PDE4D explained

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] [9]}

Further reading

• Wang Q . Molecular genetics of coronary artery disease . Current Opinion in Cardiology . 20 . 3 . 182–8 . May 2005 . 15861005 . 1579824 . 10.1097/01.hco.0000160373.77190.f1 .
• Swinnen JV, Joseph DR, Conti M . 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 . Nov 1989 . 2554303 . 298247 . 10.1073/pnas.86.21.8197 . 1989PNAS...86.8197S . free .
• Milatovich A, Bolger G, Michaeli T, Francke U . Chromosome localizations of genes for five cAMP-specific phosphodiesterases in man and mouse . Somatic Cell and Molecular Genetics . 20 . 2 . 75–86 . Mar 1994 . 8009369 . 10.1007/BF02290677 . 19182571 .
• Baecker PA, Obernolte R, Bach C, Yee C, Shelton ER . Isolation of a cDNA encoding a human rolipram-sensitive cyclic AMP phosphodiesterase (PDE IVD) . Gene . 138 . 1–2 . 253–6 . Jan 1994 . 8125310 . 10.1016/0378-1119(94)90818-4 .
• Bolger G, Michaeli T, Martins T, St John T, Steiner B, Rodgers L, Riggs M, Wigler M, Ferguson K . 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 . Oct 1993 . 8413254 . 364715 . 10.1128/mcb.13.10.6558.
• 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 . 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 . Nov 2015 . 26575822 . 4815894. 10.1038/bjc.2015.335 .
• Böttcher R, Dulla K, van Strijp D, Dits N, Verhoef EI, Baillie GS, van Leenders GJ, Houslay MD, Jenster G, Hoffmann R . 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 . Oct 2016 . 27683107 . 5342582 . 10.18632/oncotarget.12204 .
• Henderson DJ, Byrne A, Dulla K, Jenster G, Hoffmann R, Baillie GS, Houslay MD . 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 . Mar 2014 . 24518597 . 3950871 . 10.1038/bjc.2014.22 .
• 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 . The Journal of Biological Chemistry . 271 . 28 . 16526–34 . Jul 1996 . 8663227 . 10.1074/jbc.271.28.16526 . free .
• Némoz G, Zhang R, Sette C, Conti M . Identification of cyclic AMP-phosphodiesterase variants from the PDE4D gene expressed in human peripheral mononuclear cells . FEBS Letters . 384 . 1 . 97–102 . Apr 1996 . 8797812 . 10.1016/0014-5793(96)00300-6 . 42228241 .
• Bolger GB, Erdogan S, Jones RE, Loughney K, Scotland G, Hoffmann R, Wilkinson I, Farrell C, Houslay MD . 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 . Dec 1997 . 9371713 . 1218953 . 10.1042/bj3280539.
• Hoffmann R, Baillie GS, MacKenzie SJ, Yarwood SJ, Houslay MD . The MAP kinase ERK2 inhibits the cyclic AMP-specific phosphodiesterase HSPDE4D3 by phosphorylating it at Ser579 . The EMBO Journal . 18 . 4 . 893–903 . Feb 1999 . 10022832 . 1171182 . 10.1093/emboj/18.4.893 .
• Yarwood SJ, Steele MR, Scotland G, Houslay MD, Bolger GB . The RACK1 signaling scaffold protein selectively interacts with the cAMP-specific phosphodiesterase PDE4D5 isoform . The Journal of Biological Chemistry . 274 . 21 . 14909–17 . May 1999 . 10329691 . 10.1074/jbc.274.21.14909 . free .
• Beard MB, O'Connell JC, Bolger GB, Houslay MD . The unique N-terminal domain of the cAMP phosphodiesterase PDE4D4 allows for interaction with specific SH3 domains . FEBS Letters . 460 . 1 . 173–7 . Oct 1999 . 10571082 . 10.1016/S0014-5793(99)01335-6 . 42574718 . free .
• MacKenzie SJ, Baillie GS, McPhee I, Bolger GB, Houslay MD . 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 . Jun 2000 . 10828059 . 10.1074/jbc.275.22.16609 . free .
• Miró X, Casacuberta JM, Gutiérrez-López MD, de Landázuri MO, Puigdomènech P . 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 . Aug 2000 . 10913353 . 10.1006/bbrc.2000.3146 .
• Verde I, Pahlke G, Salanova M, Zhang G, Wang S, Coletti D, Onuffer J, Jin SL, Conti M . 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 . Apr 2001 . 11134006 . 10.1074/jbc.M006546200 . free . 11573/1681344 . free .
• Zauli G, Milani D, Mirandola P, Mazzoni M, Secchiero P, Miscia S, Capitani S . 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 . Feb 2001 . 11156964 . 10.1096/fj.00-0354com . free . 26315564 .
• Dodge KL, Khouangsathiene S, Kapiloff MS, Mouton R, Hill EV, Houslay MD, Langeberg LK, Scott JD . mAKAP assembles a protein kinase A/PDE4 phosphodiesterase cAMP signaling module . The EMBO Journal . 20 . 8 . 1921–30 . Apr 2001 . 11296225 . 125429 . 10.1093/emboj/20.8.1921 .
• Steele MR, McCahill A, Thompson DS, MacKenzie C, Isaacs NW, Houslay MD, Bolger GB . Identification of a surface on the beta-propeller protein RACK1 that interacts with the cAMP-specific phosphodiesterase PDE4D5 . Cellular Signalling . 13 . 7 . 507–13 . Jul 2001 . 11516626 . 10.1016/S0898-6568(01)00167-X .
• 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 . Localization of a susceptibility gene for common forms of stroke to 5q12 . American Journal of Human Genetics . 70 . 3 . 593–603 . Mar 2002 . 11833004 . 384939 . 10.1086/339252 .
• Moon E, Lee R, Near R, Weintraub L, Wolda S, Lerner A . Inhibition of PDE3B augments PDE4 inhibitor-induced apoptosis in a subset of patients with chronic lymphocytic leukemia . Clinical Cancer Research . 8 . 2 . 589–95 . Feb 2002 . 11839681 .
• Le Jeune IR, Shepherd M, Van Heeke G, Houslay MD, Hall IP . 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 . Sep 2002 . 12121997 . 10.1074/jbc.M204832200 . free .

Notes and References

1. Web site: 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 . 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 . Apr 2001 . 11134006 . 10.1074/jbc.M006546200 . free . 11573/1681344 . free .
3. Yarwood SJ, Steele MR, Scotland G, Houslay MD, Bolger GB . The RACK1 signaling scaffold protein selectively interacts with the cAMP-specific phosphodiesterase PDE4D5 isoform . The Journal of Biological Chemistry . 274 . 21 . 14909–17 . May 1999 . 10329691 . 10.1074/jbc.274.21.14909 . free .
4. Steele MR, McCahill A, Thompson DS, MacKenzie C, Isaacs NW, Houslay MD, Bolger GB . Identification of a surface on the beta-propeller protein RACK1 that interacts with the cAMP-specific phosphodiesterase PDE4D5 . Cellular Signalling . 13 . 7 . 507–13 . Jul 2001 . 11516626 . 10.1016/S0898-6568(01)00167-X .
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 . Exome sequencing identifies PDE4D mutations as another cause of acrodysostosis . American Journal of Human Genetics . 90 . 4 . 740–5 . Apr 2012 . 22464250 . 3322219 . 10.1016/j.ajhg.2012.03.003 .
6. Zhang HT . Cyclic AMP-specific phosphodiesterase-4 as a target for the development of antidepressant drugs . Current Pharmaceutical Design . 15 . 14 . 1688–98 . 2009 . 19442182 . 10.2174/138161209788168092 .
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 . 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 . Nov 2015 . 26575822 . 4815894. 10.1038/bjc.2015.335 .
8. Böttcher R, Dulla K, van Strijp D, Dits N, Verhoef EI, Baillie GS, van Leenders GJ, Houslay MD, Jenster G, Hoffmann R . 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 . Oct 2016 . 27683107 . 5342582 . 10.18632/oncotarget.12204.
9. Henderson DJ, Byrne A, Dulla K, Jenster G, Hoffmann R, Baillie GS, Houslay MD . 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 . Mar 2014 . 24518597 . 3950871 . 10.1038/bjc.2014.22 .