PDE4D

Protein-coding gene in the species Homo sapiens
PDE4D
Available structures
PDBOrtholog search: PDBe RCSB
List of PDB id codes

1MKD, 1OYN, 1PTW, 1Q9M, 1TB7, 1TBB, 1XOM, 1XON, 1XOQ, 1XOR, 1Y2B, 1Y2C, 1Y2D, 1Y2E, 1Y2K, 1ZKN, 2FM0, 2FM5, 2PW3, 2QYN, 3G4G, 3G4I, 3G4K, 3G4L, 3G58, 3IAD, 3IAK, 3K4S, 3SL3, 3SL4, 3SL5, 3SL6, 3SL8, 3V9B, 4OGB, 4W1O, 4WCU

Identifiers
AliasesPDE4D, ACRDYS2, DPDE3, HSPDE43, PDE4DN2, STRK1, phosphodiesterase 4D
External IDsOMIM: 600129; MGI: 99555; HomoloGene: 129755; GeneCards: PDE4D; OMA:PDE4D - orthologs
Gene location (Human)
Chromosome 5 (human)
Chr.Chromosome 5 (human)[1]
Chromosome 5 (human)
Genomic location for PDE4D
Genomic location for PDE4D
Band5q11.2-q12.1Start58,969,038 bp[1]
End60,522,120 bp[1]
Gene location (Mouse)
Chromosome 13 (mouse)
Chr.Chromosome 13 (mouse)[2]
Chromosome 13 (mouse)
Genomic location for PDE4D
Genomic location for PDE4D
Band13 D2.1|13 59.69 cMStart108,586,482 bp[2]
End110,089,995 bp[2]
RNA expression pattern
Bgee
HumanMouse (ortholog)
Top expressed in
  • glutes

  • muscle of arm

  • biceps brachii

  • Skeletal muscle tissue of rectus abdominis

  • triceps brachii muscle

  • Skeletal muscle tissue of biceps brachii

  • thoracic diaphragm

  • Achilles tendon

  • gastrocnemius muscle

  • vastus lateralis muscle
Top expressed in
  • muscle of thigh

  • skeletal muscle tissue

  • quadriceps femoris muscle

  • olfactory bulb

  • Cortex of frontal lobe

  • right kidney

  • proximal tubule

  • superior frontal gyrus

  • primary visual cortex

  • thymus
More reference expression data
BioGPS




More reference expression data
Gene ontology
Molecular function
  • ATPase binding
  • scaffold protein binding
  • cAMP binding
  • metal ion binding
  • beta-2 adrenergic receptor binding
  • protein binding
  • phosphoric diester hydrolase activity
  • enzyme binding
  • hydrolase activity
  • ubiquitin protein ligase binding
  • transmembrane transporter binding
  • 3',5'-cyclic-AMP phosphodiesterase activity
  • 3',5'-cyclic-nucleotide phosphodiesterase activity
Cellular component
  • cytoplasm
  • cytosol
  • centrosome
  • microtubule organizing center
  • apical plasma membrane
  • cytoskeleton
  • membrane
  • calcium channel complex
  • voltage-gated calcium channel complex
  • plasma membrane
  • nuclear membrane
Biological process
  • establishment of endothelial barrier
  • smooth muscle contraction
  • positive regulation of interleukin-5 production
  • multicellular organism growth
  • human ageing
  • regulation of signaling receptor activity
  • positive regulation of interferon-gamma production
  • neutrophil chemotaxis
  • positive regulation of interleukin-2 production
  • regulation of cell communication by electrical coupling involved in cardiac conduction
  • adrenergic receptor signaling pathway
  • cellular response to lipopolysaccharide
  • T cell receptor signaling pathway
  • adenylate cyclase-activating adrenergic receptor signaling pathway involved in positive regulation of heart rate
  • cAMP-mediated signaling
  • cellular response to cAMP
  • signal transduction
  • leukocyte migration
  • negative regulation of relaxation of cardiac muscle
  • regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum
  • negative regulation of heart contraction
  • regulation of heart rate
  • regulation of ryanodine-sensitive calcium-release channel activity
  • cAMP catabolic process
  • cellular response to epinephrine stimulus
  • regulation of cardiac muscle cell contraction
  • negative regulation of peptidyl-serine phosphorylation
  • G protein-coupled receptor signaling pathway
  • negative regulation of cAMP-mediated signaling
Sources:Amigo / QuickGO
Orthologs
SpeciesHumanMouse
Entrez

5144

238871

Ensembl

ENSG00000113448

ENSMUSG00000021699

UniProt

Q08499

Q01063

RefSeq (mRNA)
NM_001104631
NM_001165899
NM_001197218
NM_001197219
NM_001197220

NM_001197221
NM_001197222
NM_001197223
NM_006203
NM_001349241
NM_001349242
NM_001349243
NM_001364599
NM_001364600
NM_001364601
NM_001364602
NM_001364603
NM_001364604

NM_011056
NM_177252

RefSeq (protein)
NP_001098101
NP_001159371
NP_001184147
NP_001184148
NP_001184149

NP_001184150
NP_001184151
NP_001184152
NP_006194
NP_001336170
NP_001336171
NP_001336172
NP_001351528
NP_001351529
NP_001351530
NP_001351531
NP_001351532
NP_001351533

NP_035186
NP_001389812
NP_001389813
NP_001389814
NP_001389815

NP_001389816
NP_001389817

Location (UCSC)Chr 5: 58.97 – 60.52 MbChr 13: 108.59 – 110.09 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

cAMP-specific 3',5'-cyclic phosphodiesterase 4D is an enzyme that in humans is encoded by the PDE4D gene.

Function

The PDE4D gene is complex and has at least 9 different isoforms that encode functional proteins. These proteins degrade the second messenger cAMP, which is a key signal transduction molecule in multiple cell types, including vascular cells (Dominiczak and McBride, 2003).[supplied by OMIM][5]

Interactions

PDE4D has been shown to interact with myomegalin[6] and GNB2L1.[7][8]

Clinical relevance

Mutations in this gene have been associated to cases of acrodysostosis.[9]

This is the subtype of PDE4 that appears to be involved in the emetic and antidepressant effects of PDE4 inhibitors.[10]

Furthermore, changes in expression of the isoform PDE4D7 have been proposed as prostate cancer biomarker. [11] [12] [13]

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000113448 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000021699 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ "Entrez Gene: PDE4D phosphodiesterase 4D, cAMP-specific (phosphodiesterase E3 dunce homolog, Drosophila)".
  6. ^ Verde I, Pahlke G, Salanova M, Zhang G, Wang S, Coletti D, Onuffer J, Jin SL, Conti M (Apr 2001). "Myomegalin is a novel protein of the golgi/centrosome that interacts with a cyclic nucleotide phosphodiesterase". The Journal of Biological Chemistry. 276 (14): 11189–98. doi:10.1074/jbc.M006546200. hdl:11573/1681344. PMID 11134006.
  7. ^ Yarwood SJ, Steele MR, Scotland G, Houslay MD, Bolger GB (May 1999). "The RACK1 signaling scaffold protein selectively interacts with the cAMP-specific phosphodiesterase PDE4D5 isoform". The Journal of Biological Chemistry. 274 (21): 14909–17. doi:10.1074/jbc.274.21.14909. PMID 10329691.
  8. ^ Steele MR, McCahill A, Thompson DS, MacKenzie C, Isaacs NW, Houslay MD, Bolger GB (Jul 2001). "Identification of a surface on the beta-propeller protein RACK1 that interacts with the cAMP-specific phosphodiesterase PDE4D5". Cellular Signalling. 13 (7): 507–13. doi:10.1016/S0898-6568(01)00167-X. PMID 11516626.
  9. ^ Michot C, Le Goff C, Goldenberg A, Abhyankar A, Klein C, Kinning E, Guerrot AM, Flahaut P, Duncombe A, Baujat G, Lyonnet S, Thalassinos C, Nitschke P, Casanova JL, Le Merrer M, Munnich A, Cormier-Daire V (Apr 2012). "Exome sequencing identifies PDE4D mutations as another cause of acrodysostosis". American Journal of Human Genetics. 90 (4): 740–5. doi:10.1016/j.ajhg.2012.03.003. PMC 3322219. PMID 22464250.
  10. ^ Zhang HT (2009). "Cyclic AMP-specific phosphodiesterase-4 as a target for the development of antidepressant drugs". Current Pharmaceutical Design. 15 (14): 1688–98. doi:10.2174/138161209788168092. PMID 19442182.
  11. ^ Böttcher R, Henderson DJ, Dulla K, van Strijp D, Waanders LF, Tevz G, Lehman ML, Merkle D, van Leenders GJ, Baillie GS, Jenster G, Houslay MD, Hoffmann R (Nov 2015). "Human phosphodiesterase 4D7 (PDE4D7) expression is increased in TMPRSS2-ERG-positive primary prostate cancer and independently adds to a reduced risk of post-surgical disease progression". British Journal of Cancer. 113 (10): 1502–11. doi:10.1038/bjc.2015.335. PMC 4815894. PMID 26575822.
  12. ^ Böttcher R, Dulla K, van Strijp D, Dits N, Verhoef EI, Baillie GS, van Leenders GJ, Houslay MD, Jenster G, Hoffmann R (Oct 2016). "Human PDE4D isoform composition is deregulated in primary prostate cancer and indicative for disease progression and development of distant metastases". Oncotarget. 7 (43): 70669–70684. doi:10.18632/oncotarget.12204. PMC 5342582. PMID 27683107.
  13. ^ Henderson DJ, Byrne A, Dulla K, Jenster G, Hoffmann R, Baillie GS, Houslay MD (Mar 2014). "The cAMP phosphodiesterase-4D7 (PDE4D7) is downregulated in androgen-independent prostate cancer cells and mediates proliferation by compartmentalising cAMP at the plasma membrane of VCaP prostate cancer cells". British Journal of Cancer. 110 (5): 1278–87. doi:10.1038/bjc.2014.22. PMC 3950871. PMID 24518597.

Further reading

  • Wang Q (May 2005). "Molecular genetics of coronary artery disease". Current Opinion in Cardiology. 20 (3): 182–8. doi:10.1097/01.hco.0000160373.77190.f1. PMC 1579824. PMID 15861005.
  • Swinnen JV, Joseph DR, Conti M (Nov 1989). "The mRNA encoding a high-affinity cAMP phosphodiesterase is regulated by hormones and cAMP". Proceedings of the National Academy of Sciences of the United States of America. 86 (21): 8197–201. Bibcode:1989PNAS...86.8197S. doi:10.1073/pnas.86.21.8197. PMC 298247. PMID 2554303.
  • Milatovich A, Bolger G, Michaeli T, Francke U (Mar 1994). "Chromosome localizations of genes for five cAMP-specific phosphodiesterases in man and mouse". Somatic Cell and Molecular Genetics. 20 (2): 75–86. doi:10.1007/BF02290677. PMID 8009369. S2CID 19182571.
  • Baecker PA, Obernolte R, Bach C, Yee C, Shelton ER (Jan 1994). "Isolation of a cDNA encoding a human rolipram-sensitive cyclic AMP phosphodiesterase (PDE IVD)". Gene. 138 (1–2): 253–6. doi:10.1016/0378-1119(94)90818-4. PMID 8125310.
  • Bolger G, Michaeli T, Martins T, St John T, Steiner B, Rodgers L, Riggs M, Wigler M, Ferguson K (Oct 1993). "A family of human phosphodiesterases homologous to the dunce learning and memory gene product of Drosophila melanogaster are potential targets for antidepressant drugs". Molecular and Cellular Biology. 13 (10): 6558–71. doi:10.1128/mcb.13.10.6558. PMC 364715. PMID 8413254.
  • Böttcher R, Henderson DJ, Dulla K, van Strijp D, Waanders LF, Tevz G, Lehman ML, Merkle D, van Leenders GJ, Baillie GS, Jenster G, Houslay MD, Hoffmann R (Nov 2015). "Human phosphodiesterase 4D7 (PDE4D7) expression is increased in TMPRSS2-ERG-positive primary prostate cancer and independently adds to a reduced risk of post-surgical disease progression". British Journal of Cancer. 113 (10): 1502–11. doi:10.1038/bjc.2015.335. PMC 4815894. PMID 26575822.
  • Böttcher R, Dulla K, van Strijp D, Dits N, Verhoef EI, Baillie GS, van Leenders GJ, Houslay MD, Jenster G, Hoffmann R (Oct 2016). "Human PDE4D isoform composition is deregulated in primary prostate cancer and indicative for disease progression and development of distant metastases". Oncotarget. 7 (43): 70669–70684. doi:10.18632/oncotarget.12204. PMC 5342582. PMID 27683107.
  • Henderson DJ, Byrne A, Dulla K, Jenster G, Hoffmann R, Baillie GS, Houslay MD (Mar 2014). "The cAMP phosphodiesterase-4D7 (PDE4D7) is downregulated in androgen-independent prostate cancer cells and mediates proliferation by compartmentalising cAMP at the plasma membrane of VCaP prostate cancer cells". British Journal of Cancer. 110 (5): 1278–87. doi:10.1038/bjc.2014.22. PMC 3950871. PMID 24518597.
  • Sette C, Conti M (Jul 1996). "Phosphorylation and activation of a cAMP-specific phosphodiesterase by the cAMP-dependent protein kinase. Involvement of serine 54 in the enzyme activation". The Journal of Biological Chemistry. 271 (28): 16526–34. doi:10.1074/jbc.271.28.16526. PMID 8663227.
  • Némoz G, Zhang R, Sette C, Conti M (Apr 1996). "Identification of cyclic AMP-phosphodiesterase variants from the PDE4D gene expressed in human peripheral mononuclear cells". FEBS Letters. 384 (1): 97–102. doi:10.1016/0014-5793(96)00300-6. PMID 8797812. S2CID 42228241.
  • Bolger GB, Erdogan S, Jones RE, Loughney K, Scotland G, Hoffmann R, Wilkinson I, Farrell C, Houslay MD (Dec 1997). "Characterization of five different proteins produced by alternatively spliced mRNAs from the human cAMP-specific phosphodiesterase PDE4D gene". The Biochemical Journal. 328 (Pt 2): 539–48. doi:10.1042/bj3280539. PMC 1218953. PMID 9371713.
  • Hoffmann R, Baillie GS, MacKenzie SJ, Yarwood SJ, Houslay MD (Feb 1999). "The MAP kinase ERK2 inhibits the cyclic AMP-specific phosphodiesterase HSPDE4D3 by phosphorylating it at Ser579". The EMBO Journal. 18 (4): 893–903. doi:10.1093/emboj/18.4.893. PMC 1171182. PMID 10022832.
  • Yarwood SJ, Steele MR, Scotland G, Houslay MD, Bolger GB (May 1999). "The RACK1 signaling scaffold protein selectively interacts with the cAMP-specific phosphodiesterase PDE4D5 isoform". The Journal of Biological Chemistry. 274 (21): 14909–17. doi:10.1074/jbc.274.21.14909. PMID 10329691.
  • Beard MB, O'Connell JC, Bolger GB, Houslay MD (Oct 1999). "The unique N-terminal domain of the cAMP phosphodiesterase PDE4D4 allows for interaction with specific SH3 domains". FEBS Letters. 460 (1): 173–7. doi:10.1016/S0014-5793(99)01335-6. PMID 10571082. S2CID 42574718.
  • MacKenzie SJ, Baillie GS, McPhee I, Bolger GB, Houslay MD (Jun 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. 275 (22): 16609–17. doi:10.1074/jbc.275.22.16609. PMID 10828059.
  • Miró X, Casacuberta JM, Gutiérrez-López MD, de Landázuri MO, Puigdomènech P (Aug 2000). "Phosphodiesterases 4D and 7A splice variants in the response of HUVEC cells to TNF-alpha(1)". Biochemical and Biophysical Research Communications. 274 (2): 415–21. doi:10.1006/bbrc.2000.3146. PMID 10913353.
  • Verde I, Pahlke G, Salanova M, Zhang G, Wang S, Coletti D, Onuffer J, Jin SL, Conti M (Apr 2001). "Myomegalin is a novel protein of the golgi/centrosome that interacts with a cyclic nucleotide phosphodiesterase". The Journal of Biological Chemistry. 276 (14): 11189–98. doi:10.1074/jbc.M006546200. hdl:11573/1681344. PMID 11134006.
  • Zauli G, Milani D, Mirandola P, Mazzoni M, Secchiero P, Miscia S, Capitani S (Feb 2001). "HIV-1 Tat protein down-regulates CREB transcription factor expression in PC12 neuronal cells through a phosphatidylinositol 3-kinase/AKT/cyclic nucleoside phosphodiesterase pathway". FASEB Journal. 15 (2): 483–91. doi:10.1096/fj.00-0354com. PMID 11156964. S2CID 26315564.
  • Dodge KL, Khouangsathiene S, Kapiloff MS, Mouton R, Hill EV, Houslay MD, Langeberg LK, Scott JD (Apr 2001). "mAKAP assembles a protein kinase A/PDE4 phosphodiesterase cAMP signaling module". The EMBO Journal. 20 (8): 1921–30. doi:10.1093/emboj/20.8.1921. PMC 125429. PMID 11296225.
  • Steele MR, McCahill A, Thompson DS, MacKenzie C, Isaacs NW, Houslay MD, Bolger GB (Jul 2001). "Identification of a surface on the beta-propeller protein RACK1 that interacts with the cAMP-specific phosphodiesterase PDE4D5". Cellular Signalling. 13 (7): 507–13. doi:10.1016/S0898-6568(01)00167-X. PMID 11516626.
  • Gretarsdottir S, Sveinbjörnsdottir S, Jonsson HH, Jakobsson F, Einarsdottir E, Agnarsson U, Shkolny D, Einarsson G, Gudjonsdottir HM, Valdimarsson EM, Einarsson OB, Thorgeirsson G, Hadzic R, Jonsdottir S, Reynisdottir ST, Bjarnadottir SM, Gudmundsdottir T, Gudlaugsdottir GJ, Gill R, Lindpaintner K, Sainz J, Hannesson HH, Sigurdsson GT, Frigge ML, Kong A, Gudnason V, Stefansson K, Gulcher JR (Mar 2002). "Localization of a susceptibility gene for common forms of stroke to 5q12". American Journal of Human Genetics. 70 (3): 593–603. doi:10.1086/339252. PMC 384939. PMID 11833004.
  • Moon E, Lee R, Near R, Weintraub L, Wolda S, Lerner A (Feb 2002). "Inhibition of PDE3B augments PDE4 inhibitor-induced apoptosis in a subset of patients with chronic lymphocytic leukemia". Clinical Cancer Research. 8 (2): 589–95. PMID 11839681.
  • Le Jeune IR, Shepherd M, Van Heeke G, Houslay MD, Hall IP (Sep 2002). "Cyclic AMP-dependent transcriptional up-regulation of phosphodiesterase 4D5 in human airway smooth muscle cells. Identification and characterization of a novel PDE4D5 promoter". The Journal of Biological Chemistry. 277 (39): 35980–9. doi:10.1074/jbc.M204832200. PMID 12121997.
  • v
  • t
  • e
  • 1mkd: crystal structure of PDE4D catalytic domain and zardaverine complex
    1mkd: crystal structure of PDE4D catalytic domain and zardaverine complex
  • 1oyn: Crystal structure of PDE4D2 in complex with (R,S)-rolipram
    1oyn: Crystal structure of PDE4D2 in complex with (R,S)-rolipram
  • 1ptw: The Crystal Structure of AMP-Bound PDE4 Suggests a Mechanism for Phosphodiesterase Catalysis
    1ptw: The Crystal Structure of AMP-Bound PDE4 Suggests a Mechanism for Phosphodiesterase Catalysis
  • 1q9m: Three dimensional structures of PDE4D in complex with roliprams and implication on inhibitor selectivity
    1q9m: Three dimensional structures of PDE4D in complex with roliprams and implication on inhibitor selectivity
  • 1tb7: Catalytic Domain Of Human Phosphodiesterase 4D In Complex With AMP
    1tb7: Catalytic Domain Of Human Phosphodiesterase 4D In Complex With AMP
  • 1tbb: Catalytic Domain Of Human Phosphodiesterase 4D In Complex With Rolipram
    1tbb: Catalytic Domain Of Human Phosphodiesterase 4D In Complex With Rolipram
  • 1xom: Catalytic Domain Of Human Phosphodiesterase 4D In Complex With Cilomilast
    1xom: Catalytic Domain Of Human Phosphodiesterase 4D In Complex With Cilomilast
  • 1xon: Catalytic Domain Of Human Phosphodiesterase 4D In Complex With Piclamilast
    1xon: Catalytic Domain Of Human Phosphodiesterase 4D In Complex With Piclamilast
  • 1xoq: Catalytic Domain Of Human Phosphodiesterase 4D In Complex With Roflumilast
    1xoq: Catalytic Domain Of Human Phosphodiesterase 4D In Complex With Roflumilast
  • 1xor: Catalytic Domain Of Human Phosphodiesterase 4D In Complex With Zardaverine
    1xor: Catalytic Domain Of Human Phosphodiesterase 4D In Complex With Zardaverine
  • 1y2b: Catalytic Domain Of Human Phosphodiesterase 4D In Complex With 3,5-dimethyl-1H-pyrazole-4-carboxylic acid ethyl ester
    1y2b: Catalytic Domain Of Human Phosphodiesterase 4D In Complex With 3,5-dimethyl-1H-pyrazole-4-carboxylic acid ethyl ester
  • 1y2c: Catalytic Domain Of Human Phosphodiesterase 4D In Complex With 3,5-dimethyl-1-phenyl-1H-pyrazole-4-carboxylic acid ethyl ester
    1y2c: Catalytic Domain Of Human Phosphodiesterase 4D In Complex With 3,5-dimethyl-1-phenyl-1H-pyrazole-4-carboxylic acid ethyl ester
  • 1y2d: Catalytic Domain Of Human Phosphodiesterase 4D In Complex With 1-(4-methoxy-phenyl)-3,5-dimethyl-1H-pyrazole-4-carboxylic acid ethyl ester
    1y2d: Catalytic Domain Of Human Phosphodiesterase 4D In Complex With 1-(4-methoxy-phenyl)-3,5-dimethyl-1H-pyrazole-4-carboxylic acid ethyl ester
  • 1y2e: Catalytic Domain Of Human Phosphodiesterase 4D In Complex With 1-(4-amino-phenyl)-3,5-dimethyl-1H-pyrazole-4-carboxylic acid ethyl ester
    1y2e: Catalytic Domain Of Human Phosphodiesterase 4D In Complex With 1-(4-amino-phenyl)-3,5-dimethyl-1H-pyrazole-4-carboxylic acid ethyl ester
  • 1y2k: Catalytic Domain Of Human Phosphodiesterase 4D In Complex With 3,5-dimethyl-1-(3-nitro-phenyl)-1H-pyrazole-4-carboxylic acid ethyl ester
    1y2k: Catalytic Domain Of Human Phosphodiesterase 4D In Complex With 3,5-dimethyl-1-(3-nitro-phenyl)-1H-pyrazole-4-carboxylic acid ethyl ester
  • 1zkn: Structure of PDE4D2-IBMX
    1zkn: Structure of PDE4D2-IBMX
  • 2fm0: Crystal structure of PDE4D in complex with L-869298
    2fm0: Crystal structure of PDE4D in complex with L-869298
  • 2fm5: Crystal structure of PDE4D2 in complex with inhibitor L-869299
    2fm5: Crystal structure of PDE4D2 in complex with inhibitor L-869299