RBCC

Full text data of PRKACA

PRKACA (PKACA) [Confidence: high (present in two of the MS resources)]
cAMP-dependent protein kinase catalytic subunit alpha; PKA C-alpha; 2.7.11.11

hRBCD IPI00396630
IPI00396630 Splice isoform 1 of P17612 cAMP-dependent protein kinase, alpha-catalytic subunit Splice isoform 1 of P17612 cAMP-dependent protein kinase, alpha-catalytic subunit membrane n/a n/a n/a n/a n/a n/a 1 n/a 7 n/a n/a n/a n/a n/a n/a n/a n/a 2 n/a n/a cytoplasmic n/a found at its expected molecular weight found at molecular weight

Comments
Isoform P17612-2 was detected.

UniProt P17612
ID KAPCA_HUMAN Reviewed; 351 AA.
AC P17612; Q32P54; Q9H2Y0; Q9NRB4; Q9NRH9;
DT 01-AUG-1990, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2007, sequence version 2.
DT 22-JAN-2014, entry version 163.
DE RecName: Full=cAMP-dependent protein kinase catalytic subunit alpha;
DE Short=PKA C-alpha;
DE EC=2.7.11.11;
GN Name=PRKACA; Synonyms=PKACA;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=2843813; DOI=10.1093/nar/16.16.8189;
RA Maldonado F., Hanks S.K.;
RT "A cDNA clone encoding human cAMP-dependent protein kinase catalytic
RT subunit C alpha.";
RL Nucleic Acids Res. 16:8189-8190(1988).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Thalamus;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG SeattleSNPs variation discovery resource;
RL Submitted (JUN-2006) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Eye, and Testis;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-189 (ISOFORM 2), SUBCELLULAR LOCATION,
RP AND TISSUE SPECIFICITY.
RX PubMed=10906071;
RA Reinton N., Orstavik S., Haugen T.B., Jahnsen T., Tasken K.,
RA Skalhegg B.S.;
RT "A novel isoform of human cyclic 3',5'-adenosine monophosphate-
RT dependent protein kinase, c alpha-s, localizes to sperm midpiece.";
RL Biol. Reprod. 63:607-611(2000).
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-152 (ISOFORM 2).
RC TISSUE=Testis;
RX PubMed=10982398; DOI=10.1091/mbc.11.9.3031;
RA San Agustin J.T., Wilkerson C.G., Witman G.B.;
RT "The unique catalytic subunit of sperm cAMP-dependent protein kinase
RT is the product of an alternative C-alpha mRNA expressed specifically
RT in spermatogenic cells.";
RL Mol. Biol. Cell 11:3031-3044(2000).
RN [8]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-39 (ISOFORM 2).
RC TISSUE=Testis;
RX PubMed=10841548; DOI=10.1073/pnas.97.12.6433;
RA Desseyn J.-L., Burton K.A., McKnight G.S.;
RT "Expression of a nonmyristylated variant of the catalytic subunit of
RT protein kinase A during male germ-cell development.";
RL Proc. Natl. Acad. Sci. U.S.A. 97:6433-6438(2000).
RN [9]
RP AUTOPHOSPHORYLATION, PHOSPHORYLATION AT THR-196, PHOSPHORYLATION AT
RP THR-198 BY PDK1, AND MUTAGENESIS OF ARG-195; GLY-201 AND THR-202.
RX PubMed=12372837; DOI=10.1074/jbc.M204970200;
RA Moore M.J., Kanter J.R., Jones K.C., Taylor S.S.;
RT "Phosphorylation of the catalytic subunit of protein kinase A.
RT Autophosphorylation versus phosphorylation by phosphoinositide-
RT dependent kinase-1.";
RL J. Biol. Chem. 277:47878-47884(2002).
RN [10]
RP INTERACTION WITH RAB13.
RX PubMed=15096524; DOI=10.1083/jcb.200312118;
RA Koehler K., Louvard D., Zahraoui A.;
RT "Rab13 regulates PKA signaling during tight junction assembly.";
RL J. Cell Biol. 165:175-180(2004).
RN [11]
RP FUNCTION AS NFKB1 KINASE.
RX PubMed=15642694; DOI=10.1074/jbc.M412180200;
RA Guan H., Hou S., Ricciardi R.P.;
RT "DNA binding of repressor nuclear factor-kappaB p50/p50 depends on
RT phosphorylation of Ser337 by the protein kinase A catalytic subunit.";
RL J. Biol. Chem. 280:9957-9962(2005).
RN [12]
RP FUNCTION AS CLDN3 KINASE.
RX PubMed=15905176; DOI=10.1074/jbc.M502003200;
RA D'Souza T., Agarwal R., Morin P.J.;
RT "Phosphorylation of claudin-3 at threonine 192 by cAMP-dependent
RT protein kinase regulates tight junction barrier function in ovarian
RT cancer cells.";
RL J. Biol. Chem. 280:26233-26240(2005).
RN [13]
RP FUNCTION, AND INTERACTION WITH AICDA.
RX PubMed=16387847; DOI=10.1073/pnas.0509969103;
RA Pasqualucci L., Kitaura Y., Gu H., Dalla-Favera R.;
RT "PKA-mediated phosphorylation regulates the function of activation-
RT induced deaminase (AID) in B cells.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:395-400(2006).
RN [14]
RP FUNCTION IN PROTEASOME REGULATION, AND FUNCTION AS PSMC5/RPT6 KINASE.
RX PubMed=17565987; DOI=10.1074/jbc.M702439200;
RA Zhang F., Hu Y., Huang P., Toleman C.A., Paterson A.J., Kudlow J.E.;
RT "Proteasome function is regulated by cyclic AMP-dependent protein
RT kinase through phosphorylation of Rpt6.";
RL J. Biol. Chem. 282:22460-22471(2007).
RN [15]
RP FUNCTION AS RYR2 KINASE.
RX PubMed=17693412; DOI=10.1074/jbc.M703510200;
RA Xiao B., Tian X., Xie W., Jones P.P., Cai S., Wang X., Jiang D.,
RA Kong H., Zhang L., Chen K., Walsh M.P., Cheng H., Chen S.R.W.;
RT "Functional consequence of protein kinase A-dependent phosphorylation
RT of the cardiac ryanodine receptor: sensitization of store overload-
RT induced Ca2+ release.";
RL J. Biol. Chem. 282:30256-30264(2007).
RN [16]
RP PHOSPHORYLATION, AND ENZYME REGULATION.
RX PubMed=17909264; DOI=10.1677/JME-07-0048;
RA Ichikawa T., Horie-Inoue K., Ikeda K., Blumberg B., Inoue S.;
RT "Vitamin K2 induces phosphorylation of protein kinase A and expression
RT of novel target genes in osteoblastic cells.";
RL J. Mol. Endocrinol. 39:239-247(2007).
RN [17]
RP FUNCTION AS ALPHA-DIFLUOROMETHYLORNITHINE ANTAGONIST.
RX PubMed=17333334; DOI=10.1007/s10549-007-9536-5;
RA Xu H., Washington S., Verderame M.F., Manni A.;
RT "Activation of protein kinase A (PKA) signaling mitigates the
RT antiproliferative and antiinvasive effects of alpha-
RT difluoromethylornithine in breast cancer cells.";
RL Breast Cancer Res. Treat. 107:63-70(2008).
RN [18]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-49 AND SER-339, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [19]
RP FUNCTION, AND INTERACTION WITH APOBEC3G.
RX PubMed=18836454; DOI=10.1038/nsmb.1497;
RA Shirakawa K., Takaori-Kondo A., Yokoyama M., Izumi T., Matsui M.,
RA Io K., Sato T., Sato H., Uchiyama T.;
RT "Phosphorylation of APOBEC3G by protein kinase A regulates its
RT interaction with HIV-1 Vif.";
RL Nat. Struct. Mol. Biol. 15:1184-1191(2008).
RN [20]
RP ENZYME REGULATION, AND MUTAGENESIS OF TYR-205.
RX PubMed=18178622; DOI=10.1073/pnas.0709214104;
RA Masterson L.R., Mascioni A., Traaseth N.J., Taylor S.S., Veglia G.;
RT "Allosteric cooperativity in protein kinase A.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:506-511(2008).
RN [21]
RP SUBCELLULAR LOCATION.
RX PubMed=19210988; DOI=10.1016/j.yexcr.2008.12.026;
RA Yan X., Walkiewicz M., Carlson J., Leiphon L., Grove B.;
RT "Gravin dynamics regulates the subcellular distribution of PKA.";
RL Exp. Cell Res. 315:1247-1259(2009).
RN [22]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19369195; DOI=10.1074/mcp.M800588-MCP200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [23]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-339, AND MASS
RP SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [24]
RP FUNCTION IN PLATELETS, FUNCTION AS VASP KINASE, AND INTERACTION WITH
RP NFKB1; NFKB2 AND NFKBIA.
RX PubMed=20356841; DOI=10.1074/jbc.M109.077602;
RA Gambaryan S., Kobsar A., Rukoyatkina N., Herterich S., Geiger J.,
RA Smolenski A., Lohmann S.M., Walter U.;
RT "Thrombin and collagen induce a feedback inhibitory signaling pathway
RT in platelets involving dissociation of the catalytic subunit of
RT protein kinase A from an NFkappaB-IkappaB complex.";
RL J. Biol. Chem. 285:18352-18363(2010).
RN [25]
RP FUNCTION IN OSTEOBLAST DIFFERENTIATION, AND ENZYME REGULATION.
RX PubMed=19949837; DOI=10.1007/s11010-009-0344-6;
RA Wang W., Zhang X., Zheng J., Yang J.;
RT "High glucose stimulates adipogenic and inhibits osteogenic
RT differentiation in MG-63 cells through cAMP/protein kinase
RT A/extracellular signal-regulated kinase pathway.";
RL Mol. Cell. Biochem. 338:115-122(2010).
RN [26]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [27]
RP FUNCTION AS RORA KINASE.
RX PubMed=21514275; DOI=10.1016/j.bbrc.2011.04.046;
RA Ermisch M., Firla B., Steinhilber D.;
RT "Protein kinase A activates and phosphorylates ROR?4 in vitro and
RT takes part in ROR? activation by CaMK-IV.";
RL Biochem. Biophys. Res. Commun. 408:442-446(2011).
RN [28]
RP FUNCTION AS KINASE, TISSUE SPECIFICITY, AND INTERACTION WITH
RP PRKAR1A/PKR1 AND PRKAR2A/PKR2.
RX PubMed=21812984; DOI=10.1186/1471-2091-12-40;
RA Vetter M.M., Zenn H.-M., Mendez E., van den Boom H., Herberg F.W.,
RA Skaalhegg B.S.;
RT "The testis-specific C?2 subunit of PKA is kinetically
RT indistinguishable from the common C?1 subunit of PKA.";
RL BMC Biochem. 12:40-40(2011).
RN [29]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=21423175; DOI=10.1038/ncb2209;
RA Lignitto L., Carlucci A., Sepe M., Stefan E., Cuomo O., Nistico R.,
RA Scorziello A., Savoia C., Garbi C., Annunziato L., Feliciello A.;
RT "Control of PKA stability and signalling by the RING ligase praja2.";
RL Nat. Cell Biol. 13:412-422(2011).
RN [30]
RP X-RAY CRYSTALLOGRAPHY (2.20 ANGSTROMS) OF 15-351, AND PHOSPHORYLATION
RP AT THR-198 AND SER-339.
RX PubMed=16765046; DOI=10.1016/j.bmcl.2006.05.092;
RA Lin X., Murray J.M., Rico A.C., Wang M.X., Chu D.T., Zhou Y.,
RA Del Rosario M., Kaufman S., Ma S., Fang E., Crawford K.,
RA Jefferson A.B.;
RT "Discovery of 2-pyrimidyl-5-amidothiophenes as potent inhibitors for
RT AKT: synthesis and SAR studies.";
RL Bioorg. Med. Chem. Lett. 16:4163-4168(2006).
RN [31]
RP X-RAY CRYSTALLOGRAPHY (1.90 ANGSTROMS), PHOSPHORYLATION AT THR-198 AND
RP SER-339, AND ENZYME REGULATION.
RX PubMed=20137943; DOI=10.1016/j.bmcl.2010.01.067;
RA Zeng Q., Allen J.G., Bourbeau M.P., Wang X., Yao G., Tadesse S.,
RA Rider J.T., Yuan C.C., Hong F.-T., Lee M.R., Zhang S., Lofgren J.A.,
RA Freeman D.J., Yang S., Li C., Tominey E., Huang X., Hoffman D.,
RA Yamane H.K., Fotsch C., Dominguez C., Hungate R., Zhang X.;
RT "Azole-based inhibitors of AKT/PKB for the treatment of cancer.";
RL Bioorg. Med. Chem. Lett. 20:1559-1564(2010).
RN [32]
RP X-RAY CRYSTALLOGRAPHY (2.49 ANGSTROMS), PHOSPHORYLATION AT THR-198 AND
RP SER-339, AND ENZYME REGULATION.
RX PubMed=20481595; DOI=10.1021/jm1003842;
RA Freeman-Cook K.D., Autry C., Borzillo G., Gordon D.,
RA Barbacci-Tobin E., Bernardo V., Briere D., Clark T., Corbett M.,
RA Jakubczak J., Kakar S., Knauth E., Lippa B., Luzzio M.J., Mansour M.,
RA Martinelli G., Marx M., Nelson K., Pandit J., Rajamohan F.,
RA Robinson S., Subramanyam C., Wei L., Wythes M., Morris J.;
RT "Design of selective, ATP-competitive inhibitors of Akt.";
RL J. Med. Chem. 53:4615-4622(2010).
RN [33]
RP X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) IN COMPLEX WITH ADENOSINE
RP ANALOG, PHOSPHORYLATION AT SER-11; THR-198 AND SER-339, AND ENZYME
RP REGULATION.
RX PubMed=20732331; DOI=10.1016/j.jmb.2010.08.028;
RA Pflug A., Rogozina J., Lavogina D., Enkvist E., Uri A., Engh R.A.,
RA Bossemeyer D.;
RT "Diversity of bisubstrate binding modes of adenosine analogue-
RT oligoarginine conjugates in protein kinase a and implications for
RT protein substrate interactions.";
RL J. Mol. Biol. 403:66-77(2010).
RN [34]
RP X-RAY CRYSTALLOGRAPHY (1.75 ANGSTROMS) IN COMPLEX WITH AURORA KINASE
RP INHIBITORS, PHOSPHORYLATION AT SER-11; THR-198 AND SER-339, AND
RP MUTAGENESIS OF LYS-48; LEU-96; MET-121; VAL-124; GLN-182 AND THR-184.
RX PubMed=21774789; DOI=10.1042/BJ20110592;
RA Pflug A., de Oliveira T.M., Bossemeyer D., Engh R.A.;
RT "Mutants of protein kinase A that mimic the ATP-binding site of Aurora
RT kinase.";
RL Biochem. J. 440:85-93(2011).
RN [35]
RP X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS), AND PHOSPHORYLATION AT THR-198
RP AND SER-339.
RA Behnen J., Koester H., Ritschel T., Neudert G., Heine A., Klebe G.;
RT "Experimental active site mapping as a starting point to fragment-
RT based lead discovery.";
RL Submitted (JUL-2010) to the PDB data bank.
RN [36]
RP X-RAY CRYSTALLOGRAPHY (1.58 ANGSTROMS).
RA Koester H., Craan T., Brass S., Heine A., Klebe G.;
RT "Fragment based drug design on PKA.";
RL Submitted (SEP-2010) to the PDB data bank.
RN [37]
RP VARIANTS [LARGE SCALE ANALYSIS] VAL-41; GLN-46 AND CYS-264.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C.,
RA Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S.,
RA O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S.,
RA Bhamra G., Buck G., Choudhury B., Clements J., Cole J., Dicks E.,
RA Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J.,
RA Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K.,
RA Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T.,
RA West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P.,
RA Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E.,
RA DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E.,
RA Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T.,
RA Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
CC -!- FUNCTION: Phosphorylates a large number of substrates in the
CC cytoplasm and the nucleus. Regulates the abundance of
CC compartmentalized pools of its regulatory subunits through
CC phosphorylation of PJA2 which binds and ubiquitinates these
CC subunits, leading to their subsequent proteolysis. Phosphorylates
CC CDC25B, ABL1, NFKB1, CLDN3, PSMC5/RPT6, PJA2, RYR2, RORA and VASP.
CC RORA is activated by phosphorylation. Required for glucose-
CC mediated adipogenic differentiation increase and osteogenic
CC differentiation inhibition from osteoblasts. Involved in the
CC regulation of platelets in response to thrombin and collagen;
CC maintains circulating platelets in a resting state by
CC phosphorylating proteins in numerous platelet inhibitory pathways
CC when in complex with NF-kappa-B (NFKB1 and NFKB2) and I-kappa-B-
CC alpha (NFKBIA), but thrombin and collagen disrupt these complexes
CC and free active PRKACA stimulates platelets and leads to platelet
CC aggregation by phosphorylating VASP. Prevents the
CC antiproliferative and anti-invasive effects of alpha-
CC difluoromethylornithine in breast cancer cells when activated.
CC RYR2 channel activity is potentiated by phosphorylation in
CC presence of luminal Ca(2+), leading to reduced amplitude and
CC increased frequency of store overload-induced Ca(2+) release
CC (SOICR) characterized by an increased rate of Ca(2+) release and
CC propagation velocity of spontaneous Ca(2+) waves, despite reduced
CC wave amplitude and resting cytosolic Ca(2+). PSMC5/RPT6 activation
CC by phosphorylation stimulates proteasome. Negatively regulates
CC tight junctions (TJs) in ovarian cancer cells via CLDN3
CC phosphorylation. NFKB1 phosphorylation promotes NF-kappa-B p50-p50
CC DNA binding. Involved in embryonic development by down-regulating
CC the Hedgehog (Hh) signaling pathway that determines embryo pattern
CC formation and morphogenesis. Prevents meiosis resumption in
CC prophase-arrested oocytes via CDC25B inactivation by
CC phosphorylation. May also regulate rapid eye movement (REM) sleep
CC in the pedunculopontine tegmental (PPT). Phosphorylates APOBEC3G
CC and AICDA. Isoform 2 phosphorylates and activates ABL1 in sperm
CC flagellum to promote spermatozoa capacitation.
CC -!- CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein.
CC -!- ENZYME REGULATION: Allosterically activated by various compounds,
CC including ATP. Activated by cAMP; the nucleotide acts as a dynamic
CC and allosteric activator by coupling the two lobes of apo PKA,
CC enhancing the enzyme dynamics synchronously and priming it for
CC catalysis. Inhibited by H89 (N-[2-[[3-(4-Bromophenyl)-2-
CC propenyl]amino]ethyl]-5-isoquinolinesulfonamide), spiroindoline,
CC azole-based inhibitors, (3s)-amino-aminomethylbenzamide analogs,
CC ARC-1032 (6-{[(2S,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-
CC dihydroxyoxolan-2-yl]formamido}-N-[(1R)-4-carbamimidamido-1-
CC carbamoylbutyl]hexanamide), ARC-1034 (6-{[(2S,3S,4R,5R)-5-(6-
CC amino-9H-purin-9-yl)-3,4-dihydroxyoxolan-2-yl]formamido}-N-[(1R)-
CC 4-carbamimidamido-1-{[(1R)-4-carbamimidamido-1-
CC carbamoylbutyl]carbamoyl}butyl]hexanamide), ARC-582, ARC-902 (Adc-
CC 6-aminohexanoic acid-(D-Arg)(6)-NH(2)), ARC-1012 ((2R)-6-amino-2-
CC (6-{[(2S,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxyoxolan-
CC 2-yl]formamido}hexanamido)-N-(5-{[(1R)-4-carbamimidamido-1-{[(1R)-
CC 4-carbamimidamido-1-
CC carbamoylbutyl]carbamoyl}butyl]carbamoyl}pentyl)hexanamide) and
CC ARC-1039 (6-{[(2S,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-
CC dihydroxyoxolan-2-yl]formamido}-N-[(1R)-1-[(5-{[(1R)-4-
CC carbamimidamido-1-{[(1R)-4-carbamimidamido-1-
CC carbamoylbutyl]carbamoyl}butyl]carbamoyl}pentyl)carbamoyl]ethyl]he
CC xanamide).
CC -!- SUBUNIT: A number of inactive tetrameric holoenzymes are produced
CC by the combination of homo- or heterodimers of the different
CC regulatory subunits associated with two catalytic subunits. cAMP
CC causes the dissociation of the inactive holoenzyme into a dimer of
CC regulatory subunits bound to four cAMP and two free monomeric
CC catalytic subunits. The cAMP-dependent protein kinase catalytic
CC subunit binds PJA2. Both isoforms 1 and 2 forms activate cAMP-
CC sensitive PKAI and PKAII holoenzymes by interacting with
CC regulatory subunit (R) of PKA, PRKAR1A/PKR1 and PRKAR2A/PKR2,
CC respectively. Interacts with NFKB1, NFKB2 and NFKBIA in platelets;
CC these interactions are disrupted by thrombin and collagen. Binds
CC to ABL1 in spermatozoa and with CDC25B in oocytes. Interacts with
CC APOBEC3G and AICDA. Interacts with RAB13; downstream effector of
CC RAB13 involved in tight junction assembly.
CC -!- INTERACTION:
CC Q9NQ31:AKIP1; NbExp=4; IntAct=EBI-476586, EBI-517035;
CC P49841:GSK3B; NbExp=5; IntAct=EBI-476586, EBI-373586;
CC P10644:PRKAR1A; NbExp=2; IntAct=EBI-476586, EBI-476431;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Cell membrane. Nucleus (By
CC similarity). Mitochondrion (By similarity). Note=Translocates into
CC the nucleus (monomeric catalytic subunit). The inactive holoenzyme
CC is found in the cytoplasm. Distributed throughout the cytoplasm in
CC meiotically incompetent oocytes. Associated to mitochondrion as
CC meiotic competence is acquired. Aggregates around the germinal
CC vesicles (GV) at the immature GV stage oocytes (By similarity).
CC -!- SUBCELLULAR LOCATION: Isoform 2: Cell projection, cilium,
CC flagellum. Note=Expressed in the midpiece region of the sperm
CC flagellum.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1; Synonyms=C-alpha-1;
CC IsoId=P17612-1; Sequence=Displayed;
CC Name=2; Synonyms=C-alpha-2, C-alpha-S, C(s);
CC IsoId=P17612-2; Sequence=VSP_004759;
CC -!- TISSUE SPECIFICITY: Isoform 1 is ubiquitous. Isoform 2 is sperm-
CC specific and is enriched in pachytene spermatocytes but is not
CC detected in round spermatids.
CC -!- PTM: Asn-3 is partially deaminated to Asp giving rise to 2 major
CC isoelectric variants, called CB and CA respectively (By
CC similarity).
CC -!- PTM: Autophosphorylated. Phosphorylation is enhanced by vitamin
CC K(2). Phosphorylated on threonine and serine residues.
CC Phosphorylation on Thr-198 is required for full activity.
CC -!- PTM: Phosphorylated at Tyr-331 by activated receptor tyrosine
CC kinases EGFR and PDGFR; this increases catalytic efficienncy (By
CC similarity).
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. AGC Ser/Thr
CC protein kinase family. cAMP subfamily.
CC -!- SIMILARITY: Contains 1 AGC-kinase C-terminal domain.
CC -!- SIMILARITY: Contains 1 protein kinase domain.
CC -!- WEB RESOURCE: Name=SeattleSNPs;
CC URL="http://pga.gs.washington.edu/data/prkaca/";
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DR EMBL; X07767; CAA30597.1; -; mRNA.
DR EMBL; AK290147; BAF82836.1; -; mRNA.
DR EMBL; DQ667173; ABG25918.1; -; Genomic_DNA.
DR EMBL; CH471106; EAW84399.1; -; Genomic_DNA.
DR EMBL; BC039846; AAH39846.1; -; mRNA.
DR EMBL; BC108259; AAI08260.1; -; mRNA.
DR EMBL; AF208004; AAG35720.1; -; mRNA.
DR EMBL; AF239744; AAF76426.1; -; mRNA.
DR EMBL; AF224718; AAF75622.1; -; mRNA.
DR PIR; S01404; OKHU2C.
DR RefSeq; NP_002721.1; NM_002730.3.
DR RefSeq; NP_997401.1; NM_207518.1.
DR UniGene; Hs.631630; -.
DR PDB; 2GU8; X-ray; 2.20 A; A=15-351.
DR PDB; 3AGL; X-ray; 2.10 A; A/B=1-351.
DR PDB; 3AGM; X-ray; 2.00 A; A=1-351.
DR PDB; 3AMA; X-ray; 1.75 A; A=1-351.
DR PDB; 3AMB; X-ray; 2.25 A; A=1-351.
DR PDB; 3L9L; X-ray; 2.00 A; A/B=1-351.
DR PDB; 3L9M; X-ray; 1.90 A; A/B=1-351.
DR PDB; 3L9N; X-ray; 2.00 A; A=1-351.
DR PDB; 3MVJ; X-ray; 2.49 A; A/B/E=1-351.
DR PDB; 3NX8; X-ray; 2.00 A; A=1-351.
DR PDB; 3OOG; X-ray; 2.00 A; A=1-351.
DR PDB; 3OVV; X-ray; 1.58 A; A=1-351.
DR PDB; 3OWP; X-ray; 1.88 A; A=1-351.
DR PDB; 3OXT; X-ray; 2.20 A; A=1-351.
DR PDB; 3P0M; X-ray; 2.03 A; A=1-351.
DR PDB; 3POO; X-ray; 1.60 A; A=1-351.
DR PDB; 3VQH; X-ray; 1.95 A; A=1-351.
DR PDB; 4AE6; X-ray; 2.10 A; A/B=16-351.
DR PDB; 4AE9; X-ray; 2.30 A; A/B=16-351.
DR PDBsum; 2GU8; -.
DR PDBsum; 3AGL; -.
DR PDBsum; 3AGM; -.
DR PDBsum; 3AMA; -.
DR PDBsum; 3AMB; -.
DR PDBsum; 3L9L; -.
DR PDBsum; 3L9M; -.
DR PDBsum; 3L9N; -.
DR PDBsum; 3MVJ; -.
DR PDBsum; 3NX8; -.
DR PDBsum; 3OOG; -.
DR PDBsum; 3OVV; -.
DR PDBsum; 3OWP; -.
DR PDBsum; 3OXT; -.
DR PDBsum; 3P0M; -.
DR PDBsum; 3POO; -.
DR PDBsum; 3VQH; -.
DR PDBsum; 4AE6; -.
DR PDBsum; 4AE9; -.
DR ProteinModelPortal; P17612; -.
DR SMR; P17612; 15-351.
DR DIP; DIP-33878N; -.
DR IntAct; P17612; 54.
DR MINT; MINT-95365; -.
DR STRING; 9606.ENSP00000309591; -.
DR BindingDB; P17612; -.
DR ChEMBL; CHEMBL2094138; -.
DR GuidetoPHARMACOLOGY; 1476; -.
DR PhosphoSite; P17612; -.
DR DMDM; 125205; -.
DR PaxDb; P17612; -.
DR PRIDE; P17612; -.
DR DNASU; 5566; -.
DR Ensembl; ENST00000308677; ENSP00000309591; ENSG00000072062.
DR Ensembl; ENST00000589994; ENSP00000466651; ENSG00000072062.
DR GeneID; 5566; -.
DR KEGG; hsa:5566; -.
DR UCSC; uc002myc.3; human.
DR CTD; 5566; -.
DR GeneCards; GC19M014202; -.
DR HGNC; HGNC:9380; PRKACA.
DR HPA; CAB010361; -.
DR MIM; 601639; gene.
DR neXtProt; NX_P17612; -.
DR PharmGKB; PA33748; -.
DR eggNOG; COG0515; -.
DR HOGENOM; HOG000233033; -.
DR HOVERGEN; HBG108317; -.
DR InParanoid; P17612; -.
DR KO; K04345; -.
DR OMA; MASNPND; -.
DR OrthoDB; EOG7VX8WD; -.
DR PhylomeDB; P17612; -.
DR BRENDA; 2.7.11.11; 2681.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_115566; Cell Cycle.
DR Reactome; REACT_116125; Disease.
DR Reactome; REACT_13685; Neuronal System.
DR Reactome; REACT_15518; Transmembrane transport of small molecules.
DR Reactome; REACT_604; Hemostasis.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; P17612; -.
DR ChiTaRS; PRKACA; human.
DR EvolutionaryTrace; P17612; -.
DR GeneWiki; PRKACA; -.
DR GenomeRNAi; 5566; -.
DR NextBio; 21564; -.
DR PRO; PR:P17612; -.
DR ArrayExpress; P17612; -.
DR Bgee; P17612; -.
DR CleanEx; HS_PRKACA; -.
DR Genevestigator; P17612; -.
DR GO; GO:0031588; C:AMP-activated protein kinase complex; IDA:BHF-UCL.
DR GO; GO:0034704; C:calcium channel complex; TAS:BHF-UCL.
DR GO; GO:0005952; C:cAMP-dependent protein kinase complex; NAS:UniProtKB.
DR GO; GO:0005813; C:centrosome; IDA:UniProtKB.
DR GO; GO:0005929; C:cilium; IEA:UniProtKB-KW.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005739; C:mitochondrion; IEA:UniProtKB-SubCell.
DR GO; GO:0031594; C:neuromuscular junction; IEA:Ensembl.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0097225; C:sperm midpiece; IDA:UniProtKB.
DR GO; GO:0005524; F:ATP binding; NAS:UniProtKB.
DR GO; GO:0004691; F:cAMP-dependent protein kinase activity; IDA:BHF-UCL.
DR GO; GO:0031625; F:ubiquitin protein ligase binding; IDA:UniProtKB.
DR GO; GO:0007202; P:activation of phospholipase C activity; TAS:Reactome.
DR GO; GO:0034199; P:activation of protein kinase A activity; TAS:Reactome.
DR GO; GO:0007596; P:blood coagulation; TAS:Reactome.
DR GO; GO:0035584; P:calcium-mediated signaling using intracellular calcium source; TAS:BHF-UCL.
DR GO; GO:0086064; P:cell communication by electrical coupling involved in cardiac conduction; TAS:BHF-UCL.
DR GO; GO:0071872; P:cellular response to epinephrine stimulus; TAS:BHF-UCL.
DR GO; GO:0071377; P:cellular response to glucagon stimulus; TAS:Reactome.
DR GO; GO:0071333; P:cellular response to glucose stimulus; IDA:UniProtKB.
DR GO; GO:0071374; P:cellular response to parathyroid hormone stimulus; IEA:Ensembl.
DR GO; GO:0051480; P:cytosolic calcium ion homeostasis; TAS:BHF-UCL.
DR GO; GO:0006112; P:energy reserve metabolic process; TAS:Reactome.
DR GO; GO:0007173; P:epidermal growth factor receptor signaling pathway; TAS:Reactome.
DR GO; GO:0008543; P:fibroblast growth factor receptor signaling pathway; TAS:Reactome.
DR GO; GO:0000086; P:G2/M transition of mitotic cell cycle; TAS:Reactome.
DR GO; GO:0006094; P:gluconeogenesis; TAS:Reactome.
DR GO; GO:0045087; P:innate immune response; TAS:Reactome.
DR GO; GO:0007243; P:intracellular protein kinase cascade; TAS:Reactome.
DR GO; GO:0001707; P:mesoderm formation; IEA:Ensembl.
DR GO; GO:0048011; P:neurotrophin TRK receptor signaling pathway; TAS:Reactome.
DR GO; GO:0018105; P:peptidyl-serine phosphorylation; IDA:BHF-UCL.
DR GO; GO:0071158; P:positive regulation of cell cycle arrest; ISS:UniProtKB.
DR GO; GO:0046827; P:positive regulation of protein export from nucleus; IEA:Ensembl.
DR GO; GO:0046777; P:protein autophosphorylation; IEA:Ensembl.
DR GO; GO:0010881; P:regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion; TAS:BHF-UCL.
DR GO; GO:0002027; P:regulation of heart rate; TAS:BHF-UCL.
DR GO; GO:0050796; P:regulation of insulin secretion; TAS:Reactome.
DR GO; GO:0045667; P:regulation of osteoblast differentiation; IDA:UniProtKB.
DR GO; GO:0061136; P:regulation of proteasomal protein catabolic process; IDA:UniProtKB.
DR GO; GO:0043393; P:regulation of protein binding; TAS:BHF-UCL.
DR GO; GO:0060314; P:regulation of ryanodine-sensitive calcium-release channel activity; TAS:BHF-UCL.
DR GO; GO:0050804; P:regulation of synaptic transmission; IEA:Ensembl.
DR GO; GO:2000810; P:regulation of tight junction assembly; IDA:UniProtKB.
DR GO; GO:0044281; P:small molecule metabolic process; TAS:Reactome.
DR GO; GO:0048240; P:sperm capacitation; ISS:UniProtKB.
DR GO; GO:0055085; P:transmembrane transport; TAS:Reactome.
DR GO; GO:0019433; P:triglyceride catabolic process; TAS:Reactome.
DR GO; GO:0006833; P:water transport; TAS:Reactome.
DR InterPro; IPR000961; AGC-kinase_C.
DR InterPro; IPR011009; Kinase-like_dom.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR002290; Ser/Thr_dual-sp_kinase_dom.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR Pfam; PF00069; Pkinase; 1.
DR SMART; SM00133; S_TK_X; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS51285; AGC_KINASE_CTER; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; ATP-binding; cAMP; Cell membrane;
KW Cell projection; Cilium; Complete proteome; Cytoplasm; Flagellum;
KW Kinase; Lipoprotein; Membrane; Mitochondrion; Myristate;
KW Nucleotide-binding; Nucleus; Phosphoprotein; Polymorphism;
KW Reference proteome; Serine/threonine-protein kinase; Transferase.
FT INIT_MET 1 1 Removed (By similarity).
FT CHAIN 2 351 cAMP-dependent protein kinase catalytic
FT subunit alpha.
FT /FTId=PRO_0000086052.
FT DOMAIN 44 298 Protein kinase.
FT DOMAIN 299 351 AGC-kinase C-terminal.
FT NP_BIND 50 58 ATP.
FT NP_BIND 122 128 ATP (By similarity).
FT NP_BIND 169 172 ATP (By similarity).
FT ACT_SITE 167 167 Proton acceptor (By similarity).
FT BINDING 73 73 ATP (By similarity).
FT MOD_RES 3 3 Deamidated asparagine (By similarity).
FT MOD_RES 11 11 Phosphoserine; by autocatalysis (By
FT similarity).
FT MOD_RES 49 49 Phosphothreonine.
FT MOD_RES 140 140 Phosphoserine (By similarity).
FT MOD_RES 196 196 Phosphothreonine.
FT MOD_RES 198 198 Phosphothreonine; by PDPK1.
FT MOD_RES 202 202 Phosphothreonine.
FT MOD_RES 331 331 Phosphotyrosine (By similarity).
FT MOD_RES 339 339 Phosphoserine.
FT LIPID 2 2 N-myristoyl glycine (By similarity).
FT VAR_SEQ 1 15 MGNAAAAKKGSEQES -> MASNSSD (in isoform
FT 2).
FT /FTId=VSP_004759.
FT VARIANT 41 41 L -> V (in dbSNP:rs56029020).
FT /FTId=VAR_040591.
FT VARIANT 46 46 R -> Q (in dbSNP:rs56085217).
FT /FTId=VAR_040592.
FT VARIANT 264 264 S -> C (in dbSNP:rs35635531).
FT /FTId=VAR_040593.
FT MUTAGEN 48 48 K->R: Enhanced basal kinase activity;
FT when associated with Q-96, L-121, A-124,
FT K-182 and A-184.
FT MUTAGEN 96 96 L->Q: Enhanced basal kinase activity;
FT when associated with R-48, L-121, A-124,
FT K-182 and A-184.
FT MUTAGEN 121 121 M->L: Enhanced basal kinase activity;
FT when associated with R-48, Q-96, A-124,
FT K-182 and A-184.
FT MUTAGEN 124 124 V->A: Enhanced basal kinase activity;
FT when associated with R-48, Q-96, L-121,
FT K-182 and A-184.
FT MUTAGEN 182 182 Q->K: Enhanced basal kinase activity;
FT when associated with R-48, Q-96, L-121,
FT A-124 and A-184.
FT MUTAGEN 184 184 T->A: Enhanced basal kinase activity;
FT when associated with R-48, Q-96, L-121,
FT A-124 and K-182.
FT MUTAGEN 195 195 R->A: No phosphorylation.
FT MUTAGEN 201 201 G->A: No phosphorylation.
FT MUTAGEN 202 202 T->A: No phosphorylation.
FT MUTAGEN 205 205 Y->A: Loss of allosteric regulation.
FT HELIX 3 6
FT HELIX 16 32
FT HELIX 41 43
FT STRAND 44 53
FT STRAND 56 63
FT TURN 64 66
FT STRAND 69 76
FT HELIX 77 82
FT HELIX 86 98
FT STRAND 107 112
FT STRAND 114 122
FT HELIX 129 136
FT HELIX 141 160
FT HELIX 170 172
FT STRAND 173 175
FT STRAND 181 183
FT HELIX 203 205
FT HELIX 208 211
FT STRAND 212 214
FT HELIX 219 234
FT HELIX 244 253
FT HELIX 264 273
FT TURN 278 280
FT TURN 282 284
FT TURN 286 289
FT HELIX 290 293
FT HELIX 296 298
FT HELIX 303 307
FT TURN 345 350
SQ SEQUENCE 351 AA; 40590 MW; BF6D3ECD2614E5AB CRC64;
MGNAAAAKKG SEQESVKEFL AKAKEDFLKK WESPAQNTAH LDQFERIKTL GTGSFGRVML
VKHKETGNHY AMKILDKQKV VKLKQIEHTL NEKRILQAVN FPFLVKLEFS FKDNSNLYMV
MEYVPGGEMF SHLRRIGRFS EPHARFYAAQ IVLTFEYLHS LDLIYRDLKP ENLLIDQQGY
IQVTDFGFAK RVKGRTWTLC GTPEYLAPEI ILSKGYNKAV DWWALGVLIY EMAAGYPPFF
ADQPIQIYEK IVSGKVRFPS HFSSDLKDLL RNLLQVDLTK RFGNLKNGVN DIKNHKWFAT
TDWIAIYQRK VEAPFIPKFK GPGDTSNFDD YEEEEIRVSI NEKCGKEFSE F
//

MIM 601639
*RECORD*
*FIELD* NO
601639
*FIELD* TI
*601639 PROTEIN KINASE, cAMP-DEPENDENT, CATALYTIC, ALPHA; PRKACA
*FIELD* TX
Most of the effects of cAMP in the eukaryotic cell are mediated through
read morethe phosphorylation of target proteins on serine or threonine residues
by the cAMP-dependent protein kinase (EC 2.7.1.37). The inactive
cAMP-dependent protein kinase is a tetramer composed of 2 regulatory and
2 catalytic subunits. The cooperative binding of 4 molecules of cAMP
dissociates the enzyme in a regulatory subunit dimer and 2 free active
catalytic subunits. In the human, 4 different regulatory subunits
(PRKAR1A, 188830; PRKAR1B, 176911; PRKAR2A, 176910; and PRKAR2B, 176912)
and 3 catalytic subunits (PRKACA; PRKACB, 176892; and PRKACG 176893)
have been identified.

MAPPING

Using PCR and Southern blot analysis, Tasken et al. (1996) assigned the
PRKACA gene to chromosome 19. By 2-color fluorescence in situ
hybridization, they regionalized the assignment to 19p13.1.

GENE FUNCTION

Studying hippocampal slices from rats of different ages, Yasuda et al.
(2003) found that protein kinase A is required for long-term
potentiation (LTP) in neonatal tissue (less than 9 postnatal days).
After that time, LTP requires calcium/calmodulin-dependent protein
kinase II (see CAMK2A, 114078). Yasuda et al. (2003) suggested that
developmental changes in synapse morphology, including a shift from
dendritic shafts to dendritic spines and compartmentalization of
calcium, may underlie the changes in kinase activity.

BIOCHEMICAL FEATURES

- Crystal Structure

Kim et al. (2005) determined the crystal structure of the cAMP-dependent
protein kinase catalytic subunit bound to a deletion mutant of the
regulatory subunit (RI-alpha; PRKAR1A, 188830) at 2.0-angstrom
resolution. This structure defines a previously unidentified extended
interface in which the large lobe of the catalytic subunit is like a
stable scaffold where tyr247 in the G helix and trp196 in the
phosphorylated activation loop serve as anchor points for binding the
RI-alpha subunit. These residues compete with cAMP for the
phosphate-binding cassette in RI-alpha. In contrast to this catalytic
subunit, RI-alpha undergoes major conformational changes when the
complex is compared with cAMP-bound RI-alpha. Kim et al. (2005)
concluded that the complex provides a molecular mechanism for inhibition
of PKA and suggests how cAMP binding leads to activation.

Zhang et al. (2012) described the 2.3-angstrom structure of full-length
tetrameric RII-beta (PRKAR2B; 176912)(2):catalytic subunit-alpha(2)
holoenzyme. The structure showing a dimer of dimers provided a
mechanistic understanding of allosteric activation by cAMP. The
heterodimers are anchored together by an interface created by the
beta-4/beta-5 loop in the RII-beta subunit, which docks onto the
carboxyl-terminal tail of the adjacent C subunit, thereby forcing the C
subunit into a fully closed conformation in the absence of nucleotide.
Diffusion of magnesium ATP into these crystals trapped not ATP but the
reaction products adenosine diphosphate and the phosphorylated RII-beta
subunit. This complex has implications for the
dissociation-reassociation cycling of PKA. The quaternary structure of
the RII-beta tetramer differs appreciably from the model of the RI-alpha
tetramer, confirming the small-angle x-ray scattering prediction that
the structures of each PKA tetramer are different.

ANIMAL MODEL

The intracellular second messenger cAMP affects cell physiology by
directly interacting with effector molecules that include cyclic
nucleotide-gated ion channels, cAMP-regulated G protein exchange
factors, and cAMP-dependent protein kinases (PKA). Two catalytic
subunits, C-alpha (PRKACA) and C-beta (PRKACB), are expressed in the
mouse and mediate the effects of PKA. Skalhegg et al. (2002) generated a
null mutation in the major catalytic subunit of PKA, C-alpha, and
observed early postnatal lethality in the majority of C-alpha knockout
mice. Surprisingly, a small percentage of C-alpha knockout mice,
although runted, survived to adulthood. This growth retardation was not
due to decreased GH (139250) production but did correlate with a
reduction in IGF1 (147440) mRNA in the liver and diminished production
of the major urinary proteins in kidney. In these animals, compensatory
increases in C-beta levels occurred in brain whereas many tissues,
including skeletal muscle, heart, and sperm, contained less than 10% of
the normal PKA activity. Analysis of sperm in C-alpha knockout males
revealed that spermatogenesis progressed normally but that mature sperm
had defective forward motility.

*FIELD* RF
1. Kim, C.; Xuong, N.-H.; Taylor, S. S.: Crystal structure of a complex
between the catalytic and regulatory (RI-alpha) subunits of PKA. Science 307:
690-696, 2005.

2. Skalhegg, B. S.; Huang, Y.; Su, T.; Idzerda, R. L.; McKnight, G.
S.; Burton, K. A.: Mutation of the C-alpha subunit of PKA leads to
growth retardation and sperm dysfunction. Molec. Endocr. 16: 630-639,
2002.

3. Tasken, K.; Solberg, R.; Zhao, Y.; Hansson, V.; Jahnsen, T.; Siciliano,
M. J.: The gene encoding the catalytic subunit C-alpha of cAMP-dependent
protein kinase (locus PRKACA) localizes to human chromosome region
19p13.1. Genomics 36: 535-538, 1996.

4. Yasuda, H.; Barth, A. L.; Stellwagen, D.; Malenka, R. C.: A developmental
switch in the signaling cascades for LTP induction. Nature Neurosci. 6:
15-16, 2003.

5. Zhang, P.; Smith-Nguyen, E. V.; Keshwani, M. M.; Deal, M. S.; Kornev,
A. P.; Taylor, S. S.: Structure and allostery of the PKA RII-beta
tetrameric holoenzyme. Science 335: 712-716, 2012.

*FIELD* CN
Ada Hamosh - updated: 2/27/2012
Ada Hamosh - updated: 2/25/2005
Cassandra L. Kniffin - updated: 12/3/2002
John A. Phillips, III - updated: 10/10/2002

*FIELD* CD
Lori M. Kelman: 1/21/1997

*FIELD* ED
alopez: 02/28/2012
alopez: 2/28/2012
terry: 2/27/2012
wwang: 3/3/2005
terry: 2/25/2005
alopez: 1/9/2003
alopez: 12/3/2002
ckniffin: 12/3/2002
alopez: 10/10/2002
jamie: 1/21/1997

RBCC Red Blood Cell Collection

Full text data of PRKACA