NSMA2_RAT
ID NSMA2_RAT Reviewed; 655 AA.
AC O35049;
DT 30-AUG-2005, integrated into UniProtKB/Swiss-Prot.
DT 30-AUG-2005, sequence version 2.
DT 03-AUG-2022, entry version 131.
DE RecName: Full=Sphingomyelin phosphodiesterase 3 {ECO:0000305};
DE EC=3.1.4.12 {ECO:0000269|PubMed:15059969};
DE AltName: Full=Confluent 3Y1 cell-associated protein 1;
DE AltName: Full=Neutral sphingomyelinase 2;
DE Short=nSMase-2;
DE Short=nSMase2;
DE AltName: Full=Neutral sphingomyelinase II;
GN Name=Smpd3 {ECO:0000312|RGD:619754}; Synonyms=Cca1;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=9218439; DOI=10.1074/jbc.272.29.18082;
RA Hayashi Y., Kiyono T., Fujita M., Ishibashi M.;
RT "cca1 is required for formation of growth-arrested confluent monolayer of
RT rat 3Y1 cells.";
RL J. Biol. Chem. 272:18082-18086(1997).
RN [2]
RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=10823942; DOI=10.1073/pnas.97.11.5895;
RA Hofmann K., Tomiuk S., Wolff G., Stoffel W.;
RT "Cloning and characterization of the mammalian brain-specific, Mg2+-
RT dependent neutral sphingomyelinase.";
RL Proc. Natl. Acad. Sci. U.S.A. 97:5895-5900(2000).
RN [3]
RP FUNCTION, ENZYME ACTIVITY, COFACTOR, AND SUBCELLULAR LOCATION.
RX PubMed=15059969; DOI=10.1096/fj.03-0875fje;
RA Karakashian A.A., Giltiay N.V., Smith G.M., Nikolova-Karakashian M.N.;
RT "Expression of neutral sphingomyelinase-2 (NSMase-2) in primary rat
RT hepatocytes modulates IL-beta-induced JNK activation.";
RL FASEB J. 18:968-970(2004).
RN [4]
RP FUNCTION.
RX PubMed=14720208; DOI=10.1046/j.1471-4159.2003.02165.x;
RA Won J.-S., Im Y.-B., Khan M., Singh A.K., Singh I.;
RT "The role of neutral sphingomyelinase produced ceramide in
RT lipopolysaccharide-mediated expression of inducible nitric oxide
RT synthase.";
RL J. Neurochem. 88:583-593(2004).
RN [5]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-289, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22673903; DOI=10.1038/ncomms1871;
RA Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C.,
RA Olsen J.V.;
RT "Quantitative maps of protein phosphorylation sites across 14 different rat
RT organs and tissues.";
RL Nat. Commun. 3:876-876(2012).
CC -!- FUNCTION: Catalyzes the hydrolysis of sphingomyelin to form ceramide
CC and phosphocholine. Ceramide mediates numerous cellular functions, such
CC as apoptosis and growth arrest, and is capable of regulating these 2
CC cellular events independently. Also hydrolyzes
CC sphingosylphosphocholine. Binds to anionic phospholipids (APLs) such as
CC phosphatidylserine (PS) and phosphatidic acid (PA) that modulate
CC enzymatic activity and subcellular location (By similarity). Regulates
CC the cell cycle by acting as a growth suppressor in confluent cells.
CC Acts as a regulator of postnatal development and participates in bone
CC and dentin mineralization. May be involved in IL-1-beta-induced JNK
CC activation in hepatocytes. May act as a mediator in transcriptional
CC regulation of NOS2/iNOS via the NF-kappa-B activation under
CC inflammatory conditions. {ECO:0000250|UniProtKB:Q9JJY3,
CC ECO:0000269|PubMed:14720208, ECO:0000269|PubMed:15059969}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a sphingomyelin + H2O = an N-acylsphing-4-enine + H(+) +
CC phosphocholine; Xref=Rhea:RHEA:19253, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:17636, ChEBI:CHEBI:52639,
CC ChEBI:CHEBI:295975; EC=3.1.4.12;
CC Evidence={ECO:0000269|PubMed:15059969};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:19254;
CC Evidence={ECO:0000250|UniProtKB:Q9NY59};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + N-(15Z-tetracosenoyl)sphing-4-enine-1-phosphocholine =
CC H(+) + N-(15Z-tetracosenoyl)-sphing-4-enine + phosphocholine;
CC Xref=Rhea:RHEA:45320, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:74450, ChEBI:CHEBI:74535, ChEBI:CHEBI:295975;
CC Evidence={ECO:0000250|UniProtKB:Q9NY59};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:45321;
CC Evidence={ECO:0000250|UniProtKB:Q9NY59};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + N-(tetracosanoyl)-sphing-4-enine-1-phosphocholine = H(+)
CC + N-tetracosanoyl-sphing-4-enine + phosphocholine;
CC Xref=Rhea:RHEA:45324, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:72965, ChEBI:CHEBI:83360, ChEBI:CHEBI:295975;
CC Evidence={ECO:0000250|UniProtKB:Q9NY59};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:45325;
CC Evidence={ECO:0000250|UniProtKB:Q9NY59};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=an N-(acyl)-sphingosylphosphocholine + H2O = an N-acyl-
CC sphingoid base + H(+) + phosphocholine; Xref=Rhea:RHEA:45300,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:64583,
CC ChEBI:CHEBI:83273, ChEBI:CHEBI:295975;
CC Evidence={ECO:0000250|UniProtKB:Q9NY59};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:45301;
CC Evidence={ECO:0000250|UniProtKB:Q9NY59};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=1-hexadecanoyl-sn-glycero-3-phosphocholine + H2O = 1-
CC hexadecanoyl-sn-glycerol + H(+) + phosphocholine;
CC Xref=Rhea:RHEA:41119, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:72998, ChEBI:CHEBI:75542, ChEBI:CHEBI:295975;
CC Evidence={ECO:0000250|UniProtKB:Q9NY59};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:41120;
CC Evidence={ECO:0000250|UniProtKB:Q9NY59};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=1-O-octadecyl-sn-glycero-3-phosphocholine + H2O = 1-O-
CC octadecyl-sn-glycerol + H(+) + phosphocholine; Xref=Rhea:RHEA:39923,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:74001,
CC ChEBI:CHEBI:75216, ChEBI:CHEBI:295975;
CC Evidence={ECO:0000250|UniProtKB:Q9NY59};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:39924;
CC Evidence={ECO:0000250|UniProtKB:Q9NY59};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a sphingosylphosphocholine + H2O = a sphingoid base + H(+) +
CC phosphocholine; Xref=Rhea:RHEA:45296, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:84410, ChEBI:CHEBI:85171,
CC ChEBI:CHEBI:295975; Evidence={ECO:0000250|UniProtKB:Q9NY59};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:45297;
CC Evidence={ECO:0000250|UniProtKB:Q9NY59};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + N-(hexadecanoyl)-sphing-4-enine-1-phosphocholine = H(+)
CC + N-hexadecanoylsphing-4-enine + phosphocholine;
CC Xref=Rhea:RHEA:45644, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:72959, ChEBI:CHEBI:78646, ChEBI:CHEBI:295975;
CC Evidence={ECO:0000250|UniProtKB:Q9JJY3};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:45645;
CC Evidence={ECO:0000250|UniProtKB:Q9JJY3};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000269|PubMed:15059969};
CC -!- ACTIVITY REGULATION: Inhibited by nSMase inhibitor GW4869. Binding of
CC anionic phospholipids (APLs) such as phosphatidylserine (PS) and
CC phosphatidic acid (PA) increases enzymatic activity.
CC {ECO:0000250|UniProtKB:Q9JJY3}.
CC -!- PATHWAY: Lipid metabolism; sphingolipid metabolism.
CC {ECO:0000269|PubMed:15059969}.
CC -!- SUBCELLULAR LOCATION: Golgi apparatus membrane
CC {ECO:0000269|PubMed:10823942}; Lipid-anchor
CC {ECO:0000269|PubMed:10823942}. Cell membrane
CC {ECO:0000269|PubMed:15059969}; Lipid-anchor
CC {ECO:0000269|PubMed:15059969}. Note=May localize to detergent-resistant
CC subdomains of Golgi membranes of hypothalamic neurosecretory neurons
CC (PubMed:10823942).
CC -!- TISSUE SPECIFICITY: In brain sections, it is restricted to neurons and
CC especially prominent in large cells, including Purkinje cells,
CC pyramidal cells, neurons of the dentate gyrus granular layer, and
CC neurons in the pontine nuclei. Also present in the hypothalamic nuclei,
CC neurons in the piriform cortex, and nuclei of the brainstem (at protein
CC level). Mainly expressed in brain and jejunum. Weakly or not expressed
CC in heart, spleen, lung, liver, kidney and testis.
CC {ECO:0000269|PubMed:10823942}.
CC -!- PTM: Palmitoylated, palmitoylation-deficient proteins are targeted for
CC lysosomal degradation. {ECO:0000250}.
CC -!- SIMILARITY: Belongs to the neutral sphingomyelinase family.
CC {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAA22932.1; Type=Frameshift; Evidence={ECO:0000305};
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DR EMBL; AB000215; BAA22932.1; ALT_FRAME; mRNA.
DR PIR; T00011; T00011.
DR RefSeq; NP_446057.1; NM_053605.1.
DR AlphaFoldDB; O35049; -.
DR SMR; O35049; -.
DR BioGRID; 250193; 1.
DR STRING; 10116.ENSRNOP00000000274; -.
DR BindingDB; O35049; -.
DR ChEMBL; CHEMBL4523130; -.
DR iPTMnet; O35049; -.
DR PhosphoSitePlus; O35049; -.
DR jPOST; O35049; -.
DR PaxDb; O35049; -.
DR PRIDE; O35049; -.
DR GeneID; 94338; -.
DR KEGG; rno:94338; -.
DR UCSC; RGD:619754; rat.
DR CTD; 55512; -.
DR RGD; 619754; Smpd3.
DR eggNOG; ENOG502QVS2; Eukaryota.
DR InParanoid; O35049; -.
DR OrthoDB; 455705at2759; -.
DR PhylomeDB; O35049; -.
DR Reactome; R-RNO-1660662; Glycosphingolipid metabolism.
DR Reactome; R-RNO-5626978; TNFR1-mediated ceramide production.
DR SABIO-RK; O35049; -.
DR UniPathway; UPA00222; -.
DR PRO; PR:O35049; -.
DR Proteomes; UP000002494; Unplaced.
DR GO; GO:0005737; C:cytoplasm; IDA:RGD.
DR GO; GO:0005576; C:extracellular region; IEA:InterPro.
DR GO; GO:0005794; C:Golgi apparatus; ISO:RGD.
DR GO; GO:0000137; C:Golgi cis cisterna; ISO:RGD.
DR GO; GO:0000139; C:Golgi membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0016020; C:membrane; IDA:RGD.
DR GO; GO:0005886; C:plasma membrane; ISS:UniProtKB.
DR GO; GO:0042802; F:identical protein binding; ISO:RGD.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0061751; F:neutral sphingomyelin phosphodiesterase activity; ISO:RGD.
DR GO; GO:0070300; F:phosphatidic acid binding; ISS:UniProtKB.
DR GO; GO:0001786; F:phosphatidylserine binding; ISS:UniProtKB.
DR GO; GO:0004620; F:phospholipase activity; IBA:GO_Central.
DR GO; GO:0008081; F:phosphoric diester hydrolase activity; ISO:RGD.
DR GO; GO:0004767; F:sphingomyelin phosphodiesterase activity; ISS:UniProtKB.
DR GO; GO:0007568; P:aging; IEP:RGD.
DR GO; GO:0014824; P:artery smooth muscle contraction; IMP:RGD.
DR GO; GO:0030509; P:BMP signaling pathway; ISO:RGD.
DR GO; GO:0060348; P:bone development; ISO:RGD.
DR GO; GO:0098868; P:bone growth; ISO:RGD.
DR GO; GO:0030282; P:bone mineralization; ISO:RGD.
DR GO; GO:0051216; P:cartilage development; ISO:RGD.
DR GO; GO:0070301; P:cellular response to hydrogen peroxide; ISO:RGD.
DR GO; GO:0071347; P:cellular response to interleukin-1; IEP:RGD.
DR GO; GO:0071286; P:cellular response to magnesium ion; ISO:RGD.
DR GO; GO:0140052; P:cellular response to oxidised low-density lipoprotein particle stimulus; ISO:RGD.
DR GO; GO:1901653; P:cellular response to peptide; ISO:RGD.
DR GO; GO:0034614; P:cellular response to reactive oxygen species; ISO:RGD.
DR GO; GO:0071461; P:cellular response to redox state; ISO:RGD.
DR GO; GO:0071356; P:cellular response to tumor necrosis factor; ISO:RGD.
DR GO; GO:0006672; P:ceramide metabolic process; ISO:RGD.
DR GO; GO:0002063; P:chondrocyte development; ISO:RGD.
DR GO; GO:0003433; P:chondrocyte development involved in endochondral bone morphogenesis; ISO:RGD.
DR GO; GO:0032963; P:collagen metabolic process; ISO:RGD.
DR GO; GO:0097187; P:dentinogenesis; ISO:RGD.
DR GO; GO:0071897; P:DNA biosynthetic process; ISO:RGD.
DR GO; GO:0090494; P:dopamine uptake; IMP:RGD.
DR GO; GO:0001958; P:endochondral ossification; ISO:RGD.
DR GO; GO:0085029; P:extracellular matrix assembly; ISO:RGD.
DR GO; GO:0070314; P:G1 to G0 transition; ISO:RGD.
DR GO; GO:0002244; P:hematopoietic progenitor cell differentiation; ISO:RGD.
DR GO; GO:0048286; P:lung alveolus development; ISO:RGD.
DR GO; GO:0030324; P:lung development; ISO:RGD.
DR GO; GO:0140014; P:mitotic nuclear division; ISO:RGD.
DR GO; GO:0035264; P:multicellular organism growth; ISO:RGD.
DR GO; GO:0051481; P:negative regulation of cytosolic calcium ion concentration; IMP:RGD.
DR GO; GO:1900126; P:negative regulation of hyaluronan biosynthetic process; ISO:RGD.
DR GO; GO:0001503; P:ossification; ISO:RGD.
DR GO; GO:0030072; P:peptide hormone secretion; ISO:RGD.
DR GO; GO:0048008; P:platelet-derived growth factor receptor signaling pathway; ISO:RGD.
DR GO; GO:0015774; P:polysaccharide transport; ISO:RGD.
DR GO; GO:2000304; P:positive regulation of ceramide biosynthetic process; IMP:RGD.
DR GO; GO:1903543; P:positive regulation of exosomal secretion; IMP:BHF-UCL.
DR GO; GO:0045840; P:positive regulation of mitotic nuclear division; ISO:RGD.
DR GO; GO:1901224; P:positive regulation of NIK/NF-kappaB signaling; IMP:RGD.
DR GO; GO:0045429; P:positive regulation of nitric oxide biosynthetic process; IMP:RGD.
DR GO; GO:0048661; P:positive regulation of smooth muscle cell proliferation; ISO:RGD.
DR GO; GO:0043491; P:protein kinase B signaling; ISO:RGD.
DR GO; GO:0061035; P:regulation of cartilage development; ISO:RGD.
DR GO; GO:1900125; P:regulation of hyaluronan biosynthetic process; ISO:RGD.
DR GO; GO:0002685; P:regulation of leukocyte migration; ISO:RGD.
DR GO; GO:0001932; P:regulation of protein phosphorylation; ISO:RGD.
DR GO; GO:0060541; P:respiratory system development; ISO:RGD.
DR GO; GO:0007165; P:signal transduction; ISO:RGD.
DR GO; GO:0001501; P:skeletal system development; ISO:RGD.
DR GO; GO:0090520; P:sphingolipid mediated signaling pathway; ISO:RGD.
DR GO; GO:0006665; P:sphingolipid metabolic process; ISO:RGD.
DR GO; GO:0006685; P:sphingomyelin catabolic process; ISO:RGD.
DR GO; GO:0006684; P:sphingomyelin metabolic process; ISS:UniProtKB.
DR CDD; cd09078; nSMase; 1.
DR Gene3D; 3.60.10.10; -; 1.
DR InterPro; IPR036691; Endo/exonu/phosph_ase_sf.
DR InterPro; IPR017766; Sphingomyelinase/PLipase_C.
DR SUPFAM; SSF56219; SSF56219; 1.
PE 1: Evidence at protein level;
KW Cell cycle; Cell membrane; Developmental protein; Golgi apparatus;
KW Hydrolase; Lipid metabolism; Lipoprotein; Magnesium; Membrane;
KW Metal-binding; Palmitate; Phosphoprotein; Reference proteome;
KW Sphingolipid metabolism.
FT CHAIN 1..655
FT /note="Sphingomyelin phosphodiesterase 3"
FT /id="PRO_0000075694"
FT TOPO_DOM 1..10
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT INTRAMEM 11..31
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 32..64
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT INTRAMEM 65..85
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 86..655
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT REGION 209..237
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 250..320
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 269..296
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 639
FT /note="Proton acceptor"
FT /evidence="ECO:0000250"
FT BINDING 362
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000250"
FT SITE 510
FT /note="Important for substrate recognition"
FT /evidence="ECO:0000250"
FT MOD_RES 178
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9JJY3"
FT MOD_RES 289
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT LIPID 53
FT /note="S-palmitoyl cysteine"
FT /evidence="ECO:0000250"
FT LIPID 59
FT /note="S-palmitoyl cysteine"
FT /evidence="ECO:0000250"
FT LIPID 395
FT /note="S-palmitoyl cysteine"
FT /evidence="ECO:0000250"
FT LIPID 396
FT /note="S-palmitoyl cysteine"
FT /evidence="ECO:0000250"
SQ SEQUENCE 655 AA; 71272 MW; 2338F6EBACDA8AD4 CRC64;
MVLYTTPFPN SCLSALHAVS WALIFPCYWL VDRLVASFIP TTYEKRQRAD DPCYLQLFCT
VLFTPVYLAL LVAALPFAFL GFIFWSPLQS ARRPYSYSRL EDKSPAGGAA LLSEWKGTGA
GKSFCFATAN VCLLPDSLAR LNNVFNTQAR AKEIGQRIRN GAARPQIKIY IDSPTNTSIS
AASFSSLVSP QGSDGARAVP GSIKRTASVE YKGDGGRHPS DEAANGPASG EQADGSLEDS
CIVRIGGEEG GRAQEADDPA PGSQARNGAG GTPKGQTPNH NQRDGDSGSL GSPSASRESL
VKARAGQDSG GSGEPGSNSK LLYKTSVVKK AAARRRRHPD EAFDHEVSAF FPANLDFLCL
QEVFDKRAAA KLKEQLHGYF EYILYDVGVY GCHGCCNFKC LNSGLFFASR YPVMDVAYHC
YPNGCSFDAL ASKGALFLKV QVGSTPQDQR IVGYIACTHL HAPPEDSAIR CEQLDLLQDW
LADFRKSTSS TSTANPEELV VFDVICGDLN FDNCSSDDKL EQQHSLFTRY KDPCRLGPGE
EKPWAIGTLL DINGLYDEDV CTPDNLQKVL ESEEGRREYL AFPTSKSPGA GQKGRKDLLK
GNGRRIDYML HAEEGLCPDW KAEVEEFSFI TQLSGLTDHL PVAMRLMVSA GEEEA
