stroke 56 18420948
2006 Evaluation of single nucleotide polymorphisms in the phosphodiesterase 4D gene (PDE4D) and their association with ischaemic stroke in a large German cohort. Journal of neurology, neurosurgery, and psychiatry 56 16543535
2017 Polymorphisms of MTHFR, eNOS, ACE, AGT, ApoE, PON1, PDE4D, and Ischemic Stroke: Meta-Analysis. Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association 54 28760411
2005 Linkage of ischemic stroke to the PDE4D region on 5q in a Swedish population. Stroke 53 16020760
2013 Different mutations in PDE4D associated with developmental disorders with mirror phenotypes. Journal of medical genetics 52 24203977
2011 PDE4D and PDE4B function in distinct subcellular compartments in mouse embryonic fibroblasts. The Journal of biological chemistry 51 21288894
2009 The role of the PDE4D cAMP phosphodiesterase in the regulation of glucagon-like peptide-1 release. British journal of pharmacology 51 19371330
2018 Reactivation of cAMP Pathway by PDE4D Inhibition Represents a Novel Druggable Axis for Overcoming Tamoxifen Resistance in ER-positive Breast Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 49 29386221
2019 Integrin α5β1 regulates PP2A complex assembly through PDE4D in atherosclerosis. The Journal of clinical investigation 46 31408443
2012 Identification of novel mutations confirms PDE4D as a major gene causing acrodysostosis. Human mutation 46 23033274
2010 Association of PDE4D and IL-1 gene polymorphism with ischemic stroke in a Han Chinese population. Brain research bulletin 46 19786079
2006 Polymorphisms of the phosphodiesterase 4D, cAMP-specific (PDE4D) gene and risk of ischemic stroke: a prospective, nested case-control evaluation. Stroke 46 16825591
2003 Cloning and characterization of novel PDE4D isoforms PDE4D6 and PDE4D7. Cellular signalling 46 12834813
2002 Differential distribution of PDE4D splice variant mRNAs in rat brain suggests association with specific pathways and presynaptical localization. Synapse (New York, N.Y.) 46 12125047
2014 Heterozygous mutations in cyclic AMP phosphodiesterase-4D (PDE4D) and protein kinase A (PKA) provide new insights into the molecular pathology of acrodysostosis. Cellular signalling 43 25064455
2004 The induction of cyclic nucleotide phosphodiesterase 4 gene (PDE4D) impairs memory in a water maze task. Behavioural brain research 41 15302115
2014 Discovery of triazines as selective PDE4B versus PDE4D inhibitors. Bioorganic & medicinal chemistry letters 40 24998378
2010 Sex-differential genetic effect of phosphodiesterase 4D (PDE4D) on carotid atherosclerosis. BMC medical genetics 40 20540798
2016 Screening of PRKAR1A and PDE4D in a Large Italian Series of Patients Clinically Diagnosed With Albright Hereditary Osteodystrophy and/or Pseudohypoparathyroidism. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 39 26763073
2007 PDE4D and ALOX5AP genetic variants and risk for Ischemic Cerebrovascular Disease in Sweden. Journal of the neurological sciences 39 17655870
1996 Identification of cyclic AMP-phosphodiesterase variants from the PDE4D gene expressed in human peripheral mononuclear cells. FEBS letters 39 8797812
2006 Effects of ciclamilast, a new PDE 4 PDE4 inhibitor, on airway hyperresponsiveness, PDE4D expression and airway inflammation in a murine model of asthma. European journal of pharmacology 38 16956605
2005 Familial aggregation, the PDE4D gene, and ischemic stroke in a genetically isolated population. Neurology 38 16162858
2020 A Novel PDE4D Inhibitor BPN14770 Reverses Scopolamine-Induced Cognitive Deficits via cAMP/SIRT1/Akt/Bcl-2 Pathway. Frontiers in cell and developmental biology 36 33363155
2008 Critical role of PDE4D in beta2-adrenoceptor-dependent cAMP signaling in mouse embryonic fibroblasts. The Journal of biological chemistry 36 18508768
2008 Stroke genetics--focus on PDE4D gene. International journal of stroke : official journal of the International Stroke Society 36 18705898
2016 New insights into selective PDE4D inhibitors: 3-(Cyclopentyloxy)-4-methoxybenzaldehyde O-(2-(2,6-dimethylmorpholino)-2-oxoethyl) oxime (GEBR-7b) structural development and promising activities to restore memory impairment. European journal of medicinal chemistry 33 27560284
2021 circ_0023461 Silencing Protects Cardiomyocytes from Hypoxia-Induced Dysfunction through Targeting miR-370-3p/PDE4D Signaling. Oxidative medicine and cellular longevity 31 34630853
2009 Phosphodiesterase 4D (PDE4D) gene variants and the risk of ischemic stroke in a South Indian population. Journal of the neurological sciences 31 19608201
1995 Chromosomal localization of the human and rat genes (PDE4D and PDE4B) encoding the cAMP-specific phosphodiesterases 3 and 4. Cytogenetics and cell genetics 31 7835077
2017 PDE4D promotes FAK-mediated cell invasion in BRAF-mutated melanoma. Oncogene 30 28092671
2010 Meta-analysis of association between variation in the PDE4D gene and ischemic cerebral infarction risk in Asian populations. Neurogenetics 30 20182758
2009 Lack of association between variations of PDE4D and ischemic stroke in the Japanese population. Stroke 30 19246712
2021 Overexpression of PDE4D in mouse liver is sufficient to trigger NAFLD and hypertension in a CD36-TGF-β1 pathway: therapeutic role of roflumilast. Pharmacological research 29 34826603
2007 Identification and characterization of novel mouse PDE4D isoforms: molecular cloning, subcellular distribution and detection of isoform-specific intracellular localization signals. Cellular signalling 29 18006274
2015 PDE4D phosphorylation: A coincidence detector integrating multiple signaling pathways. Cellular signalling 28 26562185
2014 Targeted disruption of the heat shock protein 20-phosphodiesterase 4D (PDE4D) interaction protects against pathological cardiac remodelling in a mouse model of hypertrophy. FEBS open bio 27 25426411
2015 PDK1/Akt/PDE4D axis identified as a target for asthma remedy synergistic with β2 AR agonists by a natural agent arctigenin. Allergy 26 26335809
2011 Meta-analysis of homogeneous subgroups reveals association between PDE4D gene variants and ischemic stroke. Neuroepidemiology 26 21677445
2008 Ischaemic stroke in hypertensive patients is associated with variations in the PDE4D genome region. European journal of human genetics : EJHG 26 18398440
2015 Phosphodiesterase4D (PDE4D)--A risk factor for atrial fibrillation and stroke? Journal of the neurological sciences 25 26671126
2018 Expanding the phenotypic spectrum of variants in PDE4D/PRKAR1A: from acrodysostosis to acroscyphodysplasia. European journal of human genetics : EJHG 23 30006632
2023 Resveratrol prevents Drp1-mediated mitochondrial fission in the diabetic kidney through the PDE4D/PKA pathway. Phytotherapy research : PTR 22 37767771
2022 PDE4D binds and interacts with YAP to cooperatively promote HCC progression. Cancer letters 22 35597479
2016 Human PDE4D isoform composition is deregulated in primary prostate cancer and indicative for disease progression and development of distant metastases. Oncotarget 22 27683107
2011 Association of the phosphodiesterase 4D (PDE4D) gene and cardioembolic stroke in an Australian cohort. International journal of stroke : official journal of the International Stroke Society 22 21989204
2009 Association between the PDE4D gene and ischaemic stroke in the Chinese Han population. Clinical science (London, England : 1979) 22 19196240
2007 Expression of the cAMP-phosphodiesterase PDE4D isoforms and age-related changes in follicle-stimulating hormone-stimulated PDE4 activities in immature rat sertoli cells. Biology of reproduction 22 17215491
2020 Mapping Phosphodiesterase 4D (PDE4D) in Macaque Dorsolateral Prefrontal Cortex: Postsynaptic Compartmentalization in Layer III Pyramidal Cell Circuits. Frontiers in neuroanatomy 21 33328902
2018 PDE4D regulates Spine Plasticity and Memory in the Retrosplenial Cortex. Scientific reports 21 29497131
2015 Association between PDE4D gene and ischemic stroke: recent advancements. The International journal of neuroscience 21 26004910
2025 PDE4D inhibition ameliorates cardiac hypertrophy and heart failure by activating mitophagy. Redox biology 20 40015131
2018 Inhibition of TPL2 by interferon-α suppresses bladder cancer through activation of PDE4D. Journal of experimental & clinical cancer research : CR 20 30482227
2012 A new model of Pde4d deficiency: genetic knock-down of PDE4D enzyme in rats produces an antidepressant phenotype without spatial cognitive effects. Genes, brain, and behavior 20 22487514
2021 Long Non-coding RNAMALAT1 Knockdown Alleviates Cerebral Ischemia/Reperfusion Injury of Rats Through Regulating the miR-375/PDE4D Axis. Frontiers in neurology 17 33519668
2023 PDE4D/cAMP/IL-23 axis determines the immunotherapy efficacy of lung adenocarcinoma via activating the IL-9 autocrine loop of cytotoxic T lymphocytes. Cancer letters 16 37196909
2014 Synthesis, biological evaluation, and molecular modeling of new 3-(cyclopentyloxy)-4-methoxybenzaldehyde O-(2-(2,6-dimethylmorpholino)-2-oxoethyl) Oxime (GEBR-7b) related phosphodiesterase 4D (PDE4D) inhibitors. Journal of medicinal chemistry 16 25126889
2012 Association of SNP41, SNP56 and a novel SNP in PDE4D gene with stroke and its subtypes. Gene 16 22771915
2022 PDE4D targeting enhances anti-tumor effects of sorafenib in clear cell renal cell carcinoma and attenuates MAPK/ERK signaling in a CRAF-dependent manner. Translational oncology 15 35196602
2013 Genetic polymorphism in PDE4D gene and risk of ischemic stroke in Chinese population: a meta-analysis. PloS one 15 23799094
2012 A large-sample assessment of possible association between ischaemic stroke and rs12188950 in the PDE4D gene. European journal of human genetics : EJHG 15 22274584
2023 Moderate-Intensity Intermittent Training Alters the DNA Methylation Pattern of PDE4D Gene in Hippocampus to Improve the Ability of Spatial Learning and Memory in Aging Rats Reduced by D-Galactose. Brain sciences 13 36979232
2023 Baicalein promotes the microglia M2 polarization and suppresses apoptosis by targeting HMOX1/PDE4D to alleviate Alzheimer's disease. Immunobiology 13 38006681
2020 Phosphodiesterase PDE4D Is Decreased in Frontal Cortex of Aged Rats and Positively Correlated With Working Memory Performance and Inversely Correlated With PKA Phosphorylation of Tau. Frontiers in aging neuroscience 13 33192469
2019 Association between PDE4D polymorphism and ischemic stroke in young population. Saudi journal of biological sciences 13 31303835
2017 Association between PDE4D rs966221 polymorphism and risk of ischemic stroke: a systematic review and meta-analysis. Metabolic brain disease 13 29234926
2023 Endoplasmic reticulum stress in pancreatic β cells induces incretin desensitization and β-cell dysfunction via ATF4-mediated PDE4D expression. American journal of physiology. Endocrinology and metabolism 12 37729023
2022 Circ_0101874 overexpression strengthens PDE4D expression by targeting miR-335-5p to promote neuronal injury in ischemic stroke. Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association 12 36252429
2021 Design, synthesis, biological evaluation and structural characterization of novel GEBR library PDE4D inhibitors. European journal of medicinal chemistry 12 34171658
2016 Further Insights in the Binding Mode of Selective Inhibitors to Human PDE4D Enzyme Combining Docking and Molecular Dynamics. Molecular informatics 12 27546041
2007 PDE4D gene in the STRK1 region on 5q12: susceptibility gene for ischemic stroke. Current medicinal chemistry 12 18220751
2006 Role of FLAP and PDE4D in myocardial infarction and stroke: target discovery and future treatment options. Current treatment options in cardiovascular medicine 12 16635437
2023 Resveratrol ameliorates diabetic encephalopathy through PDE4D/PKA/Drp1 signaling. Brain research bulletin 11 37722608

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