ID   PDE8A_MOUSE             Reviewed;         823 AA.
AC   O88502; Q059P6;
DT   15-JUL-1999, integrated into UniProtKB/Swiss-Prot.
DT   01-NOV-1998, sequence version 1.
DT   27-MAR-2024, entry version 182.
DE   RecName: Full=High affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8A;
DE            Short=MmPDE8;
DE            EC=3.1.4.53 {ECO:0000269|PubMed:9671792};
GN   Name=Pde8a; Synonyms=Pde8;
OS   Mus musculus (Mouse).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC   Murinae; Mus; Mus.
OX   NCBI_TaxID=10090;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA], CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL
RP   PROPERTIES, TISSUE SPECIFICITY, AND DEVELOPMENTAL STAGE.
RC   TISSUE=Testis;
RX   PubMed=9671792; DOI=10.1073/pnas.95.15.8991;
RA   Soderling S.H., Bayuga S.J., Beavo J.A.;
RT   "Cloning and characterization of a cAMP-specific cyclic nucleotide
RT   phosphodiesterase.";
RL   Proc. Natl. Acad. Sci. U.S.A. 95:8991-8996(1998).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Brain;
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   [3]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-456, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=19144319; DOI=10.1016/j.immuni.2008.11.006;
RA   Trost M., English L., Lemieux S., Courcelles M., Desjardins M.,
RA   Thibault P.;
RT   "The phagosomal proteome in interferon-gamma-activated macrophages.";
RL   Immunity 30:143-154(2009).
RN   [4]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-382 AND SER-452, AND
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Brain, Brown adipose tissue, Heart, Kidney, Lung, Spleen, and
RC   Testis;
RX   PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA   Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA   Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT   "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL   Cell 143:1174-1189(2010).
RN   [5]
RP   DISRUPTION PHENOTYPE.
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).
CC   -!- FUNCTION: Hydrolyzes the second messenger cAMP, which is a key
CC       regulator of many important physiological processes. May be involved in
CC       maintaining basal levels of the cyclic nucleotide and/or in the cAMP
CC       regulation of germ cell development. Binding to RAF1 reduces RAF1 'Ser-
CC       259' inhibitory-phosphorylation and stimulates RAF1-dependent EGF-
CC       activated ERK-signaling. Protects against cell death induced by
CC       hydrogen peroxide and staurosporine. {ECO:0000250|UniProtKB:O60658}.
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:0000269|PubMed:9671792};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:25278;
CC         Evidence={ECO:0000269|PubMed:9671792};
CC   -!- COFACTOR:
CC       Name=a divalent metal cation; Xref=ChEBI:CHEBI:60240;
CC         Evidence={ECO:0000250};
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:0000250};
CC   -!- ACTIVITY REGULATION: Inhibited by dipyridimole. Insensitive to
CC       selective PDE inhibitor rolipram and to the non-selective inhibitor,
CC       IBMX.
CC   -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC       Kinetic parameters:
CC         KM=0.15 uM for cAMP {ECO:0000269|PubMed:9671792};
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:0000250|UniProtKB:O60658}.
CC   -!- TISSUE SPECIFICITY: Expressed in multiple tissues, with highest levels
CC       in testis, followed by liver, heart, skeletal muscle, and kidney. In
CC       the testis, expressed specifically in the seminiferous tubules, in
CC       postmitotic pachytene spermatocytes (PubMed:9671792). Low expression,
CC       if any, in lung, smooth muscle, pancreas, thyroid, thymus, submaxillary
CC       gland, spleen, prostate, epididymus, uterus (PubMed:9671792).
CC       {ECO:0000269|PubMed:9671792}.
CC   -!- DEVELOPMENTAL STAGE: Expressed in embryos at 7 dpc. Not detected at
CC       later stages, including 11, 15 and 17 dpc (PubMed:9671792). In the
CC       testis, expression restricted to middle and late pachytene
CC       spermatocytes (PubMed:9671792). {ECO:0000269|PubMed:9671792}.
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-355 by PKA under elevated cAMP conditions,
CC       this enhances catalytic activity. {ECO:0000250}.
CC   -!- DISRUPTION PHENOTYPE: Reduced phosphorylation of Mapk1/Erk2 and
CC       Mapk3/Erk1, both basal levels and those induced by EGF treatment.
CC       {ECO:0000269|PubMed:23509299}.
CC   -!- SIMILARITY: Belongs to the cyclic nucleotide phosphodiesterase family.
CC       PDE8 subfamily. {ECO:0000305}.
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DR   EMBL; AF067806; AAC40194.1; -; mRNA.
DR   EMBL; BC125578; AAI25579.1; -; mRNA.
DR   EMBL; BC132145; AAI32146.1; -; mRNA.
DR   CCDS; CCDS40005.1; -.
DR   RefSeq; NP_032829.1; NM_008803.2.
DR   AlphaFoldDB; O88502; -.
DR   SMR; O88502; -.
DR   BioGRID; 202082; 12.
DR   STRING; 10090.ENSMUSP00000026672; -.
DR   iPTMnet; O88502; -.
DR   PhosphoSitePlus; O88502; -.
DR   jPOST; O88502; -.
DR   MaxQB; O88502; -.
DR   PaxDb; 10090-ENSMUSP00000026672; -.
DR   PeptideAtlas; O88502; -.
DR   ProteomicsDB; 294042; -.
DR   Antibodypedia; 679; 317 antibodies from 33 providers.
DR   DNASU; 18584; -.
DR   Ensembl; ENSMUST00000026672.8; ENSMUSP00000026672.8; ENSMUSG00000025584.18.
DR   GeneID; 18584; -.
DR   KEGG; mmu:18584; -.
DR   UCSC; uc009ibt.1; mouse.
DR   AGR; MGI:1277116; -.
DR   CTD; 5151; -.
DR   MGI; MGI:1277116; Pde8a.
DR   VEuPathDB; HostDB:ENSMUSG00000025584; -.
DR   eggNOG; KOG1229; Eukaryota.
DR   GeneTree; ENSGT00940000156422; -.
DR   HOGENOM; CLU_005940_4_2_1; -.
DR   InParanoid; O88502; -.
DR   OMA; QQCIEWA; -.
DR   OrthoDB; 5479253at2759; -.
DR   PhylomeDB; O88502; -.
DR   TreeFam; TF314638; -.
DR   BRENDA; 3.1.4.53; 3474.
DR   Reactome; R-MMU-418555; G alpha (s) signalling events.
DR   UniPathway; UPA00762; UER00747.
DR   BioGRID-ORCS; 18584; 1 hit in 77 CRISPR screens.
DR   ChiTaRS; Pde8a; mouse.
DR   PRO; PR:O88502; -.
DR   Proteomes; UP000000589; Chromosome 7.
DR   RNAct; O88502; Protein.
DR   Bgee; ENSMUSG00000025584; Expressed in seminiferous tubule of testis and 228 other cell types or tissues.
DR   GO; GO:0004115; F:3',5'-cyclic-AMP phosphodiesterase activity; IDA:MGI.
DR   GO; GO:0047555; F:3',5'-cyclic-GMP phosphodiesterase activity; ISO:MGI.
DR   GO; GO:0019900; F:kinase binding; ISO:MGI.
DR   GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR   GO; GO:0030295; F:protein kinase activator activity; ISO:MGI.
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; O88502; MM.
PE   1: Evidence at protein level;
KW   cAMP; Hydrolase; Metal-binding; Phosphoprotein; Reference proteome.
FT   CHAIN           1..823
FT                   /note="High affinity cAMP-specific and IBMX-insensitive
FT                   3',5'-cyclic phosphodiesterase 8A"
FT                   /id="PRO_0000198839"
FT   DOMAIN          209..280
FT                   /note="PAS"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00140"
FT   DOMAIN          283..325
FT                   /note="PAC"
FT   DOMAIN          475..814
FT                   /note="PDEase"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01192"
FT   REGION          1..55
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          338..373
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        343..360
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   ACT_SITE        551
FT                   /note="Proton donor"
FT                   /evidence="ECO:0000250|UniProtKB:O76083"
FT   BINDING         555
FT                   /ligand="a divalent metal cation"
FT                   /ligand_id="ChEBI:CHEBI:60240"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000250|UniProtKB:O60658"
FT   BINDING         591
FT                   /ligand="a divalent metal cation"
FT                   /ligand_id="ChEBI:CHEBI:60240"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000250|UniProtKB:O60658"
FT   BINDING         592
FT                   /ligand="a divalent metal cation"
FT                   /ligand_id="ChEBI:CHEBI:60240"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000250|UniProtKB:O60658"
FT   BINDING         592
FT                   /ligand="a divalent metal cation"
FT                   /ligand_id="ChEBI:CHEBI:60240"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000250|UniProtKB:O60658"
FT   BINDING         720
FT                   /ligand="a divalent metal cation"
FT                   /ligand_id="ChEBI:CHEBI:60240"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000250|UniProtKB:O60658"
FT   MOD_RES         355
FT                   /note="Phosphoserine; by PKA"
FT                   /evidence="ECO:0000250|UniProtKB:O60658"
FT   MOD_RES         382
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:21183079"
FT   MOD_RES         452
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:21183079"
FT   MOD_RES         456
FT                   /note="Phosphotyrosine"
FT                   /evidence="ECO:0007744|PubMed:19144319"
SQ   SEQUENCE   823 AA;  93171 MW;  7FD9BE4BAEB9BCF2 CRC64;
     MGCAPSIHTS ENRTFSHSDG EDEDVDVDVP GPAPRSIQRW STAPGLVEPQ PRDNGASKVS
     VADVQFGPMR FHQDQLQVLL VFTKEDSQCN GFHRACEKAG FKCTVTKEVQ TVLTCFQDKL
     HDIIIIDHRY PRQMDAETLC RSIRSSKFSE NTVIVGVVRR VDKEESSLMP FLAAGFTRRF
     IENPNVMACY NELLQLACGE VRSQLKLRAC NSVFTALEKS QEAIEITSED HIIQYANPAF
     ESTMGYQSGE LIGKELAQVP INEKKGDLLD AINSCVTVDK EWQGVYHTQK KNGDNIQQNV
     KIIPVIGQGG KIRHYVSIIR VCNGNNKVET TTECVQTDSQ TDNQAGKHKD RRKHSMDAKA
     VSSRTSDVSS QRRHSSLARI HSMMIEAPIT KVINIINAAQ ENSPVPVTEA LNRVLDILRT
     TELYSPQFNA QDDPHATDLV GGLMSDGLRR FSGNEYILAT KNLPPLSNNL ATPVSLHDVP
     PRIALAIENE EQWDFDIFEL EVATQNRPLI YLGLKTFARF GMCEFLQCSE TTLRSWFQMI
     ESNYHSSNPY HNSTHAADVL HATAYFLSRD KIKETLDRID EVAALIAATV HDVDHPGRTN
     SFLCNAGNQL AVLYNDTAVL ESHHVALAFQ LTLENDQCNI FKQMERNDYR TLRQSIIDMV
     LATEMTKHFE HVNKFINSIN KPLTAQESEE PDRSLEDIKA MLKTPESRAL IKRMMIKCAD
     VSNPCRPLEH CIEWAARISE EYFSQTDEEK QLDLPVVMPV FDRNTCSIPK SQISFIDYFI
     TDMFDAWDAF VDLPNLMQHL DDNFRYWKGL DEKKLRSLRP PPE
//