PRKAR2A explained

cAMP-dependent protein kinase type II-alpha regulatory subunit is an enzyme that in humans is encoded by the PRKAR2A gene.^[1]

Function

cAMP is a signaling molecule important for a variety of cellular functions. cAMP exerts its effects by activating the cAMP-dependent Protein Kinase, more commonly called Protein Kinase A (PKA), which transduces the signal through phosphorylation of different target proteins. The inactive holoenzyme of PKA is a tetramer composed of two regulatory and two catalytic subunits. cAMP causes the dissociation of the inactive holoenzyme into a dimer of regulatory subunits bound to four cAMP and two free monomeric catalytic subunits. Four different regulatory subunits and three catalytic subunits of PKA have been identified in humans. The protein encoded by this gene is one of the regulatory subunits. This subunit can be phosphorylated by the activated catalytic subunit. It may interact with various A-kinase anchoring proteins (AKAPs) and determine the subcellular localization of PKA. This subunit has been shown to regulate protein transport from endosomes to the Golgi apparatus and further to the endoplasmic reticulum (ER).^[2]

Interactions

PRKAR2A has been shown to interact with:

• AKAP11,^{[3] [4]}
• AKAP13,^[5]
• AKAP1,^{[6] [7]}
• AKAP2,^{[8] [9]}
• AKAP3,^{[10] [11]}
• AKAP8,^{[12] [13]}
• AKAP9,^{[8] [14]}
• ARFGEF2,^[15]
• CBFA2T3^[16]
• GSK3B,^[3]
• PDE4A,^[17] and
• RUNX1T1.^[18]

See also

• Protein kinase
• AMPK
• cAMP

Further reading

• Cho-Chung YS, Nesterova MV . Tumor reversion: protein kinase A isozyme switching . Annals of the New York Academy of Sciences . 1058 . 76–86 . Nov 2005 . 1 . 16394127 . 10.1196/annals.1359.014 . 2005NYASA1058...76C . 45471438 .
• Harrich D, McMillan N, Munoz L, Apolloni A, Meredith L . Will diverse Tat interactions lead to novel antiretroviral drug targets? . Current Drug Targets . 7 . 12 . 1595–606 . Dec 2006 . 17168834 . 10.2174/138945006779025338 .
• Skålhegg BS, Landmark B, Foss KB, Lohmann SM, Hansson V, Lea T, Jahnsen T . Identification, purification, and characterization of subunits of cAMP-dependent protein kinase in human testis. Reverse mobilities of human RII alpha and RII beta on sodium dodecyl sulfate-polyacrylamide gel electrophoresis compared with rat and bovine RIIs . The Journal of Biological Chemistry . 267 . 8 . 5374–9 . Mar 1992 . 10.1016/S0021-9258(18)42776-7 . 1544918 . free .
• Carr DW, Hausken ZE, Fraser ID, Stofko-Hahn RE, Scott JD . Association of the type II cAMP-dependent protein kinase with a human thyroid RII-anchoring protein. Cloning and characterization of the RII-binding domain . The Journal of Biological Chemistry . 267 . 19 . 13376–82 . Jul 1992 . 10.1016/S0021-9258(18)42221-1 . 1618839 . free .
• Hofmann B, Nishanian P, Baldwin RL, Insixiengmay P, Nel A, Fahey JL . HIV inhibits the early steps of lymphocyte activation, including initiation of inositol phospholipid metabolism . Journal of Immunology . 145 . 11 . 3699–705 . Dec 1990 . 10.4049/jimmunol.145.11.3699 . 1978848 . free .
• Scott JD, Stofko RE, McDonald JR, Comer JD, Vitalis EA, Mangili JA . Type II regulatory subunit dimerization determines the subcellular localization of the cAMP-dependent protein kinase . The Journal of Biological Chemistry . 265 . 35 . 21561–6 . Dec 1990 . 10.1016/S0021-9258(18)45777-8 . 2147685 . free .
• Oyen O, Myklebust F, Scott JD, Hansson V, Jahnsen T . Human testis cDNA for the regulatory subunit RII alpha of cAMP-dependent protein kinase encodes an alternate amino-terminal region . FEBS Letters . 246 . 1–2 . 57–64 . Mar 1989 . 2540040 . 10.1016/0014-5793(89)80253-4 . 690410 . free .
• Obar RA, Dingus J, Bayley H, Vallee RB . The RII subunit of cAMP-dependent protein kinase binds to a common amino-terminal domain in microtubule-associated proteins 2A, 2B, and 2C . Neuron . 3 . 5 . 639–45 . Nov 1989 . 2561973 . 10.1016/0896-6273(89)90274-2 . 1329548 .
• Rubino HM, Dammerman M, Shafit-Zagardo B, Erlichman J . Localization and characterization of the binding site for the regulatory subunit of type II cAMP-dependent protein kinase on MAP2 . Neuron . 3 . 5 . 631–8 . Nov 1989 . 2701845 . 10.1016/0896-6273(89)90273-0 . 45499202 .
• Hemmings BA, Aitken A, Cohen P, Rymond M, Hofmann F . Phosphorylation of the type-II regulatory subunit of cyclic-AMP-dependent protein kinase by glycogen synthase kinase 3 and glycogen synthase kinase 5 . European Journal of Biochemistry . 127 . 3 . 473–81 . Oct 1982 . 6293815 . 10.1111/j.1432-1033.1982.tb06896.x . free .
• Hofmann B, Nishanian P, Nguyen T, Insixiengmay P, Fahey JL . Human immunodeficiency virus proteins induce the inhibitory cAMP/protein kinase A pathway in normal lymphocytes . Proceedings of the National Academy of Sciences of the United States of America . 90 . 14 . 6676–80 . Jul 1993 . 7688126 . 46995 . 10.1073/pnas.90.14.6676 . 1993PNAS...90.6676H . free .
• Pariset C, Weinman S . Differential localization of two isoforms of the regulatory subunit RII alpha of cAMP-dependent protein kinase in human sperm: biochemical and cytochemical study . Molecular Reproduction and Development . 39 . 4 . 415–22 . Dec 1994 . 7893490 . 10.1002/mrd.1080390410 . 36203256 .
• Cheley S, Panchal RG, Carr DW, Scott JD, Bayley H . Type II regulatory subunits of cAMP-dependent protein kinase and their binding proteins in the nervous system of Aplysia californica . The Journal of Biological Chemistry . 269 . 4 . 2911–20 . Jan 1994 . 10.1016/S0021-9258(17)42028-X . 7905481 . free .
• Hausken ZE, Coghlan VM, Hastings CA, Reimann EM, Scott JD . Type II regulatory subunit (RII) of the cAMP-dependent protein kinase interaction with A-kinase anchor proteins requires isoleucines 3 and 5 . The Journal of Biological Chemistry . 269 . 39 . 24245–51 . Sep 1994 . 10.1016/S0021-9258(19)51074-2 . 7929081 . free .
• Hofmann B, Nishanian P, Fan J, Nguyen T, Fahey JL . HIV Gag p17 protein impairs proliferation of normal lymphocytes in vitro . AIDS . 8 . 7 . 1016–7 . Jul 1994 . 7946090 . 10.1097/00002030-199407000-00025 .
• Beebe SJ, Salomonsky P, Holroyd C, Becker D . Differential expression of cyclic AMP-dependent protein kinase isozymes in normal human melanocytes and malignant melanomas . Cell Growth & Differentiation . 4 . 12 . 1005–12 . Dec 1993 . 8117614 .
• Coghlan VM, Langeberg LK, Fernandez A, Lamb NJ, Scott JD . Cloning and characterization of AKAP 95, a nuclear protein that associates with the regulatory subunit of type II cAMP-dependent protein kinase . The Journal of Biological Chemistry . 269 . 10 . 7658–65 . Mar 1994 . 10.1016/S0021-9258(17)37338-6 . 8125992 . free .
• Lester LB, Coghlan VM, Nauert B, Scott JD . Cloning and characterization of a novel A-kinase anchoring protein. AKAP 220, association with testicular peroxisomes . The Journal of Biological Chemistry . 271 . 16 . 9460–5 . Apr 1996 . 8621616 . 10.1074/jbc.271.16.9460 . free .
• Foss KB, Solberg R, Simard J, Myklebust F, Hansson V, Jahnsen T, Taskén K . Molecular cloning, upstream sequence and promoter studies of the human gene for the regulatory subunit RII alpha of cAMP-dependent protein kinase . Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression . 1350 . 1 . 98–108 . Jan 1997 . 9003463 . 10.1016/S0167-4781(96)00152-2 .
• Dransfield DT, Bradford AJ, Smith J, Martin M, Roy C, Mangeat PH, Goldenring JR . Ezrin is a cyclic AMP-dependent protein kinase anchoring protein . The EMBO Journal . 16 . 1 . 35–43 . Jan 1997 . 9009265 . 1169611 . 10.1093/emboj/16.1.35 .

Notes and References

1. Taskén K, Naylor SL, Solberg R, Jahnsen T . Mapping of the gene encoding the regulatory subunit RII alpha of cAMP-dependent protein kinase (locus PRKAR2A) to human chromosome region 3p21.3-p21.2 . Genomics . 50 . 3 . 378–81 . Jun 1998 . 9676433 . 10.1006/geno.1998.5326 .
2. Web site: Entrez Gene: PRKAR2A protein kinase, cAMP-dependent, regulatory, type II, alpha.
3. Tanji C, Yamamoto H, Yorioka N, Kohno N, Kikuchi K, Kikuchi A . A-kinase anchoring protein AKAP220 binds to glycogen synthase kinase-3beta (GSK-3beta) and mediates protein kinase A-dependent inhibition of GSK-3beta . The Journal of Biological Chemistry . 277 . 40 . 36955–61 . Oct 2002 . 12147701 . 10.1074/jbc.M206210200 . free .
4. Lester LB, Coghlan VM, Nauert B, Scott JD . Cloning and characterization of a novel A-kinase anchoring protein. AKAP 220, association with testicular peroxisomes . The Journal of Biological Chemistry . 271 . 16 . 9460–5 . Apr 1996 . 8621616 . 10.1074/jbc.271.16.9460. free .
5. Carr DW, Hausken ZE, Fraser ID, Stofko-Hahn RE, Scott JD . Association of the type II cAMP-dependent protein kinase with a human thyroid RII-anchoring protein. Cloning and characterization of the RII-binding domain . The Journal of Biological Chemistry . 267 . 19 . 13376–82 . Jul 1992 . 10.1016/S0021-9258(18)42221-1 . 1618839 . free .
6. Herberg FW, Maleszka A, Eide T, Vossebein L, Tasken K . Analysis of A-kinase anchoring protein (AKAP) interaction with protein kinase A (PKA) regulatory subunits: PKA isoform specificity in AKAP binding . Journal of Molecular Biology . 298 . 2 . 329–39 . Apr 2000 . 10764601 . 10.1006/jmbi.2000.3662 .
7. Kapiloff MS, Schillace RV, Westphal AM, Scott JD . mAKAP: an A-kinase anchoring protein targeted to the nuclear membrane of differentiated myocytes . Journal of Cell Science . 112 . 16. 2725–36 . Aug 1999 . 10.1242/jcs.112.16.2725 . 10413680 .
8. Alto NM, Soderling SH, Hoshi N, Langeberg LK, Fayos R, Jennings PA, Scott JD . Bioinformatic design of A-kinase anchoring protein-in silico: a potent and selective peptide antagonist of type II protein kinase A anchoring . Proceedings of the National Academy of Sciences of the United States of America . 100 . 8 . 4445–50 . Apr 2003 . 12672969 . 153575 . 10.1073/pnas.0330734100 . 2003PNAS..100.4445A . free .
9. Dong F, Feldmesser M, Casadevall A, Rubin CS . Molecular characterization of a cDNA that encodes six isoforms of a novel murine A kinase anchor protein . The Journal of Biological Chemistry . 273 . 11 . 6533–41 . Mar 1998 . 9497389 . 10.1074/jbc.273.11.6533. free .
10. Vijayaraghavan S, Liberty GA, Mohan J, Winfrey VP, Olson GE, Carr DW . Isolation and molecular characterization of AKAP110, a novel, sperm-specific protein kinase A-anchoring protein . Molecular Endocrinology . 13 . 5 . 705–17 . May 1999 . 10319321 . 10.1210/mend.13.5.0278 . free .
11. Carr DW, Fujita A, Stentz CL, Liberty GA, Olson GE, Narumiya S . Identification of sperm-specific proteins that interact with A-kinase anchoring proteins in a manner similar to the type II regulatory subunit of PKA . The Journal of Biological Chemistry . 276 . 20 . 17332–8 . May 2001 . 11278869 . 10.1074/jbc.M011252200 . free .
12. Eide T, Coghlan V, Orstavik S, Holsve C, Solberg R, Skâlhegg BS, Lamb NJ, Langeberg L, Fernandez A, Scott JD, Jahnsen T, Taskén K . Molecular cloning, chromosomal localization, and cell cycle-dependent subcellular distribution of the A-kinase anchoring protein, AKAP95 . Experimental Cell Research . 238 . 2 . 305–16 . Feb 1998 . 9473338 . 10.1006/excr.1997.3855 .
13. Collas P, Le Guellec K, Taskén K . The A-kinase-anchoring protein AKAP95 is a multivalent protein with a key role in chromatin condensation at mitosis . The Journal of Cell Biology . 147 . 6 . 1167–80 . Dec 1999 . 10601332 . 2168084 . 10.1083/jcb.147.6.1167.
14. Takahashi M, Shibata H, Shimakawa M, Miyamoto M, Mukai H, Ono Y . Characterization of a novel giant scaffolding protein, CG-NAP, that anchors multiple signaling enzymes to centrosome and the golgi apparatus . The Journal of Biological Chemistry . 274 . 24 . 17267–74 . Jun 1999 . 10358086 . 10.1074/jbc.274.24.17267. free .
15. Li H, Adamik R, Pacheco-Rodriguez G, Moss J, Vaughan M . Protein kinase A-anchoring (AKAP) domains in brefeldin A-inhibited guanine nucleotide-exchange protein 2 (BIG2) . Proceedings of the National Academy of Sciences of the United States of America . 100 . 4 . 1627–32 . Feb 2003 . 12571360 . 149883 . 10.1073/pnas.0337678100 . 2003PNAS..100.1627L . free .
16. Schillace RV, Andrews SF, Liberty GA, Davey MP, Carr DW . Identification and characterization of myeloid translocation gene 16b as a novel a kinase anchoring protein in T lymphocytes . Journal of Immunology . 168 . 4 . 1590–9 . Feb 2002 . 11823486 . 10.4049/jimmunol.168.4.1590. free .
17. 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 .
18. Fukuyama T, Sueoka E, Sugio Y, Otsuka T, Niho Y, Akagi K, Kozu T . MTG8 proto-oncoprotein interacts with the regulatory subunit of type II cyclic AMP-dependent protein kinase in lymphocytes . Oncogene . 20 . 43 . 6225–32 . Sep 2001 . 11593431 . 10.1038/sj.onc.1204794 . free .