ID PDE8A_HUMAN Reviewed; 829 AA. AC O60658; B3KXE6; H0YMZ7; Q6P9H3; Q969I1; Q96PC9; Q96PD0; Q96PD1; Q96T71; AC Q9UMB7; Q9UMC3; DT 15-JUL-1999, integrated into UniProtKB/Swiss-Prot. DT 19-SEP-2002, sequence version 2. DT 27-MAR-2024, entry version 217. DE RecName: Full=High affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8A; DE EC=3.1.4.53 {ECO:0000250|UniProtKB:O95263}; GN Name=PDE8A; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2; 3; 4 AND 5). RC TISSUE=Testis; RX PubMed=11738832; DOI=10.1016/s0378-1119(01)00783-1; RA Wang P., Wu P., Egan R.W., Billah M.M.; RT "Human phosphodiesterase 8A splice variants: cloning, gene organization, RT and tissue distribution."; RL Gene 280:183-194(2001). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RX PubMed=11371644; DOI=10.1073/pnas.101131098; RA Glavas N.A., Ostenson C., Schaefer J.B., Vasta V., Beavo J.A.; RT "T cell activation up-regulates cyclic nucleotide phosphodiesterases 8A1 RT and 7A3."; RL Proc. Natl. Acad. Sci. U.S.A. 98:6319-6324(2001). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 6), NUCLEOTIDE SEQUENCE RP [LARGE SCALE MRNA] OF 381-829 (ISOFORM 1), AND VARIANT GLY-112. RC TISSUE=Hippocampus; 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., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., 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., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA 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 [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16572171; DOI=10.1038/nature04601; RA Zody M.C., Garber M., Sharpe T., Young S.K., Rowen L., O'Neill K., RA Whittaker C.A., Kamal M., Chang J.L., Cuomo C.A., Dewar K., RA FitzGerald M.G., Kodira C.D., Madan A., Qin S., Yang X., Abbasi N., RA Abouelleil A., Arachchi H.M., Baradarani L., Birditt B., Bloom S., RA Bloom T., Borowsky M.L., Burke J., Butler J., Cook A., DeArellano K., RA DeCaprio D., Dorris L. III, Dors M., Eichler E.E., Engels R., Fahey J., RA Fleetwood P., Friedman C., Gearin G., Hall J.L., Hensley G., Johnson E., RA Jones C., Kamat A., Kaur A., Locke D.P., Madan A., Munson G., Jaffe D.B., RA Lui A., Macdonald P., Mauceli E., Naylor J.W., Nesbitt R., Nicol R., RA O'Leary S.B., Ratcliffe A., Rounsley S., She X., Sneddon K.M.B., RA Stewart S., Sougnez C., Stone S.M., Topham K., Vincent D., Wang S., RA Zimmer A.R., Birren B.W., Hood L., Lander E.S., Nusbaum C.; RT "Analysis of the DNA sequence and duplication history of human chromosome RT 15."; RL Nature 440:671-675(2006). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT GLY-112. RC TISSUE=Liver, and Placenta; 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 project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [7] RP NUCLEOTIDE SEQUENCE [MRNA] OF 117-829 (ISOFORMS 1 AND 2). RX PubMed=9618252; DOI=10.1006/bbrc.1998.8684; RA Fisher D.A., Smith J.F., Pillar J.S., St Denis S.H., Cheng J.B.; RT "Isolation and characterization of PDE8A, a novel human cAMP-specific RT phosphodiesterase."; RL Biochem. Biophys. Res. Commun. 246:570-577(1998). RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 554-829. RG The European IMAGE consortium; RL Submitted (JUL-1999) to the EMBL/GenBank/DDBJ databases. RN [9] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-20 AND SER-457, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. 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 the RT kinome across the cell cycle."; RL Mol. Cell 31:438-448(2008). RN [10] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-457, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [11] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-457, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [12] RP PHOSPHORYLATION AT SER-359. RX PubMed=22673573; DOI=10.1016/j.febslet.2012.04.033; RA Brown K.M., Lee L.C., Findlay J.E., Day J.P., Baillie G.S.; RT "Cyclic AMP-specific phosphodiesterase, PDE8A1, is activated by protein RT kinase A-mediated phosphorylation."; RL FEBS Lett. 586:1631-1637(2012). RN [13] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-20 AND SER-457, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma, and Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [14] RP FUNCTION, INTERACTION WITH RAF1, MUTAGENESIS OF 454-ARG-ARG-455 AND RP 460-GLU-LYS-461, AND IDENTIFICATION BY MASS SPECTROMETRY. RX PubMed=23509299; DOI=10.1073/pnas.1303004110; RA Brown K.M., Day J.P., Huston E., Zimmermann B., Hampel K., Christian F., RA Romano D., Terhzaz S., Lee L.C., Willis M.J., Morton D.B., Beavo J.A., RA Shimizu-Albergine M., Davies S.A., Kolch W., Houslay M.D., Baillie G.S.; RT "Phosphodiesterase-8A binds to and regulates Raf-1 kinase."; RL Proc. Natl. Acad. Sci. U.S.A. 110:E1533-E1542(2013). RN [15] RP X-RAY CRYSTALLOGRAPHY (1.90 ANGSTROMS) OF 482-819 IN COMPLEX WITH METAL RP IONS AND THE INHIBITOR IBMX, FUNCTION, COFACTOR, AND MUTAGENESIS OF RP TYR-748. RX PubMed=18983167; DOI=10.1021/bi801487x; RA Wang H., Yan Z., Yang S., Cai J., Robinson H., Ke H.; RT "Kinetic and structural studies of phosphodiesterase-8A and implication on RT the inhibitor selectivity."; RL Biochemistry 47:12760-12768(2008). CC -!- FUNCTION: Hydrolyzes the second messenger cAMP, which is a key CC regulator of many important physiological processes (PubMed:18983167). CC May be involved in maintaining basal levels of the cyclic nucleotide CC and/or in the cAMP regulation of germ cell development CC (PubMed:18983167). Binding to RAF1 reduces RAF1 'Ser-259' inhibitory- CC phosphorylation and stimulates RAF1-dependent EGF-activated ERK- CC signaling (PubMed:23509299). Protects against cell death induced by CC hydrogen peroxide and staurosporine (PubMed:23509299). CC {ECO:0000269|PubMed:18983167, ECO:0000269|PubMed:23509299}. CC -!- CATALYTIC ACTIVITY: CC Reaction=3',5'-cyclic AMP + H2O = AMP + H(+); Xref=Rhea:RHEA:25277, CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:58165, CC ChEBI:CHEBI:456215; EC=3.1.4.53; CC Evidence={ECO:0000250|UniProtKB:O95263}; CC -!- COFACTOR: CC Name=a divalent metal cation; Xref=ChEBI:CHEBI:60240; CC Evidence={ECO:0000269|PubMed:18983167}; CC Note=Binds 2 divalent metal cations per subunit. Site 1 may CC preferentially bind zinc ions, while site 2 has a preference for CC magnesium and/or manganese ions. {ECO:0000269|PubMed:18983167}; CC -!- ACTIVITY REGULATION: Inhibited by dipyridimole. Insensitive to CC selective PDE inhibitors including rolipram and zaprinast as well as to CC the non-selective inhibitor, IBMX. Unaffected by cGMP. CC {ECO:0000250|UniProtKB:O95263}. CC -!- PATHWAY: Purine metabolism; 3',5'-cyclic AMP degradation; AMP from CC 3',5'-cyclic AMP: step 1/1. CC -!- SUBUNIT: Interacts with RAF1. The interaction promotes RAF1 activity. CC {ECO:0000269|PubMed:23509299}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=6; CC Name=1; Synonyms=PDE8A1; CC IsoId=O60658-1; Sequence=Displayed; CC Name=2; Synonyms=PDE8A2; CC IsoId=O60658-2; Sequence=VSP_004597; CC Name=3; Synonyms=PDE8A3; CC IsoId=O60658-3; Sequence=VSP_041675, VSP_041677; CC Name=4; Synonyms=PDE8A4; CC IsoId=O60658-4; Sequence=VSP_041674, VSP_041676; CC Name=5; Synonyms=PDE8A5; CC IsoId=O60658-5; Sequence=VSP_041678, VSP_041679; CC Name=6; CC IsoId=O60658-6; Sequence=VSP_046017; CC -!- TISSUE SPECIFICITY: Expressed in most tissues except thymus and CC peripheral blood leukocytes. Highest levels in testis, ovary, small CC intestine and colon. CC -!- DOMAIN: Composed of a C-terminal catalytic domain containing two CC putative divalent metal sites and an N-terminal regulatory domain. CC -!- PTM: Phosphorylated at Ser-359 by PKA under elevated cAMP conditions, CC this enhances catalytic activity. {ECO:0000269|PubMed:22673573}. CC -!- MISCELLANEOUS: [Isoform 3]: May be produced at very low levels due to a CC premature stop codon in the mRNA, leading to nonsense-mediated mRNA CC decay. {ECO:0000305}. CC -!- MISCELLANEOUS: [Isoform 4]: May be produced at very low levels due to a CC premature stop codon in the mRNA, leading to nonsense-mediated mRNA CC decay. {ECO:0000305}. CC -!- MISCELLANEOUS: [Isoform 5]: May be produced at very low levels due to a CC premature stop codon in the mRNA, leading to nonsense-mediated mRNA CC decay. {ECO:0000305}. CC -!- SIMILARITY: Belongs to the cyclic nucleotide phosphodiesterase family. CC PDE8 subfamily. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAL18612.1; Type=Erroneous translation; Note=Wrong choice of CDS.; Evidence={ECO:0000305}; CC Sequence=AAL18613.1; Type=Erroneous translation; Note=Wrong choice of CDS.; Evidence={ECO:0000305}; CC Sequence=AAL18614.1; Type=Erroneous translation; Note=Wrong choice of CDS.; Evidence={ECO:0000305}; CC Sequence=BAG54458.1; Type=Miscellaneous discrepancy; Note=Intron retention.; Evidence={ECO:0000305}; CC Sequence=EAX01967.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF388183; AAL18610.1; -; mRNA. DR EMBL; AF388184; AAL18611.1; -; mRNA. DR EMBL; AF388185; AAL18612.1; ALT_SEQ; mRNA. DR EMBL; AF388186; AAL18613.1; ALT_SEQ; mRNA. DR EMBL; AF388187; AAL18614.1; ALT_SEQ; mRNA. DR EMBL; AF332653; AAK57641.1; -; mRNA. DR EMBL; AK074280; -; NOT_ANNOTATED_CDS; mRNA. DR EMBL; AK127232; BAG54458.1; ALT_SEQ; mRNA. DR EMBL; AC027078; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC087468; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471101; EAX01967.1; ALT_SEQ; Genomic_DNA. DR EMBL; BC060762; AAH60762.1; -; mRNA. DR EMBL; BC075822; AAH75822.1; -; mRNA. DR EMBL; AF056490; AAC39763.1; -; mRNA. DR EMBL; AL109687; CAB52020.1; -; mRNA. DR EMBL; AL109778; CAB52432.1; -; mRNA. DR CCDS; CCDS10336.1; -. [O60658-1] DR CCDS; CCDS10337.1; -. [O60658-2] DR CCDS; CCDS58397.1; -. [O60658-6] DR PIR; JW0088; JW0088. DR RefSeq; NP_001230066.1; NM_001243137.1. [O60658-6] DR RefSeq; NP_002596.1; NM_002605.2. [O60658-1] DR RefSeq; NP_775656.1; NM_173454.1. [O60658-2] DR RefSeq; XP_016877800.1; XM_017022311.1. DR PDB; 3ECM; X-ray; 1.90 A; A=482-819. DR PDB; 3ECN; X-ray; 2.10 A; A/B=482-819. DR PDB; 7CWA; X-ray; 2.80 A; A=482-819. DR PDB; 7CWF; X-ray; 2.80 A; A=482-819. DR PDB; 7CWG; X-ray; 2.80 A; A=482-819. DR PDB; 7VSL; X-ray; 2.50 A; A=482-819. DR PDB; 7VTV; X-ray; 2.80 A; A=482-819. DR PDB; 7VTW; X-ray; 2.80 A; A=482-819. DR PDB; 7VTX; X-ray; 2.50 A; A=482-819. DR PDBsum; 3ECM; -. DR PDBsum; 3ECN; -. DR PDBsum; 7CWA; -. DR PDBsum; 7CWF; -. DR PDBsum; 7CWG; -. DR PDBsum; 7VSL; -. DR PDBsum; 7VTV; -. DR PDBsum; 7VTW; -. DR PDBsum; 7VTX; -. DR AlphaFoldDB; O60658; -. DR SMR; O60658; -. DR BioGRID; 111177; 24. DR IntAct; O60658; 9. DR STRING; 9606.ENSP00000378056; -. DR BindingDB; O60658; -. DR ChEMBL; CHEMBL4640; -. DR DrugBank; DB07954; 3-isobutyl-1-methyl-7H-xanthine. DR DrugBank; DB00201; Caffeine. DR DrugBank; DB09283; Trapidil. DR DrugCentral; O60658; -. DR GuidetoPHARMACOLOGY; 1307; -. DR iPTMnet; O60658; -. DR PhosphoSitePlus; O60658; -. DR SwissPalm; O60658; -. DR BioMuta; PDE8A; -. DR EPD; O60658; -. DR jPOST; O60658; -. DR MassIVE; O60658; -. DR MaxQB; O60658; -. DR PaxDb; 9606-ENSP00000311453; -. DR PeptideAtlas; O60658; -. DR ProteomicsDB; 40410; -. DR ProteomicsDB; 49499; -. [O60658-1] DR ProteomicsDB; 49500; -. [O60658-2] DR ProteomicsDB; 49501; -. [O60658-3] DR ProteomicsDB; 49502; -. [O60658-4] DR ProteomicsDB; 49503; -. [O60658-5] DR Pumba; O60658; -. DR Antibodypedia; 679; 317 antibodies from 33 providers. DR DNASU; 5151; -. DR Ensembl; ENST00000310298.8; ENSP00000311453.4; ENSG00000073417.15. [O60658-1] DR Ensembl; ENST00000339708.9; ENSP00000340679.5; ENSG00000073417.15. [O60658-2] DR Ensembl; ENST00000394553.6; ENSP00000378056.1; ENSG00000073417.15. [O60658-1] DR Ensembl; ENST00000478717.5; ENSP00000432309.1; ENSG00000073417.15. [O60658-4] DR Ensembl; ENST00000557957.5; ENSP00000453808.1; ENSG00000073417.15. [O60658-6] DR GeneID; 5151; -. DR KEGG; hsa:5151; -. DR MANE-Select; ENST00000394553.6; ENSP00000378056.1; NM_002605.3; NP_002596.1. DR UCSC; uc002blh.4; human. [O60658-1] DR AGR; HGNC:8793; -. DR CTD; 5151; -. DR DisGeNET; 5151; -. DR GeneCards; PDE8A; -. DR HGNC; HGNC:8793; PDE8A. DR HPA; ENSG00000073417; Low tissue specificity. DR MIM; 602972; gene. DR neXtProt; NX_O60658; -. DR OpenTargets; ENSG00000073417; -. DR PharmGKB; PA33141; -. DR VEuPathDB; HostDB:ENSG00000073417; -. DR eggNOG; KOG1229; Eukaryota. DR GeneTree; ENSGT00940000156422; -. DR HOGENOM; CLU_005940_4_2_1; -. DR InParanoid; O60658; -. DR OMA; QQCIEWA; -. DR OrthoDB; 5479253at2759; -. DR PhylomeDB; O60658; -. DR TreeFam; TF314638; -. DR BRENDA; 3.1.4.53; 2681. DR PathwayCommons; O60658; -. DR Reactome; R-HSA-418555; G alpha (s) signalling events. DR SignaLink; O60658; -. DR SIGNOR; O60658; -. DR UniPathway; UPA00762; UER00747. DR BioGRID-ORCS; 5151; 8 hits in 1166 CRISPR screens. DR ChiTaRS; PDE8A; human. DR EvolutionaryTrace; O60658; -. DR GeneWiki; PDE8A; -. DR GenomeRNAi; 5151; -. DR Pharos; O60658; Tclin. DR PRO; PR:O60658; -. DR Proteomes; UP000005640; Chromosome 15. DR RNAct; O60658; Protein. DR Bgee; ENSG00000073417; Expressed in corpus callosum and 211 other cell types or tissues. DR ExpressionAtlas; O60658; baseline and differential. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0004115; F:3',5'-cyclic-AMP phosphodiesterase activity; IMP:UniProtKB. DR GO; GO:0047555; F:3',5'-cyclic-GMP phosphodiesterase activity; IDA:UniProtKB. DR GO; GO:0019900; F:kinase binding; IPI:UniProtKB. DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW. DR GO; GO:0030295; F:protein kinase activator activity; IMP:UniProtKB. DR GO; GO:0006198; P:cAMP catabolic process; IEA:UniProtKB-UniPathway. DR GO; GO:0071364; P:cellular response to epidermal growth factor stimulus; IMP:UniProtKB. DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IMP:UniProtKB. DR GO; GO:0006355; P:regulation of DNA-templated transcription; IEA:InterPro. DR GO; GO:0007165; P:signal transduction; IBA:GO_Central. DR CDD; cd00077; HDc; 1. DR CDD; cd00130; PAS; 1. DR Gene3D; 3.40.50.2300; -; 1. DR Gene3D; 1.10.1300.10; 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain; 1. DR Gene3D; 3.30.450.20; PAS domain; 1. DR InterPro; IPR003607; HD/PDEase_dom. DR InterPro; IPR000014; PAS. DR InterPro; IPR035965; PAS-like_dom_sf. DR InterPro; IPR013767; PAS_fold. DR InterPro; IPR023088; PDEase. DR InterPro; IPR002073; PDEase_catalytic_dom. DR InterPro; IPR036971; PDEase_catalytic_dom_sf. DR InterPro; IPR023174; PDEase_CS. DR NCBIfam; TIGR00229; sensory_box; 1. DR PANTHER; PTHR11347; CYCLIC NUCLEOTIDE PHOSPHODIESTERASE; 1. DR PANTHER; PTHR11347:SF85; HIGH AFFINITY CAMP-SPECIFIC AND IBMX-INSENSITIVE 3',5'-CYCLIC PHOSPHODIESTERASE 8A; 1. DR Pfam; PF00989; PAS; 1. DR Pfam; PF00233; PDEase_I; 1. DR PRINTS; PR00387; PDIESTERASE1. DR SMART; SM00471; HDc; 1. DR SUPFAM; SSF109604; HD-domain/PDEase-like; 1. DR SUPFAM; SSF55785; PYP-like sensor domain (PAS domain); 1. DR PROSITE; PS50112; PAS; 1. DR PROSITE; PS00126; PDEASE_I_1; 1. DR PROSITE; PS51845; PDEASE_I_2; 1. DR Genevisible; O60658; HS. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; cAMP; Hydrolase; Metal-binding; KW Phosphoprotein; Reference proteome. FT CHAIN 1..829 FT /note="High affinity cAMP-specific and IBMX-insensitive FT 3',5'-cyclic phosphodiesterase 8A" FT /id="PRO_0000198838" FT DOMAIN 213..283 FT /note="PAS" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00140" FT DOMAIN 287..329 FT /note="PAC" FT DOMAIN 480..820 FT /note="PDEase" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01192" FT REGION 16..46 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 341..360 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 454..461 FT /note="Involved in RAF1-binding" FT /evidence="ECO:0000269|PubMed:23509299" FT COMPBIAS 346..360 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 556 FT /note="Proton donor" FT /evidence="ECO:0000250|UniProtKB:O76083" FT BINDING 560 FT /ligand="a divalent metal cation" FT /ligand_id="ChEBI:CHEBI:60240" FT /ligand_label="1" FT /evidence="ECO:0000269|PubMed:18983167, FT ECO:0007744|PDB:3ECM, ECO:0007744|PDB:3ECN" FT BINDING 596 FT /ligand="a divalent metal cation" FT /ligand_id="ChEBI:CHEBI:60240" FT /ligand_label="1" FT /evidence="ECO:0000269|PubMed:18983167, FT ECO:0007744|PDB:3ECM, ECO:0007744|PDB:3ECN" FT BINDING 597 FT /ligand="a divalent metal cation" FT /ligand_id="ChEBI:CHEBI:60240" FT /ligand_label="1" FT /evidence="ECO:0000269|PubMed:18983167, FT ECO:0007744|PDB:3ECM, ECO:0007744|PDB:3ECN" FT BINDING 597 FT /ligand="a divalent metal cation" FT /ligand_id="ChEBI:CHEBI:60240" FT /ligand_label="2" FT /evidence="ECO:0000269|PubMed:18983167, FT ECO:0007744|PDB:3ECM, ECO:0007744|PDB:3ECN" FT BINDING 726 FT /ligand="a divalent metal cation" FT /ligand_id="ChEBI:CHEBI:60240" FT /ligand_label="1" FT /evidence="ECO:0000269|PubMed:18983167, FT ECO:0007744|PDB:3ECM, ECO:0007744|PDB:3ECN" FT MOD_RES 20 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18691976, FT ECO:0007744|PubMed:23186163" FT MOD_RES 359 FT /note="Phosphoserine; by PKA" FT /evidence="ECO:0000269|PubMed:22673573" FT MOD_RES 386 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:O88502" FT MOD_RES 457 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:18691976, ECO:0007744|PubMed:20068231, FT ECO:0007744|PubMed:23186163" FT MOD_RES 461 FT /note="Phosphotyrosine" FT /evidence="ECO:0000250|UniProtKB:O88502" FT VAR_SEQ 1..72 FT /note="Missing (in isoform 6)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_046017" FT VAR_SEQ 212..228 FT /note="RACNSVFTALENSEDAI -> SMQILHLKQQWAISQVN (in isoform FT 4)" FT /evidence="ECO:0000303|PubMed:11738832" FT /id="VSP_041674" FT VAR_SEQ 213..231 FT /note="ACNSVFTALENSEDAIEIT -> SGKEFTMQKRKTEIIYNKM (in FT isoform 3)" FT /evidence="ECO:0000303|PubMed:11738832" FT /id="VSP_041675" FT VAR_SEQ 229..829 FT /note="Missing (in isoform 4)" FT /evidence="ECO:0000303|PubMed:11738832" FT /id="VSP_041676" FT VAR_SEQ 232..829 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:11738832" FT /id="VSP_041677" FT VAR_SEQ 239..284 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:11738832, FT ECO:0000303|PubMed:9618252" FT /id="VSP_004597" FT VAR_SEQ 239..272 FT /note="YANPAFETTMGYQSGELIGKELGEVPINEKKADL -> PCCSSSWFGAAHIP FT SSAPVEVGVGLLPSWSLRRT (in isoform 5)" FT /evidence="ECO:0000303|PubMed:11738832" FT /id="VSP_041678" FT VAR_SEQ 273..829 FT /note="Missing (in isoform 5)" FT /evidence="ECO:0000303|PubMed:11738832" FT /id="VSP_041679" FT VARIANT 112 FT /note="E -> G (in dbSNP:rs17855018)" FT /evidence="ECO:0000269|PubMed:14702039, FT ECO:0000269|PubMed:15489334" FT /id="VAR_069109" FT MUTAGEN 454..455 FT /note="RR->AA: Reduces interaction with RAF1; when FT associated with A-460 and A-461." FT /evidence="ECO:0000269|PubMed:23509299" FT MUTAGEN 460..461 FT /note="EY->AA: Reduces interaction with RAF1; when FT associated with A-454 and A-455." FT /evidence="ECO:0000269|PubMed:23509299" FT MUTAGEN 748 FT /note="Y->F: Increases sensitivity to several nonselective FT or family selective PDE inhibitors." FT /evidence="ECO:0000269|PubMed:18983167" FT CONFLICT 55 FT /note="L -> V (in Ref. 2; AAK57641)" FT /evidence="ECO:0000305" FT CONFLICT 344 FT /note="H -> R (in Ref. 2; AAK57641 and 7; AAC39763)" FT /evidence="ECO:0000305" FT CONFLICT 399 FT /note="I -> V (in Ref. 2; AAK57641 and 7; AAC39763)" FT /evidence="ECO:0000305" FT HELIX 486..491 FT /evidence="ECO:0007829|PDB:3ECM" FT TURN 492..496 FT /evidence="ECO:0007829|PDB:3ECM" FT STRAND 497..499 FT /evidence="ECO:0007829|PDB:3ECM" FT HELIX 502..508 FT /evidence="ECO:0007829|PDB:3ECM" FT HELIX 513..524 FT /evidence="ECO:0007829|PDB:3ECM" FT HELIX 528..531 FT /evidence="ECO:0007829|PDB:3ECM" FT HELIX 535..547 FT /evidence="ECO:0007829|PDB:3ECM" FT STRAND 553..557 FT /evidence="ECO:0007829|PDB:3ECM" FT HELIX 558..572 FT /evidence="ECO:0007829|PDB:3ECM" FT HELIX 575..578 FT /evidence="ECO:0007829|PDB:3ECM" FT HELIX 583..595 FT /evidence="ECO:0007829|PDB:3ECM" FT TURN 596..599 FT /evidence="ECO:0007829|PDB:3ECM" FT HELIX 605..610 FT /evidence="ECO:0007829|PDB:3ECM" FT HELIX 614..618 FT /evidence="ECO:0007829|PDB:3ECM" FT TURN 619..621 FT /evidence="ECO:0007829|PDB:3ECM" FT HELIX 624..638 FT /evidence="ECO:0007829|PDB:3ECM" FT TURN 641..643 FT /evidence="ECO:0007829|PDB:3ECM" FT TURN 645..648 FT /evidence="ECO:0007829|PDB:3ECM" FT HELIX 651..666 FT /evidence="ECO:0007829|PDB:3ECM" FT HELIX 670..672 FT /evidence="ECO:0007829|PDB:3ECM" FT HELIX 673..683 FT /evidence="ECO:0007829|PDB:3ECM" FT HELIX 685..691 FT /evidence="ECO:0007829|PDB:3ECM" FT HELIX 692..694 FT /evidence="ECO:0007829|PDB:3ECN" FT HELIX 698..708 FT /evidence="ECO:0007829|PDB:3ECM" FT HELIX 711..726 FT /evidence="ECO:0007829|PDB:3ECM" FT HELIX 729..731 FT /evidence="ECO:0007829|PDB:3ECM" FT HELIX 734..758 FT /evidence="ECO:0007829|PDB:3ECM" FT TURN 769..771 FT /evidence="ECO:0007829|PDB:3ECM" FT HELIX 774..784 FT /evidence="ECO:0007829|PDB:3ECM" FT HELIX 786..797 FT /evidence="ECO:0007829|PDB:3ECM" FT HELIX 800..814 FT /evidence="ECO:0007829|PDB:3ECM" SQ SEQUENCE 829 AA; 93304 MW; 99BD05EA185A42CD CRC64; MGCAPSIHIS ERLVAEDAPS PAAPPLSSGG PRLPQGQKTA ALPRTRGAGL LESELRDGSG KKVAVADVQF GPMRFHQDQL QVLLVFTKED NQCNGFCRAC EKAGFKCTVT KEAQAVLACF LDKHHDIIII DHRNPRQLDA EALCRSIRSS KLSENTVIVG VVRRVDREEL SVMPFISAGF TRRYVENPNI MACYNELLQL EFGEVRSQLK LRACNSVFTA LENSEDAIEI TSEDRFIQYA NPAFETTMGY QSGELIGKEL GEVPINEKKA DLLDTINSCI RIGKEWQGIY YAKKKNGDNI QQNVKIIPVI GQGGKIRHYV SIIRVCNGNN KAEKISECVQ SDTHTDNQTG KHKDRRKGSL DVKAVASRAT EVSSQRRHSS MARIHSMTIE APITKVINII NAAQESSPMP VTEALDRVLE ILRTTELYSP QFGAKDDDPH ANDLVGGLMS DGLRRLSGNE YVLSTKNTQM VSSNIITPIS LDDVPPRIAR AMENEEYWDF DIFELEAATH NRPLIYLGLK MFARFGICEF LHCSESTLRS WLQIIEANYH SSNPYHNSTH SADVLHATAY FLSKERIKET LDPIDEVAAL IAATIHDVDH PGRTNSFLCN AGSELAILYN DTAVLESHHA ALAFQLTTGD DKCNIFKNME RNDYRTLRQG IIDMVLATEM TKHFEHVNKF VNSINKPLAT LEENGETDKN QEVINTMLRT PENRTLIKRM LIKCADVSNP CRPLQYCIEW AARISEEYFS QTDEEKQQGL PVVMPVFDRN TCSIPKSQIS FIDYFITDMF DAWDAFVDLP DLMQHLDNNF KYWKGLDEMK LRNLRPPPE //