PDE4D

Phosphodiesterase 4D, cAMP-specific
PDB rendering based on 1mkd.
Available structures PDB Ortholog 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
Symbols	PDE4D ; ACRDYS2; DPDE3; HSPDE4D; PDE43; PDE4DN2; STRK1
External IDs	OMIM: 600129 MGI: 99555 HomoloGene: 129755 ChEMBL: 288 GeneCards: PDE4D Gene
EC number	3.1.4.53
Gene ontology Molecular function • 3',5'-cyclic-nucleotide phosphodiesterase activity • 3',5'-cyclic-AMP phosphodiesterase activity • protein binding • drug binding • SH3 domain binding • enzyme binding • cAMP binding • ubiquitin protein ligase binding • beta-2 adrenergic receptor binding • ion channel binding • metal ion binding • ATPase binding • scaffold protein binding Cellular component • Golgi apparatus • centrosome • cytosol • voltage-gated calcium channel complex • membrane • apical plasma membrane • myofibril • calcium channel complex Biological process • regulation of heart rate • cAMP catabolic process • smooth muscle contraction • aging • memory • regulation of G-protein coupled receptor protein signaling pathway • regulation of receptor activity • regulation of protein kinase A signaling • regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum • positive regulation of smooth muscle cell migration • cAMP-mediated signaling • lung development • neutrophil chemotaxis • regulation of cAMP metabolic process • positive regulation of interferon-gamma production • positive regulation of interleukin-2 production • positive regulation of interleukin-5 production • negative regulation of peptidyl-serine phosphorylation • multicellular organism growth • cellular protein complex assembly • negative regulation of heart contraction • positive regulation of smooth muscle cell proliferation • T cell receptor signaling pathway • regulation of ryanodine-sensitive calcium-release channel activity • establishment of endothelial barrier • cellular response to lipopolysaccharide • cellular response to cAMP • cellular response to epinephrine stimulus • adrenergic receptor signaling pathway • regulation of cardiac muscle cell contraction • adrenergic receptor signaling pathway involved in positive regulation of heart rate • regulation of cell communication by electrical coupling involved in cardiac conduction • negative regulation of relaxation of cardiac muscle Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	5144	238871
Ensembl	ENSG00000113448	ENSMUSG00000021699
UniProt	Q08499	Q01063
RefSeq (mRNA)	NM_001104631	NM_011056
RefSeq (protein)	NP_001098101	NP_035186
Location (UCSC)	Chr 5: 58.97 – 60.52 Mb	Chr 13: 108.45 – 109.95 Mb
PubMed search

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]^[1]

Interactions

PDE4D has been shown to interact with myomegalin^[2] and GNB2L1.^[3][4]

Clinical relevance

Mutations in this gene have been associated to cases of acrodysostosis.^[5]

This is the subtype of PDE4 that appears to be involved in the emetic and antidepressant effects of PDE4 inhibitors.^[6]

Furthermore, changes in expression of the isoform PDE4D7 have been proposed as prostate cancer biomarker. ^{[7] [8]}

References

1. "Entrez Gene: PDE4D phosphodiesterase 4D, cAMP-specific (phosphodiesterase E3 dunce homolog, Drosophila)".
2. 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. PMID 11134006.
3. 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.
4. 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.
5. 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. PMID 22464250.
6. 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.
7. 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. PMID 26575822.
8. 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. 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.
• 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. PMID 26575822.
• 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.
• 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.
• 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. 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.
• 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.