PDE4D

Summary

Gene Symbol: PDE4D
Description: phosphodiesterase 4D
Alias: ACRDYS2, DPDE3, HSPDE4D, PDE43, PDE4DN2, STRK1, cAMP-specific 3',5'-cyclic phosphodiesterase 4D, cAMP-specific phosphodiesterase PDE4D6, phosphodiesterase 4D, cAMP-specific (phosphodiesterase E3 dunce homolog, Drosophila), testicular tissue protein Li 136
Species: human
Products:     PDE4D

Top Publications

  1. Lynch M, Baillie G, Mohamed A, Li X, Maisonneuve C, Klussmann E, et al. RNA silencing identifies PDE4D5 as the functionally relevant cAMP phosphodiesterase interacting with beta arrestin to control the protein kinase A/AKAP79-mediated switching of the beta2-adrenergic receptor to activation of ERK in HEK293B2 cells. J Biol Chem. 2005;280:33178-89 pubmed
    PDE4B and PDE4D provide >90% of PDE4 cAMP phosphodiesterase activity in human embryonic kidney (HEK293B2) cells...
  2. Sun Y, Huang Y, Chen X, Liu Y, Lu X, Shi Y, et al. Association between the PDE4D gene and ischaemic stroke in the Chinese Han population. Clin Sci (Lond). 2009;117:265-72 pubmed publisher
    Recent findings suggests that PDE4D (gene encoding phosphodiesterase 4D) is a stroke-related gene in the Icelandic population, but it is still very controversial as to whether it is a susceptible gene for stroke in other populations...
  3. Nakayama T, Asai S, Sato N, Soma M. Genotype and haplotype association study of the STRK1 region on 5q12 among Japanese: a case-control study. Stroke. 2006;37:69-76 pubmed
    ..infarction with a significant logarithm of odds score at 5q12 in whites in 2002 and subsequently identified the PDE4D gene as a susceptibility gene at this locus in 2003...
  4. Dodge Kafka K, Soughayer J, Pare G, Carlisle Michel J, Langeberg L, Kapiloff M, et al. The protein kinase A anchoring protein mAKAP coordinates two integrated cAMP effector pathways. Nature. 2005;437:574-8 pubmed
    ..Thus, two coupled cAMP-dependent feedback loops are coordinated within the context of the mAKAP complex, suggesting that local control of cAMP signalling by AKAP proteins is more intricate than previously appreciated. ..
  5. Dominiczak A, McBride M. Genetics of common polygenic stroke. Nat Genet. 2003;35:116-7 pubmed
  6. Huai Q, Wang H, Sun Y, Kim H, Liu Y, Ke H. Three-dimensional structures of PDE4D in complex with roliprams and implication on inhibitor selectivity. Structure. 2003;11:865-73 pubmed
    ..Docking of the PDE5 inhibitor sildenafil into the PDE4 catalytic pocket further helps understand inhibitor selectivity. ..
  7. Smith K, Baillie G, Hyde E, Li X, Houslay T, McCahill A, et al. 1H NMR structural and functional characterisation of a cAMP-specific phosphodiesterase-4D5 (PDE4D5) N-terminal region peptide that disrupts PDE4D5 interaction with the signalling scaffold proteins, beta-arrestin and RACK1. Cell Signal. 2007;19:2612-24 pubmed
  8. Brophy V, Ro S, Rhees B, Lui L, Lee J, Umblas N, et al. Association of phosphodiesterase 4D polymorphisms with ischemic stroke in a US population stratified by hypertension status. Stroke. 2006;37:1385-90 pubmed
    Phosphodiesterase 4D (PDE4D) underlies the STRK1 linkage peak for stroke on chromosome 5q12 identified in Iceland...
  9. Dodge K, Khouangsathiene S, Kapiloff M, Mouton R, Hill E, Houslay M, et al. mAKAP assembles a protein kinase A/PDE4 phosphodiesterase cAMP signaling module. EMBO J. 2001;20:1921-30 pubmed
    ..Disruption of PKA- mAKAP interaction prevents this enhancement of PDE4D3 activity, suggesting that the proximity of both enzymes in the mAKAP signaling complex forms a negative feedback loop to restore basal cAMP levels. ..

More Information

Publications71

  1. Song Q, Cole J, O Connell J, Stine O, Gallagher M, Giles W, et al. Phosphodiesterase 4D polymorphisms and the risk of cerebral infarction in a biracial population: the Stroke Prevention in Young Women Study. Hum Mol Genet. 2006;15:2468-78 pubmed
    An association between polymorphisms within the phosphodiesterase 4D gene (PDE4D) and ischemic stroke was initially reported in older adults from Iceland and has been supported by studies in several other primarily elderly populations...
  2. Kaname T, Ki C, Niikawa N, Baillie G, Day J, Yamamura K, et al. Heterozygous mutations in cyclic AMP phosphodiesterase-4D (PDE4D) and protein kinase A (PKA) provide new insights into the molecular pathology of acrodysostosis. Cell Signal. 2014;26:2446-59 pubmed publisher
    ..Recently, loss-of-function mutations in the gene encoding cAMP-hydrolyzing phosphodiesterase-4D (PDE4D) have been reported to cause this rare condition but the pathomechanism has not been fully elucidated...
  3. Gretarsdottir S, Sveinbjornsdottir S, Jonsson H, Jakobsson F, Einarsdottir E, Agnarsson U, et al. Localization of a susceptibility gene for common forms of stroke to 5q12. Am J Hum Genet. 2002;70:593-603 pubmed
    ..This locus on 5q12, which we have designated as "STRK1," does not correspond to known susceptibility loci for stroke or for its risk factors and represents the ..
  4. Michot C, Le Goff C, Goldenberg A, Abhyankar A, Klein C, Kinning E, et al. Exome sequencing identifies PDE4D mutations as another cause of acrodysostosis. Am J Hum Genet. 2012;90:740-5 pubmed publisher
    ..We performed exome sequencing in two of the five remaining individuals and selected phosphodiesterase 4D (PDE4D) as a candidate gene...
  5. Li X, Baillie G, Houslay M. Mdm2 directs the ubiquitination of beta-arrestin-sequestered cAMP phosphodiesterase-4D5. J Biol Chem. 2009;284:16170-82 pubmed publisher
    ..for this is the ubiquitin-interacting motif located in the extreme C terminus of PDE4D5, which is specific to the PDE4D sub-family...
  6. Bevan S, Dichgans M, Gschwendtner A, Kuhlenbäumer G, Ringelstein E, Markus H. Variation in the PDE4D gene and ischemic stroke risk: a systematic review and meta-analysis on 5200 cases and 6600 controls. Stroke. 2008;39:1966-71 pubmed publisher
    b>PDE4D was identified as the first novel gene associated with ischemic stroke risk. Replication studies have produced conflicting results, but many have been small and underpowered...
  7. Homma S, Sakamoto T, Hegab A, Saitoh W, Nomura A, Ishii Y, et al. Association of phosphodiesterase 4D gene polymorphisms with chronic obstructive pulmonary disease: relationship to interleukin 13 gene polymorphism. Int J Mol Med. 2006;18:933-9 pubmed
    ..We hypothesized that polymorphisms of the phosphodiesterase 4D (PDE4D) gene activate its protein function which leads to the downregulation of cAMP, resulting in the development of ..
  8. Hoffmann R, Baillie G, Mackenzie S, Yarwood S, Houslay M. The MAP kinase ERK2 inhibits the cyclic AMP-specific phosphodiesterase HSPDE4D3 by phosphorylating it at Ser579. EMBO J. 1999;18:893-903 pubmed
    ..We identify a novel means of cross-talk between the cAMP and ERK signalling pathways whereby cell stimuli that lead to ERK2 activation may modulate cAMP signalling. ..
  9. Beard M, O Connell J, Bolger G, Houslay M. The unique N-terminal domain of the cAMP phosphodiesterase PDE4D4 allows for interaction with specific SH3 domains. FEBS Lett. 1999;460:173-7 pubmed
    Of the five PDE4D isoenzymes, only the PDE4D4 cAMP specific phosphodiesterase was able to bind to SH3 domains...
  10. Steele M, McCahill A, Thompson D, MacKenzie C, Isaacs N, Houslay M, et al. Identification of a surface on the beta-propeller protein RACK1 that interacts with the cAMP-specific phosphodiesterase PDE4D5. Cell Signal. 2001;13:507-13 pubmed
    ..We propose that this surface of RACK1 is the major site for its interaction with the unique amino-terminal region of PDE4D5. ..
  11. Nilsson Ardnor S, Wiklund P, Lindgren P, Nilsson A, Janunger T, Escher S, et al. Linkage of ischemic stroke to the PDE4D region on 5q in a Swedish population. Stroke. 2005;36:1666-71 pubmed
    ..demonstrated linkage for common forms of stroke to chromosome 5q12 and association between phosphodiesterase4D (PDE4D) and ischemic stroke...
  12. Bolger G, Erdogan S, Jones R, Loughney K, Scotland G, Hoffmann R, et al. Characterization of five different proteins produced by alternatively spliced mRNAs from the human cAMP-specific phosphodiesterase PDE4D gene. Biochem J. 1997;328 ( Pt 2):539-48 pubmed
    We have isolated and characterized complete cDNAs for two isoforms (HSPDE4D4 and HSPDE4A5) encoded by the human PDE4D gene, one of four genes that encode cAMP-specific rolipram-inhibited 3',5'-cyclic nucleotide phosphodiesterases (type ..
  13. Saleheen D, Bukhari S, Haider S, Nazir A, Khanum S, Shafqat S, et al. Association of phosphodiesterase 4D gene with ischemic stroke in a Pakistani population. Stroke. 2005;36:2275-7 pubmed
    Identification of STRK1 locus by the deCODE group followed by the discovery of phosphodiesterase 4D (PDE4D) gene in strong association with ischemic stroke patients has provided useful insights toward understanding the genetic etiology ..
  14. Munshi A, Babu M, Kaul S, Shafi G, Anila A, Alladi S, et al. Phosphodiesterase 4D (PDE4D) gene variants and the risk of ischemic stroke in a South Indian population. J Neurol Sci. 2009;285:142-5 pubmed publisher
    ..Many of the studies of PDE4D gene have focused on the original Icelandic findings but the association between specific SNPs and haplotypes has ..
  15. Lee H, Graham J, Rimoin D, Lachman R, Krejci P, Tompson S, et al. Exome sequencing identifies PDE4D mutations in acrodysostosis. Am J Hum Genet. 2012;90:746-51 pubmed publisher
    ..Three different missense mutations in PDE4D, which encodes cyclic AMP (cAMP)-specific phosphodiesterase 4D, were found to be heterozygous in three of the ..
  16. Rosand J, Bayley N, Rost N, de Bakker P. Many hypotheses but no replication for the association between PDE4D and stroke. Nat Genet. 2006;38:1091-2; author reply 1092-3 pubmed
  17. Xu X, Li X, Li J, Ou R, Sheng W. Meta-analysis of association between variation in the PDE4D gene and ischemic cerebral infarction risk in Asian populations. Neurogenetics. 2010;11:327-33 pubmed publisher
    Phosphodiesterase 4D (PDE4D) was found to be associated with increased risk of ischemic stroke by Iceland researchers in 2003. Replication studies have produced conflicting results...
  18. Terrin A, Di Benedetto G, Pertegato V, Cheung Y, Baillie G, Lynch M, et al. PGE(1) stimulation of HEK293 cells generates multiple contiguous domains with different [cAMP]: role of compartmentalized phosphodiesterases. J Cell Biol. 2006;175:441-51 pubmed
    ..and genetic manipulation of phosphodiesterases (PDEs), we demonstrate that compartmentalized PDE4B and PDE4D are responsible for selectively modulating the concentration of cAMP in individual subcellular compartments...
  19. Stefan E, Wiesner B, Baillie G, Mollajew R, Henn V, Lorenz D, et al. Compartmentalization of cAMP-dependent signaling by phosphodiesterase-4D is involved in the regulation of vasopressin-mediated water reabsorption in renal principal cells. J Am Soc Nephrol. 2007;18:199-212 pubmed
    ..PKA and cAMP-specific phosphodiesterase-4D (PDE4D) are located on AQP2-bearing vesicles...
  20. Baillie G, Adams D, Bhari N, Houslay T, Vadrevu S, Meng D, et al. Mapping binding sites for the PDE4D5 cAMP-specific phosphodiesterase to the N- and C-domains of beta-arrestin using spot-immobilized peptide arrays. Biochem J. 2007;404:71-80 pubmed
    ..We have identified a binding site in the beta-arrestin 2 N-domain for the common PDE4D catalytic unit and two regions in the beta-arrestin 2 C-domain that confer specificity for PDE4D5 binding...
  21. Billington C, Le Jeune I, Young K, Hall I. A major functional role for phosphodiesterase 4D5 in human airway smooth muscle cells. Am J Respir Cell Mol Biol. 2008;38:1-7 pubmed
    ..previously reported that PDE4 family members are likely to be important in this process, and that expression of PDE4D variants is actively regulated at the transcriptional level...
  22. Sette C, Conti M. Phosphorylation and activation of a cAMP-specific phosphodiesterase by the cAMP-dependent protein kinase. Involvement of serine 54 in the enzyme activation. J Biol Chem. 1996;271:16526-34 pubmed
    ..These findings support the hypothesis that the PDE4D3 variant contains a regulatory domain target for phosphorylation at the amino terminus of the protein and that Ser54 in this domain plays a crucial role in activation. ..
  23. Fidani L, Clarimon J, Goulas A, Hatzitolios A, Evans W, Tsirogianni E, et al. Association of phosphodiesterase 4D gene G0 haplotype and ischaemic stroke in a Greek population. Eur J Neurol. 2007;14:745-9 pubmed
    We have examined the association of phosphodiesterase 4D (PDE4D) single nucleotide polymorphism (SNP45) and microsatellite marker AC008818-1 with ischaemic stroke, in an independent cohort of Greek patients and control individuals with ..
  24. Lynch M, Baillie G, Houslay M. cAMP-specific phosphodiesterase-4D5 (PDE4D5) provides a paradigm for understanding the unique non-redundant roles that PDE4 isoforms play in shaping compartmentalized cAMP cell signalling. Biochem Soc Trans. 2007;35:938-41 pubmed
  25. Xue H, Wang H, Song X, Li W, Sun K, Zhang W, et al. Phosphodiesterase 4D gene polymorphism is associated with ischaemic and haemorrhagic stroke. Clin Sci (Lond). 2009;116:335-40 pubmed publisher
    It has been reported that the variants of the PDE4D (phosphodiesterase 4D) gene are associated with stroke, especially with the combination of cardio-embolic and carotid stroke in the Icelandic population, but it is still very ..
  26. Le Jeune I, Shepherd M, Van Heeke G, Houslay M, Hall I. Cyclic AMP-dependent transcriptional up-regulation of phosphodiesterase 4D5 in human airway smooth muscle cells. Identification and characterization of a novel PDE4D5 promoter. J Biol Chem. 2002;277:35980-9 pubmed
    Phosphodiesterase 4D (PDE4D), part of the complex cAMP-specific PDE4 family, plays a pivotal role in the regulation of airway smooth muscle relaxation by catalyzing the hydolysis of cAMP...
  27. Perry S, Baillie G, Kohout T, McPhee I, Magiera M, Ang K, et al. Targeting of cyclic AMP degradation to beta 2-adrenergic receptors by beta-arrestins. Science. 2002;298:834-6 pubmed
  28. Li N, He Z, Xu J, Liu F, Deng S, Zhang H. Association of PDE4D and IL-1 gene polymorphism with ischemic stroke in a Han Chinese population. Brain Res Bull. 2010;81:38-42 pubmed publisher
    The single-nucleotide polymorphisms (SNPs) of the phosphodiesterase 4D (PDE4D) and interleukin-1 (IL-1) genes are associated with increased risk for the development of ischemic stroke (IS) in whites...
  29. Lõhmussaar E, Gschwendtner A, Mueller J, Org T, Wichmann E, Hamann G, et al. ALOX5AP gene and the PDE4D gene in a central European population of stroke patients. Stroke. 2005;36:731-6 pubmed
    Recent evidence has implicated the genes for 5-lipoxygenase activating protein (ALOX5AP) and phosphodiesterase 4D (PDE4D) as susceptibility genes for stroke in the Icelandic population...
  30. Wu C, Hu Z, He Z, Jia W, Wang F, Zhou Y, et al. Genome-wide association study identifies three new susceptibility loci for esophageal squamous-cell carcinoma in Chinese populations. Nat Genet. 2011;43:679-84 pubmed publisher
    ..92 × 10(-56)). These findings highlight the involvement of multiple genetic loci and gene-environment interaction in the development of esophageal cancer. ..
  31. Murdoch H, Vadrevu S, Prinz A, Dunlop A, Klussmann E, Bolger G, et al. Interaction between LIS1 and PDE4, and its role in cytoplasmic dynein function. J Cell Sci. 2011;124:2253-66 pubmed publisher
    ..This provides a further example to the growing notion that PDE4 itself may provide a signalling role independent of its catalytic activity, exemplified here by its modulation of dynein motor function. ..
  32. Hoffmann R, Wilkinson I, McCallum J, Engels P, Houslay M. cAMP-specific phosphodiesterase HSPDE4D3 mutants which mimic activation and changes in rolipram inhibition triggered by protein kinase A phosphorylation of Ser-54: generation of a molecular model. Biochem J. 1998;333 ( Pt 1):139-49 pubmed
    ..The increase in susceptibility to inhibition by rolipram upon PKA-mediated phosphorylation is suggested to involve the disruption of a hydrogen-bond involving the side-chain hydroxy group of Ser-54. ..
  33. Woo D, Kaushal R, Kissela B, Sekar P, Wolujewicz M, Pal P, et al. Association of Phosphodiesterase 4D with ischemic stroke: a population-based case-control study. Stroke. 2006;37:371-6 pubmed
    The Phosphodiesterase 4D (PDE4D) gene was reported recently to be associated with ischemic stroke in an Icelandic population. The association was found predominately with large vessel and cardioembolic stroke...
  34. Kim M, Kim J, Choi S, Lee S, Park M, Cho K. Phosphodiesterase 4D gene and risk of noncardiogenic ischemic stroke in a Korean population. J Korean Med Sci. 2009;24:307-10 pubmed publisher
    ..different populations provide apparently conflicting evidence on the association between the phosphodiesterase 4D (PDE4D) gene and ischemic stroke...
  35. Gretarsdottir S, Thorleifsson G, Reynisdottir S, Manolescu A, Jonsdottir S, Jonsdottir T, et al. The gene encoding phosphodiesterase 4D confers risk of ischemic stroke. Nat Genet. 2003;35:131-8 pubmed
    ..We found the strongest association in the gene encoding phosphodiesterase 4D (PDE4D), especially for carotid and cardiogenic stroke, the forms of stroke related to atherosclerosis...
  36. Kuhlenbaumer G, Berger K, Huge A, Lange E, Kessler C, John U, et al. Evaluation of single nucleotide polymorphisms in the phosphodiesterase 4D gene (PDE4D) and their association with ischaemic stroke in a large German cohort. J Neurol Neurosurg Psychiatry. 2006;77:521-4 pubmed
    ..which has been mapped to chromosome 5q12 in Icelandic families), has identified the phosphodiesterase 4D gene (PDE4D) gene as a good candidate gene...
  37. Bolger G, McCahill A, Yarwood S, Steele M, Warwicker J, Houslay M. Delineation of RAID1, the RACK1 interaction domain located within the unique N-terminal region of the cAMP-specific phosphodiesterase, PDE4D5. BMC Biochem. 2002;3:24 pubmed
  38. Baillie G, Sood A, McPhee I, Gall I, Perry S, Lefkowitz R, et al. beta-Arrestin-mediated PDE4 cAMP phosphodiesterase recruitment regulates beta-adrenoceptor switching from Gs to Gi. Proc Natl Acad Sci U S A. 2003;100:940-5 pubmed
    ..are treated with the selective PDE4-inhibitor rolipram or when they are transfected with a catalytically inactive PDE4D mutant (PDE4D5-D556A) that competitively inhibits isoprenaline-stimulated recruitment of native PDE4 to the beta(2)..
  39. Lövkvist H, Smith J, Luthman H, Hoglund P, Norrving B, Kristoffersson U, et al. Ischaemic stroke in hypertensive patients is associated with variations in the PDE4D genome region. Eur J Hum Genet. 2008;16:1117-25 pubmed publisher
    Previous Icelandic studies reported that single nucleotide polymorphisms (SNPs) in the phosphodiesterase 4D (PDE4D) region and the 5-lipoxygenase activating protein ALOX5AP were associated with ischaemic stroke, whereas other studies ..
  40. Zee R, Brophy V, Cheng S, Hegener H, Erlich H, Ridker P. Polymorphisms of the phosphodiesterase 4D, cAMP-specific (PDE4D) gene and risk of ischemic stroke: a prospective, nested case-control evaluation. Stroke. 2006;37:2012-7 pubmed
    In an Icelandic population, gene variants of the phosphodiesterase 4D, cAMP-specific (PDE4D) gene were reported to be risk predictors for ischemic stroke...
  41. Quarta G, Stanzione R, Evangelista A, Zanda B, Di Angelantonio E, Marchitti S, et al. Phosphodiesterase 4D and 5-lipoxygenase activating protein genes and risk of ischemic stroke in Sardinians. Eur J Hum Genet. 2009;17:1448-53 pubmed publisher
    Genetic factors contribute to the risk of ischemic stroke (IS). The phosphodiesterase-4D (PDE4D) and the 5-lipoxygenase activating protein (ALOX5AP) genes were identified as contributors to stroke in an Icelandic population...
  42. Himes B, Hunninghake G, Baurley J, Rafaels N, Sleiman P, Strachan D, et al. Genome-wide association analysis identifies PDE4D as an asthma-susceptibility gene. Am J Hum Genet. 2009;84:581-93 pubmed publisher
    ..The strongest region of association seen was on chromosome 5q12 in PDE4D. The phosphodiesterase 4D, cAMP-specific (phosphodiesterase E3 dunce homolog, Drosophila) gene (PDE4D) is a ..
  43. Kostulas K, Gretarsdottir S, Kostulas V, Manolescu A, Helgadottir A, Thorleifsson G, et al. PDE4D and ALOX5AP genetic variants and risk for Ischemic Cerebrovascular Disease in Sweden. J Neurol Sci. 2007;263:113-7 pubmed
    Genetic variants in Phosphodiesterase 4D (PDE4D) and 5-lipoxygenase activating protein (ALOX5AP) have been shown to confer risk of Ischemic Cerebrovascular Disease (ICVD) in Iceland...
  44. Lee M, Markowitz J, Lee J, Lee H. Crystal structure of phosphodiesterase 4D and inhibitor complex(1). FEBS Lett. 2002;530:53-8 pubmed
    ..The first crystal structure of PDE4D catalytic domain and a bound inhibitor, zardaverine, was determined...
  45. Staton J, Sayer M, Hankey G, Attia J, Thakkinstian A, Yi Q, et al. Association between phosphodiesterase 4D gene and ischaemic stroke. J Neurol Neurosurg Psychiatry. 2006;77:1067-9 pubmed
    An association between the phosphodiesterase 4D (PDE4D) gene and risk of ischaemic stroke in an Icelandic population has been suggested by the deCODE group...
  46. Bolger G, Baillie G, Li X, Lynch M, Herzyk P, Mohamed A, et al. Scanning peptide array analyses identify overlapping binding sites for the signalling scaffold proteins, beta-arrestin and RACK1, in cAMP-specific phosphodiesterase PDE4D5. Biochem J. 2006;398:23-36 pubmed
    ..Modelled on the PDE4D catalytic domain, these form distinct well-defined surface-exposed patches on helices-15-16, for RACK1, and helix-..
  47. Li X, Vadrevu S, Dunlop A, Day J, Advant N, Troeger J, et al. Selective SUMO modification of cAMP-specific phosphodiesterase-4D5 (PDE4D5) regulates the functional consequences of phosphorylation by PKA and ERK. Biochem J. 2010;428:55-65 pubmed publisher
    ..In the present paper, we report for the first time that PDE4 isoforms from the PDE4A and PDE4D subfamilies can be selectively modified by SUMO (small ubiquitin-related modifier)...
  48. Shifman S, Bhomra A, Smiley S, Wray N, James M, Martin N, et al. A whole genome association study of neuroticism using DNA pooling. Mol Psychiatry. 2008;13:302-12 pubmed
    ..We were able to replicate association of one SNP within the PDE4D gene in a second sample collected by our laboratory and in a family-based test in an independent sample; however, ..
  49. Munshi A, Kaul S. Stroke genetics--focus on PDE4D gene. Int J Stroke. 2008;3:188-92 pubmed publisher
    ..Recently, the deCODE group has suggested an association between the phosphodiesterase 4D (PDE4D) gene and the risk of stroke in Icelanders...
  50. Matsushita T, Kubo M, Yonemoto K, Ninomiya T, Ashikawa K, Liang B, et al. Lack of association between variations of PDE4D and ischemic stroke in the Japanese population. Stroke. 2009;40:1245-51 pubmed publisher
    After the first genomewide association study of ischemic stroke identified PDE4D as a susceptible gene, many replication studies have been conducted...
  51. Willoughby D, Wong W, Schaack J, Scott J, Cooper D. An anchored PKA and PDE4 complex regulates subplasmalemmal cAMP dynamics. EMBO J. 2006;25:2051-61 pubmed
    ..Co-immunoprecipitation confirmed that gravin maintains a signaling complex that includes PKA and PDE4D. We propose that gravin-associated PDE4D isoforms provide a means to rapidly terminate subplasmalemmal cAMP ..
  52. Yarwood S, Steele M, Scotland G, Houslay M, Bolger G. The RACK1 signaling scaffold protein selectively interacts with the cAMP-specific phosphodiesterase PDE4D5 isoform. J Biol Chem. 1999;274:14909-17 pubmed
    ..RACK1 did not interact with other PDE4D isoforms or with known PDE4A, PDE4B, and PDE4C isoforms...
  53. Bolger G, McCahill A, Huston E, Cheung Y, McSorley T, Baillie G, et al. The unique amino-terminal region of the PDE4D5 cAMP phosphodiesterase isoform confers preferential interaction with beta-arrestins. J Biol Chem. 2003;278:49230-8 pubmed
    Isoproterenol challenge of Hek-B2 cells causes a transient recruitment of the endogenous PDE4D isoforms found in these cells, namely PDE4D3 and PDE4D5, to the membrane fraction...
  54. van Rijn M, Slooter A, Schut A, Isaacs A, Aulchenko Y, Snijders P, et al. Familial aggregation, the PDE4D gene, and ischemic stroke in a genetically isolated population. Neurology. 2005;65:1203-9 pubmed
    ..of this investigation was to study the familial aggregation of ischemic stroke and the association between the PDE4D gene and ischemic stroke...
  55. Meschia J, Brott T, Brown R, Crook R, Worrall B, Kissela B, et al. Phosphodiesterase 4D and 5-lipoxygenase activating protein in ischemic stroke. Ann Neurol. 2005;58:351-61 pubmed
    ..Iceland identified risk polymorphisms in two putative candidate genes for ischemic stroke: phosphodiesterase 4D (PDE4D) and 5-lipoxygenase activating protein (ALOX5AP)...
  56. Bevan S, Porteous L, Sitzer M, Markus H. Phosphodiesterase 4D gene, ischemic stroke, and asymptomatic carotid atherosclerosis. Stroke. 2005;36:949-53 pubmed
    Phosphodiesterase 4D (PDE4D) was identified recently as the first novel stroke gene to predispose to ischemic stroke independently of conventional risk factors...
  57. Barnes A, Livera G, Huang P, Sun C, O Neal W, Conti M, et al. Phosphodiesterase 4D forms a cAMP diffusion barrier at the apical membrane of the airway epithelium. J Biol Chem. 2005;280:7997-8003 pubmed
    ..Using reverse transcription-PCR, Western blotting, and activity measurements, PDE4D was identified as the major PDE species in airway epithelia...
  58. Carlisle Michel J, Dodge K, Wong W, Mayer N, Langeberg L, Scott J. PKA-phosphorylation of PDE4D3 facilitates recruitment of the mAKAP signalling complex. Biochem J. 2004;381:587-92 pubmed
    ..Our data suggest that activation of mAKAP-anchored PKA enhances the recruitment of PDE4D3, allowing for quicker signal termination. ..
  59. Richter W, Conti M. The oligomerization state determines regulatory properties and inhibitor sensitivity of type 4 cAMP-specific phosphodiesterases. J Biol Chem. 2004;279:30338-48 pubmed
    ..Taken together, our data indicate that dimerization defines the properties of PDE4 enzymes and suggest a common structural and functional organization for all PDEs. ..
  60. Bolger G, Michaeli T, Martins T, St John T, Steiner B, Rodgers L, et al. A family of human phosphodiesterases homologous to the dunce learning and memory gene product of Drosophila melanogaster are potential targets for antidepressant drugs. Mol Cell Biol. 1993;13:6558-71 pubmed
    ..Each of the four genes demonstrated a distinctive pattern of expression in RNA from human cell lines. ..
  61. Hill E, Sheppard C, Cheung Y, Gall I, Krause E, Houslay M. Oxidative stress employs phosphatidyl inositol 3-kinase and ERK signalling pathways to activate cAMP phosphodiesterase-4D3 (PDE4D3) through multi-site phosphorylation at Ser239 and Ser579. Cell Signal. 2006;18:2056-69 pubmed
    ..We identify a novel process through which reactive oxygen species activate long PDE4 isoforms so as to reduce cAMP levels and thereby promote inflammatory responses. ..
  62. Mackenzie S, Baillie G, McPhee I, Bolger G, Houslay M. 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. J Biol Chem. 2000;275:16609-17 pubmed
    ..isoforms, are proposed to amplify the small, inherent inhibitory effect that ERK2 phosphorylation exerts on the PDE4D catalytic unit...