Full text data of DGKD
DGKD
(KIAA0145)
[Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Diacylglycerol kinase delta; DAG kinase delta; 2.7.1.107 (130 kDa diacylglycerol kinase; Diglyceride kinase delta; DGK-delta)
Diacylglycerol kinase delta; DAG kinase delta; 2.7.1.107 (130 kDa diacylglycerol kinase; Diglyceride kinase delta; DGK-delta)
hRBCD
IPI00374804
IPI00374804 Diacylglycerol kinase, Delta 130kDa isoform 1 May function as signaling molecule, ATP + 1,2-diacylglycerol = ADP + 1,2-diacyl-sn-glycerol 3-phosphate, Partially inhibited by phosphatidylserine soluble n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a cytoplasmic n/a found at its expected molecular weight found at molecular weight
IPI00374804 Diacylglycerol kinase, Delta 130kDa isoform 1 May function as signaling molecule, ATP + 1,2-diacylglycerol = ADP + 1,2-diacyl-sn-glycerol 3-phosphate, Partially inhibited by phosphatidylserine soluble n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a cytoplasmic n/a found at its expected molecular weight found at molecular weight
UniProt
Q16760
ID DGKD_HUMAN Reviewed; 1214 AA.
AC Q16760; Q14158; Q6PK55; Q8NG53;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
read moreDT 17-OCT-2006, sequence version 4.
DT 22-JAN-2014, entry version 153.
DE RecName: Full=Diacylglycerol kinase delta;
DE Short=DAG kinase delta;
DE EC=2.7.1.107;
DE AltName: Full=130 kDa diacylglycerol kinase;
DE AltName: Full=Diglyceride kinase delta;
DE Short=DGK-delta;
GN Name=DGKD; Synonyms=KIAA0145;
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] (ISOFORMS 1 AND 2), SUBCELLULAR LOCATION,
RP SUBUNIT, AND TISSUE SPECIFICITY.
RC TISSUE=Brain;
RX PubMed=12200442; DOI=10.1074/jbc.M206895200;
RA Sakane F., Imai S., Yamada K., Murakami T., Tsushima S., Kanoh H.;
RT "Alternative splicing of the human diacylglycerol kinase delta gene
RT generates two isoforms differing in their expression patterns and in
RT regulatory functions.";
RL J. Biol. Chem. 277:43519-43526(2002).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 17-1214 (ISOFORM 2).
RC TISSUE=Bone marrow;
RX PubMed=8590280; DOI=10.1093/dnares/2.4.167;
RA Nagase T., Seki N., Tanaka A., Ishikawa K., Nomura N.;
RT "Prediction of the coding sequences of unidentified human genes. IV.
RT The coding sequences of 40 new genes (KIAA0121-KIAA0160) deduced by
RT analysis of cDNA clones from human cell line KG-1.";
RL DNA Res. 2:167-174(1995).
RN [3]
RP SEQUENCE REVISION.
RA Ohara O., Nagase T., Kikuno R., Nomura N.;
RL Submitted (AUG-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 45-1214 (ISOFORM 1).
RC TISSUE=Hepatoma, and Testis;
RX PubMed=8626538; DOI=10.1074/jbc.271.14.8394;
RA Sakane F., Imai S., Kai M., Wada I., Kanoh H.;
RT "Molecular cloning of a novel diacylglycerol kinase isozyme with a
RT pleckstrin homology domain and a C-terminal tail similar to those of
RT the EPH family of protein-tyrosine kinases.";
RL J. Biol. Chem. 271:8394-8401(1996).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1068-1214.
RC TISSUE=Lymph;
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 PHOSPHORYLATION.
RX PubMed=12084710; DOI=10.1074/jbc.M202035200;
RA Imai S., Sakane F., Kanoh H.;
RT "Phorbol ester-regulated oligomerization of diacylglycerol kinase
RT delta linked to its phosphorylation and translocation.";
RL J. Biol. Chem. 277:35323-35332(2002).
RN [7]
RP FUNCTION, INTERACTION WITH AP2A2, AND MUTAGENESIS OF PHE-369; PHE-372
RP AND PHE-748.
RX PubMed=17880279; DOI=10.1042/BJ20070755;
RA Kawasaki T., Kobayashi T., Ueyama T., Shirai Y., Saito N.;
RT "Regulation of clathrin-dependent endocytosis by diacylglycerol kinase
RT delta: importance of kinase activity and binding to AP2alpha.";
RL Biochem. J. 409:471-479(2008).
RN [8]
RP STRUCTURE BY NMR OF 216-286.
RG RIKEN structural genomics initiative (RSGI);
RT "Solution structure of the C1 domain of the human diacylglycerol
RT kinase delta.";
RL Submitted (APR-2004) to the PDB data bank.
CC -!- FUNCTION: May function as signaling molecule.
CC -!- FUNCTION: Isoform 2 may be involved in cell growth and
CC tumorigenesis. Involved in clathrin-dependent endocytosis.
CC -!- CATALYTIC ACTIVITY: ATP + 1,2-diacylglycerol = ADP + 1,2-diacyl-
CC sn-glycerol 3-phosphate.
CC -!- ENZYME REGULATION: Partially inhibited by phosphatidylserine.
CC -!- SUBUNIT: The two isoforms are able to form homo- and hetero-
CC oligomer structures (at least tetramers). Isoform 2 interacts with
CC AP2A2.
CC -!- INTERACTION:
CC O75923:DYSF; NbExp=3; IntAct=EBI-719333, EBI-2799016;
CC -!- SUBCELLULAR LOCATION: Isoform 2: Cytoplasm.
CC -!- SUBCELLULAR LOCATION: Isoform 1: Membrane; Peripheral membrane
CC protein.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=2;
CC IsoId=Q16760-1; Sequence=Displayed;
CC Name=1;
CC IsoId=Q16760-2; Sequence=VSP_012891;
CC -!- TISSUE SPECIFICITY: Isoform 2 is ubiquitously expressed also in
CC tumor tissues. Isoform 1 is expressed in ovary, spleen and some
CC tumor-derived cells.
CC -!- PTM: Isoform 1 H domain is phosphorylated.
CC -!- SIMILARITY: Belongs to the eukaryotic diacylglycerol kinase
CC family.
CC -!- SIMILARITY: Contains 1 DAGKc domain.
CC -!- SIMILARITY: Contains 1 PH domain.
CC -!- SIMILARITY: Contains 2 phorbol-ester/DAG-type zinc fingers.
CC -!- SIMILARITY: Contains 1 SAM (sterile alpha motif) domain.
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; AB078966; BAC11809.1; -; mRNA.
DR EMBL; D63479; BAA09766.3; -; mRNA.
DR EMBL; D73409; BAA11134.1; -; mRNA.
DR EMBL; BC006561; AAH06561.1; -; mRNA.
DR RefSeq; NP_003639.2; NM_003648.2.
DR RefSeq; NP_690618.2; NM_152879.2.
DR UniGene; Hs.471675; -.
DR PDB; 1R79; NMR; -; A=216-286.
DR PDB; 3BQ7; X-ray; 2.90 A; A/B/C/D/E/F=1141-1208.
DR PDBsum; 1R79; -.
DR PDBsum; 3BQ7; -.
DR ProteinModelPortal; Q16760; -.
DR SMR; Q16760; 216-286, 1141-1208.
DR DIP; DIP-29646N; -.
DR IntAct; Q16760; 6.
DR MINT; MINT-87709; -.
DR STRING; 9606.ENSP00000264057; -.
DR ChEMBL; CHEMBL1075120; -.
DR DrugBank; DB00144; Phosphatidylserine.
DR PhosphoSite; Q16760; -.
DR DMDM; 116241328; -.
DR PaxDb; Q16760; -.
DR PRIDE; Q16760; -.
DR Ensembl; ENST00000264057; ENSP00000264057; ENSG00000077044.
DR Ensembl; ENST00000409813; ENSP00000386455; ENSG00000077044.
DR GeneID; 8527; -.
DR KEGG; hsa:8527; -.
DR UCSC; uc002vui.1; human.
DR CTD; 8527; -.
DR GeneCards; GC02P234279; -.
DR H-InvDB; HIX0002934; -.
DR HGNC; HGNC:2851; DGKD.
DR HPA; HPA049101; -.
DR MIM; 601826; gene.
DR neXtProt; NX_Q16760; -.
DR PharmGKB; PA27312; -.
DR eggNOG; NOG328046; -.
DR HOGENOM; HOG000234676; -.
DR HOVERGEN; HBG051346; -.
DR InParanoid; Q16760; -.
DR KO; K00901; -.
DR OMA; KKCSVLK; -.
DR OrthoDB; EOG7DVD9B; -.
DR PhylomeDB; Q16760; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_604; Hemostasis.
DR ChiTaRS; DGKD; human.
DR EvolutionaryTrace; Q16760; -.
DR GeneWiki; DGKD; -.
DR GenomeRNAi; 8527; -.
DR NextBio; 31928; -.
DR PRO; PR:Q16760; -.
DR ArrayExpress; Q16760; -.
DR Bgee; Q16760; -.
DR CleanEx; HS_DGKD; -.
DR Genevestigator; Q16760; -.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0016023; C:cytoplasmic membrane-bounded vesicle; IDA:MGI.
DR GO; GO:0005886; C:plasma membrane; IDA:MGI.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0019992; F:diacylglycerol binding; NAS:UniProtKB.
DR GO; GO:0004143; F:diacylglycerol kinase activity; TAS:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0003951; F:NAD+ kinase activity; IEA:InterPro.
DR GO; GO:0005543; F:phospholipid binding; IEA:InterPro.
DR GO; GO:0046982; F:protein heterodimerization activity; IDA:MGI.
DR GO; GO:0042803; F:protein homodimerization activity; IDA:MGI.
DR GO; GO:0016049; P:cell growth; NAS:UniProtKB.
DR GO; GO:0046339; P:diacylglycerol metabolic process; NAS:UniProtKB.
DR GO; GO:0006897; P:endocytosis; IEA:UniProtKB-KW.
DR GO; GO:0007173; P:epidermal growth factor receptor signaling pathway; NAS:UniProtKB.
DR GO; GO:0007275; P:multicellular organismal development; NAS:UniProtKB.
DR GO; GO:0030168; P:platelet activation; TAS:Reactome.
DR GO; GO:0051260; P:protein homooligomerization; IDA:UniProtKB.
DR GO; GO:0007205; P:protein kinase C-activating G-protein coupled receptor signaling pathway; NAS:UniProtKB.
DR GO; GO:0015031; P:protein transport; IEA:UniProtKB-KW.
DR GO; GO:0010033; P:response to organic substance; IDA:UniProtKB.
DR GO; GO:0019932; P:second-messenger-mediated signaling; NAS:UniProtKB.
DR Gene3D; 1.10.150.50; -; 1.
DR Gene3D; 2.30.29.30; -; 1.
DR InterPro; IPR016064; ATP-NAD_kinase_PpnK-typ.
DR InterPro; IPR000756; Diacylglycerol_kin_accessory.
DR InterPro; IPR001206; Diacylglycerol_kinase_cat_dom.
DR InterPro; IPR011993; PH_like_dom.
DR InterPro; IPR001849; Pleckstrin_homology.
DR InterPro; IPR002219; Prot_Kinase_C-like_PE/DAG-bd.
DR InterPro; IPR001660; SAM.
DR InterPro; IPR013761; SAM/pointed.
DR InterPro; IPR011510; SAM_2.
DR Pfam; PF00130; C1_1; 2.
DR Pfam; PF00609; DAGK_acc; 1.
DR Pfam; PF00781; DAGK_cat; 1.
DR Pfam; PF00169; PH; 1.
DR Pfam; PF07647; SAM_2; 1.
DR SMART; SM00109; C1; 2.
DR SMART; SM00045; DAGKa; 1.
DR SMART; SM00046; DAGKc; 1.
DR SMART; SM00233; PH; 1.
DR SMART; SM00454; SAM; 1.
DR SUPFAM; SSF111331; SSF111331; 2.
DR SUPFAM; SSF47769; SSF47769; 1.
DR PROSITE; PS50146; DAGK; 1.
DR PROSITE; PS50003; PH_DOMAIN; 1.
DR PROSITE; PS50105; SAM_DOMAIN; 1.
DR PROSITE; PS00479; ZF_DAG_PE_1; 2.
DR PROSITE; PS50081; ZF_DAG_PE_2; 2.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; ATP-binding; Complete proteome;
KW Cytoplasm; Endocytosis; Kinase; Membrane; Metal-binding;
KW Nucleotide-binding; Phosphoprotein; Protein transport;
KW Reference proteome; Repeat; Transferase; Transport; Zinc; Zinc-finger.
FT CHAIN 1 1214 Diacylglycerol kinase delta.
FT /FTId=PRO_0000218462.
FT DOMAIN 53 146 PH.
FT DOMAIN 317 451 DAGKc.
FT DOMAIN 1145 1208 SAM.
FT ZN_FING 163 213 Phorbol-ester/DAG-type 1.
FT ZN_FING 235 286 Phorbol-ester/DAG-type 2.
FT COMPBIAS 8 36 Pro-rich.
FT VAR_SEQ 1 52 MAAAAGAPPPGPPQPPPPPPPEESSDSEPEAEPGSPQKLIR
FT KVSTSGQIRQK -> MNMFLYFQ (in isoform 1).
FT /FTId=VSP_012891.
FT MUTAGEN 369 369 F->A: Reduces interaction with AP2A2;
FT when associated with A-372.
FT MUTAGEN 372 372 F->A: Reduces interaction with AP2A2;
FT when associated with A-369.
FT MUTAGEN 748 748 F->A: Reduces interaction with AP2A2.
FT CONFLICT 511 511 V -> P (in Ref. 4; BAA11134).
FT CONFLICT 828 834 RPIPLPS -> DPSHSPV (in Ref. 4; BAA11134).
FT CONFLICT 960 960 L -> V (in Ref. 1; BAC11809 and 4;
FT BAA11134).
FT CONFLICT 1054 1054 Missing (in Ref. 4; BAA11134).
FT STRAND 238 241
FT STRAND 250 252
FT TURN 259 261
FT STRAND 265 270
FT HELIX 276 281
FT HELIX 1142 1144
FT HELIX 1147 1156
FT HELIX 1160 1162
FT HELIX 1163 1168
FT HELIX 1173 1176
FT HELIX 1181 1186
FT HELIX 1192 1206
SQ SEQUENCE 1214 AA; 134525 MW; ED114429096D2112 CRC64;
MAAAAGAPPP GPPQPPPPPP PEESSDSEPE AEPGSPQKLI RKVSTSGQIR QKTIIKEGML
TKQNNSFQRS KRRYFKLRGR TLYYAKTAKS IIFDEVDLTD ASVAESSTKN VNNSFTVITP
CRKLILCADN RKEMEDWIAA LKTVQNREHF EPTQYSMDHF SGMHNWYACS HARPTYCNVC
REALSGVTSH GLSCEVCKFK AHKRCAVRAT NNCKWTTLAS IGKDIIEDAD GIAMPHQWLE
GNLPVSAKCT VCDKTCGSVL RLQDWRCLWC KAMVHTSCKE SLLTKCPLGL CKVSVIPPTA
LNSIDSDGFW KASCPPSCTS PLLVFVNSKS GDNQGVKFLR RFKQLLNPAQ VFDLMNGGPH
LGLRLFQKFD TFRILVCGGD GSVGWVLSEI DSLNLHKQCQ LGVLPLGTGN DLARVLGWGS
ACDDDTQLPQ ILEKLERAST KMLDRWSVMA YEAKLPRQAS SSTVTEDFSE DSEVQQILFY
EDSVAAHLSK ILTSDQHSVV ISSAKVLCET VKDFVARVGK AYEKTTESSE ESEVMAKKCS
VLKEKLDSLL KTLDDESQAS SSLPNPPPTI AEEAEDGDGS GSICGSTGDR LVASACPARP
QIFRPREQLM LRANSLKKAI RQIIEHTEKA VDEQNAQTQE QEGFVLGLSE SEEKMDHRVC
PPLSHSESFG VPKGRSQRKV SKSPCEKLIS KGSLSLGSSA SLPPQPGSRD GLPALNTKIL
YPNVRAGMSG SLPGGSVISR LLINADPFNS EPETLEYYTE KCVMNNYFGI GLDAKISLDF
NNKRDEHPEK CRSRTKNMMW YGVLGTKELL HRTYKNLEQK VLLECDGRPI PLPSLQGIAV
LNIPSYAGGT NFWGGTKEDD TFAAPSFDDK ILEVVAVFGS MQMAVSRVIR LQHHRIAQCR
TVKISILGDE GVPVQVDGEA WVQPPGYIRI VHKNRAQTLT RDRAFESTLK SWEDKQKCEL
PRPPSCSLHP EMLSEEEATQ MDQFGQAAGV LIHSIREIAQ SHRDMEQELA HAVNASSKSM
DRVYGKPRTT EGLNCSFVLE MVNNFRALRS ETELLLSGKM ALQLDPPQKE QLGSALAEMD
RQLRRLADTP WLCQSAEPGD EESVMLDLAK RSRSGKFRLV TKFKKEKNNK NKEAHSSLGA
PVHLWGTEEV AAWLEHLSLC EYKDIFTRHD IRGSELLHLE RRDLKDLGVT KVGHMKRILC
GIKELSRSAP AVEA
//
ID DGKD_HUMAN Reviewed; 1214 AA.
AC Q16760; Q14158; Q6PK55; Q8NG53;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
read moreDT 17-OCT-2006, sequence version 4.
DT 22-JAN-2014, entry version 153.
DE RecName: Full=Diacylglycerol kinase delta;
DE Short=DAG kinase delta;
DE EC=2.7.1.107;
DE AltName: Full=130 kDa diacylglycerol kinase;
DE AltName: Full=Diglyceride kinase delta;
DE Short=DGK-delta;
GN Name=DGKD; Synonyms=KIAA0145;
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] (ISOFORMS 1 AND 2), SUBCELLULAR LOCATION,
RP SUBUNIT, AND TISSUE SPECIFICITY.
RC TISSUE=Brain;
RX PubMed=12200442; DOI=10.1074/jbc.M206895200;
RA Sakane F., Imai S., Yamada K., Murakami T., Tsushima S., Kanoh H.;
RT "Alternative splicing of the human diacylglycerol kinase delta gene
RT generates two isoforms differing in their expression patterns and in
RT regulatory functions.";
RL J. Biol. Chem. 277:43519-43526(2002).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 17-1214 (ISOFORM 2).
RC TISSUE=Bone marrow;
RX PubMed=8590280; DOI=10.1093/dnares/2.4.167;
RA Nagase T., Seki N., Tanaka A., Ishikawa K., Nomura N.;
RT "Prediction of the coding sequences of unidentified human genes. IV.
RT The coding sequences of 40 new genes (KIAA0121-KIAA0160) deduced by
RT analysis of cDNA clones from human cell line KG-1.";
RL DNA Res. 2:167-174(1995).
RN [3]
RP SEQUENCE REVISION.
RA Ohara O., Nagase T., Kikuno R., Nomura N.;
RL Submitted (AUG-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 45-1214 (ISOFORM 1).
RC TISSUE=Hepatoma, and Testis;
RX PubMed=8626538; DOI=10.1074/jbc.271.14.8394;
RA Sakane F., Imai S., Kai M., Wada I., Kanoh H.;
RT "Molecular cloning of a novel diacylglycerol kinase isozyme with a
RT pleckstrin homology domain and a C-terminal tail similar to those of
RT the EPH family of protein-tyrosine kinases.";
RL J. Biol. Chem. 271:8394-8401(1996).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1068-1214.
RC TISSUE=Lymph;
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 PHOSPHORYLATION.
RX PubMed=12084710; DOI=10.1074/jbc.M202035200;
RA Imai S., Sakane F., Kanoh H.;
RT "Phorbol ester-regulated oligomerization of diacylglycerol kinase
RT delta linked to its phosphorylation and translocation.";
RL J. Biol. Chem. 277:35323-35332(2002).
RN [7]
RP FUNCTION, INTERACTION WITH AP2A2, AND MUTAGENESIS OF PHE-369; PHE-372
RP AND PHE-748.
RX PubMed=17880279; DOI=10.1042/BJ20070755;
RA Kawasaki T., Kobayashi T., Ueyama T., Shirai Y., Saito N.;
RT "Regulation of clathrin-dependent endocytosis by diacylglycerol kinase
RT delta: importance of kinase activity and binding to AP2alpha.";
RL Biochem. J. 409:471-479(2008).
RN [8]
RP STRUCTURE BY NMR OF 216-286.
RG RIKEN structural genomics initiative (RSGI);
RT "Solution structure of the C1 domain of the human diacylglycerol
RT kinase delta.";
RL Submitted (APR-2004) to the PDB data bank.
CC -!- FUNCTION: May function as signaling molecule.
CC -!- FUNCTION: Isoform 2 may be involved in cell growth and
CC tumorigenesis. Involved in clathrin-dependent endocytosis.
CC -!- CATALYTIC ACTIVITY: ATP + 1,2-diacylglycerol = ADP + 1,2-diacyl-
CC sn-glycerol 3-phosphate.
CC -!- ENZYME REGULATION: Partially inhibited by phosphatidylserine.
CC -!- SUBUNIT: The two isoforms are able to form homo- and hetero-
CC oligomer structures (at least tetramers). Isoform 2 interacts with
CC AP2A2.
CC -!- INTERACTION:
CC O75923:DYSF; NbExp=3; IntAct=EBI-719333, EBI-2799016;
CC -!- SUBCELLULAR LOCATION: Isoform 2: Cytoplasm.
CC -!- SUBCELLULAR LOCATION: Isoform 1: Membrane; Peripheral membrane
CC protein.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=2;
CC IsoId=Q16760-1; Sequence=Displayed;
CC Name=1;
CC IsoId=Q16760-2; Sequence=VSP_012891;
CC -!- TISSUE SPECIFICITY: Isoform 2 is ubiquitously expressed also in
CC tumor tissues. Isoform 1 is expressed in ovary, spleen and some
CC tumor-derived cells.
CC -!- PTM: Isoform 1 H domain is phosphorylated.
CC -!- SIMILARITY: Belongs to the eukaryotic diacylglycerol kinase
CC family.
CC -!- SIMILARITY: Contains 1 DAGKc domain.
CC -!- SIMILARITY: Contains 1 PH domain.
CC -!- SIMILARITY: Contains 2 phorbol-ester/DAG-type zinc fingers.
CC -!- SIMILARITY: Contains 1 SAM (sterile alpha motif) domain.
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; AB078966; BAC11809.1; -; mRNA.
DR EMBL; D63479; BAA09766.3; -; mRNA.
DR EMBL; D73409; BAA11134.1; -; mRNA.
DR EMBL; BC006561; AAH06561.1; -; mRNA.
DR RefSeq; NP_003639.2; NM_003648.2.
DR RefSeq; NP_690618.2; NM_152879.2.
DR UniGene; Hs.471675; -.
DR PDB; 1R79; NMR; -; A=216-286.
DR PDB; 3BQ7; X-ray; 2.90 A; A/B/C/D/E/F=1141-1208.
DR PDBsum; 1R79; -.
DR PDBsum; 3BQ7; -.
DR ProteinModelPortal; Q16760; -.
DR SMR; Q16760; 216-286, 1141-1208.
DR DIP; DIP-29646N; -.
DR IntAct; Q16760; 6.
DR MINT; MINT-87709; -.
DR STRING; 9606.ENSP00000264057; -.
DR ChEMBL; CHEMBL1075120; -.
DR DrugBank; DB00144; Phosphatidylserine.
DR PhosphoSite; Q16760; -.
DR DMDM; 116241328; -.
DR PaxDb; Q16760; -.
DR PRIDE; Q16760; -.
DR Ensembl; ENST00000264057; ENSP00000264057; ENSG00000077044.
DR Ensembl; ENST00000409813; ENSP00000386455; ENSG00000077044.
DR GeneID; 8527; -.
DR KEGG; hsa:8527; -.
DR UCSC; uc002vui.1; human.
DR CTD; 8527; -.
DR GeneCards; GC02P234279; -.
DR H-InvDB; HIX0002934; -.
DR HGNC; HGNC:2851; DGKD.
DR HPA; HPA049101; -.
DR MIM; 601826; gene.
DR neXtProt; NX_Q16760; -.
DR PharmGKB; PA27312; -.
DR eggNOG; NOG328046; -.
DR HOGENOM; HOG000234676; -.
DR HOVERGEN; HBG051346; -.
DR InParanoid; Q16760; -.
DR KO; K00901; -.
DR OMA; KKCSVLK; -.
DR OrthoDB; EOG7DVD9B; -.
DR PhylomeDB; Q16760; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_604; Hemostasis.
DR ChiTaRS; DGKD; human.
DR EvolutionaryTrace; Q16760; -.
DR GeneWiki; DGKD; -.
DR GenomeRNAi; 8527; -.
DR NextBio; 31928; -.
DR PRO; PR:Q16760; -.
DR ArrayExpress; Q16760; -.
DR Bgee; Q16760; -.
DR CleanEx; HS_DGKD; -.
DR Genevestigator; Q16760; -.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0016023; C:cytoplasmic membrane-bounded vesicle; IDA:MGI.
DR GO; GO:0005886; C:plasma membrane; IDA:MGI.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0019992; F:diacylglycerol binding; NAS:UniProtKB.
DR GO; GO:0004143; F:diacylglycerol kinase activity; TAS:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0003951; F:NAD+ kinase activity; IEA:InterPro.
DR GO; GO:0005543; F:phospholipid binding; IEA:InterPro.
DR GO; GO:0046982; F:protein heterodimerization activity; IDA:MGI.
DR GO; GO:0042803; F:protein homodimerization activity; IDA:MGI.
DR GO; GO:0016049; P:cell growth; NAS:UniProtKB.
DR GO; GO:0046339; P:diacylglycerol metabolic process; NAS:UniProtKB.
DR GO; GO:0006897; P:endocytosis; IEA:UniProtKB-KW.
DR GO; GO:0007173; P:epidermal growth factor receptor signaling pathway; NAS:UniProtKB.
DR GO; GO:0007275; P:multicellular organismal development; NAS:UniProtKB.
DR GO; GO:0030168; P:platelet activation; TAS:Reactome.
DR GO; GO:0051260; P:protein homooligomerization; IDA:UniProtKB.
DR GO; GO:0007205; P:protein kinase C-activating G-protein coupled receptor signaling pathway; NAS:UniProtKB.
DR GO; GO:0015031; P:protein transport; IEA:UniProtKB-KW.
DR GO; GO:0010033; P:response to organic substance; IDA:UniProtKB.
DR GO; GO:0019932; P:second-messenger-mediated signaling; NAS:UniProtKB.
DR Gene3D; 1.10.150.50; -; 1.
DR Gene3D; 2.30.29.30; -; 1.
DR InterPro; IPR016064; ATP-NAD_kinase_PpnK-typ.
DR InterPro; IPR000756; Diacylglycerol_kin_accessory.
DR InterPro; IPR001206; Diacylglycerol_kinase_cat_dom.
DR InterPro; IPR011993; PH_like_dom.
DR InterPro; IPR001849; Pleckstrin_homology.
DR InterPro; IPR002219; Prot_Kinase_C-like_PE/DAG-bd.
DR InterPro; IPR001660; SAM.
DR InterPro; IPR013761; SAM/pointed.
DR InterPro; IPR011510; SAM_2.
DR Pfam; PF00130; C1_1; 2.
DR Pfam; PF00609; DAGK_acc; 1.
DR Pfam; PF00781; DAGK_cat; 1.
DR Pfam; PF00169; PH; 1.
DR Pfam; PF07647; SAM_2; 1.
DR SMART; SM00109; C1; 2.
DR SMART; SM00045; DAGKa; 1.
DR SMART; SM00046; DAGKc; 1.
DR SMART; SM00233; PH; 1.
DR SMART; SM00454; SAM; 1.
DR SUPFAM; SSF111331; SSF111331; 2.
DR SUPFAM; SSF47769; SSF47769; 1.
DR PROSITE; PS50146; DAGK; 1.
DR PROSITE; PS50003; PH_DOMAIN; 1.
DR PROSITE; PS50105; SAM_DOMAIN; 1.
DR PROSITE; PS00479; ZF_DAG_PE_1; 2.
DR PROSITE; PS50081; ZF_DAG_PE_2; 2.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; ATP-binding; Complete proteome;
KW Cytoplasm; Endocytosis; Kinase; Membrane; Metal-binding;
KW Nucleotide-binding; Phosphoprotein; Protein transport;
KW Reference proteome; Repeat; Transferase; Transport; Zinc; Zinc-finger.
FT CHAIN 1 1214 Diacylglycerol kinase delta.
FT /FTId=PRO_0000218462.
FT DOMAIN 53 146 PH.
FT DOMAIN 317 451 DAGKc.
FT DOMAIN 1145 1208 SAM.
FT ZN_FING 163 213 Phorbol-ester/DAG-type 1.
FT ZN_FING 235 286 Phorbol-ester/DAG-type 2.
FT COMPBIAS 8 36 Pro-rich.
FT VAR_SEQ 1 52 MAAAAGAPPPGPPQPPPPPPPEESSDSEPEAEPGSPQKLIR
FT KVSTSGQIRQK -> MNMFLYFQ (in isoform 1).
FT /FTId=VSP_012891.
FT MUTAGEN 369 369 F->A: Reduces interaction with AP2A2;
FT when associated with A-372.
FT MUTAGEN 372 372 F->A: Reduces interaction with AP2A2;
FT when associated with A-369.
FT MUTAGEN 748 748 F->A: Reduces interaction with AP2A2.
FT CONFLICT 511 511 V -> P (in Ref. 4; BAA11134).
FT CONFLICT 828 834 RPIPLPS -> DPSHSPV (in Ref. 4; BAA11134).
FT CONFLICT 960 960 L -> V (in Ref. 1; BAC11809 and 4;
FT BAA11134).
FT CONFLICT 1054 1054 Missing (in Ref. 4; BAA11134).
FT STRAND 238 241
FT STRAND 250 252
FT TURN 259 261
FT STRAND 265 270
FT HELIX 276 281
FT HELIX 1142 1144
FT HELIX 1147 1156
FT HELIX 1160 1162
FT HELIX 1163 1168
FT HELIX 1173 1176
FT HELIX 1181 1186
FT HELIX 1192 1206
SQ SEQUENCE 1214 AA; 134525 MW; ED114429096D2112 CRC64;
MAAAAGAPPP GPPQPPPPPP PEESSDSEPE AEPGSPQKLI RKVSTSGQIR QKTIIKEGML
TKQNNSFQRS KRRYFKLRGR TLYYAKTAKS IIFDEVDLTD ASVAESSTKN VNNSFTVITP
CRKLILCADN RKEMEDWIAA LKTVQNREHF EPTQYSMDHF SGMHNWYACS HARPTYCNVC
REALSGVTSH GLSCEVCKFK AHKRCAVRAT NNCKWTTLAS IGKDIIEDAD GIAMPHQWLE
GNLPVSAKCT VCDKTCGSVL RLQDWRCLWC KAMVHTSCKE SLLTKCPLGL CKVSVIPPTA
LNSIDSDGFW KASCPPSCTS PLLVFVNSKS GDNQGVKFLR RFKQLLNPAQ VFDLMNGGPH
LGLRLFQKFD TFRILVCGGD GSVGWVLSEI DSLNLHKQCQ LGVLPLGTGN DLARVLGWGS
ACDDDTQLPQ ILEKLERAST KMLDRWSVMA YEAKLPRQAS SSTVTEDFSE DSEVQQILFY
EDSVAAHLSK ILTSDQHSVV ISSAKVLCET VKDFVARVGK AYEKTTESSE ESEVMAKKCS
VLKEKLDSLL KTLDDESQAS SSLPNPPPTI AEEAEDGDGS GSICGSTGDR LVASACPARP
QIFRPREQLM LRANSLKKAI RQIIEHTEKA VDEQNAQTQE QEGFVLGLSE SEEKMDHRVC
PPLSHSESFG VPKGRSQRKV SKSPCEKLIS KGSLSLGSSA SLPPQPGSRD GLPALNTKIL
YPNVRAGMSG SLPGGSVISR LLINADPFNS EPETLEYYTE KCVMNNYFGI GLDAKISLDF
NNKRDEHPEK CRSRTKNMMW YGVLGTKELL HRTYKNLEQK VLLECDGRPI PLPSLQGIAV
LNIPSYAGGT NFWGGTKEDD TFAAPSFDDK ILEVVAVFGS MQMAVSRVIR LQHHRIAQCR
TVKISILGDE GVPVQVDGEA WVQPPGYIRI VHKNRAQTLT RDRAFESTLK SWEDKQKCEL
PRPPSCSLHP EMLSEEEATQ MDQFGQAAGV LIHSIREIAQ SHRDMEQELA HAVNASSKSM
DRVYGKPRTT EGLNCSFVLE MVNNFRALRS ETELLLSGKM ALQLDPPQKE QLGSALAEMD
RQLRRLADTP WLCQSAEPGD EESVMLDLAK RSRSGKFRLV TKFKKEKNNK NKEAHSSLGA
PVHLWGTEEV AAWLEHLSLC EYKDIFTRHD IRGSELLHLE RRDLKDLGVT KVGHMKRILC
GIKELSRSAP AVEA
//
MIM
601826
*RECORD*
*FIELD* NO
601826
*FIELD* TI
*601826 DIACYLGLYCEROL KINASE, DELTA, 130-KD; DGKD
;;KIAA0145;;
DGK ISOZYME, 130-KD;;
read moreDGK-DELTA
*FIELD* TX
See 125855 for a general discussion of the diacylglycerol kinases
(DGKs). DAGK4 (DGKQ; 601207) is distinct from this entry.
CLONING
By sequencing clones obtained from an immature myeloid leukemia cell
line cDNA library, Nagase et al. (1995) cloned a partial DGKD cDNA,
which they designated KIAA0145. Northern blot analysis detected highest
expression in skeletal muscle and lower expression in all other tissues
and cell lines examined.
Sakane et al. (1996) used degenerate PCR to isolate a novel DGK
fragment, which they termed DGK-delta, from human testis mRNA. They then
cloned full-length cDNAs from human hepatoma and testis cDNA libraries.
Sequence analysis revealed that this gene encodes a 1,169-amino acid
protein containing, in addition to sequences homologous to other DGKs, a
pleckstrin homology (PH) domain and a C-terminal tail similar to those
of the EPH family of receptor tyrosine kinases. Sakane et al. (1996)
suggested that, because of its different structural features, this novel
DGK belongs to a subfamily of DGKs distinct from the alpha, beta, and
gamma DGK isoforms. Northern blot analysis showed that this gene encodes
a 6.3-kb transcript most abundant in skeletal muscle but undetectable in
brain, thymus, and retina. Sakane et al. (1996) expressed this novel DGK
gene in COS-7 cells and observed DGK activity which was independent of
phosphatidylserine, a common activator of other DGKs.
By 5-prime RACE of a human brain cDNA library, Sakane et al. (2002)
identified a splice variant of DGKD, which they called DGKD2. DGKD2
originates from an upstream first exon relative to that utilized by the
original clone, called DGKD1, and translation of DGKD2 begins at an
alternate upstream initiation methionine. The deduced 1,214-amino acid
protein has a calculated molecular mass of 135 kD, and its N terminus
contains proline-rich and glu/asp-rich sequences not found in DGKD1.
RT-PCR detected DGKD2 in all human normal and tumor tissues and cell
lines examined, with highest expression in testis, peripheral blood
leukocytes, and several tumor tissues. DGKD2 expression was high in
ovary, lower in spleen, and much weaker in tumor tissues and cell lines.
Western blot analysis showed that protein levels reflected the mRNA
levels for the 2 isoforms. The apparent molecular masses of DGKD1 and
DGKD2 in transfected COS-7 cells were 130 and 140 kD, respectively.
GENE FUNCTION
Sakane et al. (2002) found the expression of DGKD2 was induced by
treating cells with epidermal growth factor (131530) and tumor-promoting
phorbol ester. In contrast, the level of DGKD1 mRNA and protein were
suppressed by phorbol ester treatment. DGKD1 was translocated through
its PH domain from the cytoplasm to the plasma membrane in response to
phorbol esters, whereas DGKD2 remained in the cytoplasm after
stimulation. Mutation analysis indicated that the DGKD2-specific
N-terminal sequence blocked the phorbol ester-dependent translocation of
this isoform. Coimmunoprecipitation analysis showed that DGKD1 and DGKD2
were able to form homo- and heterooligomers. Murakami et al. (2003)
found that the DGKH2 isoform of DGKH (604071), which contains a
C-terminal SAM domain, could form higher-order multimers with DGKD1 and
DGKD2.
Chibalin et al. (2008) identified reduced DGKD expression and DGK
activity in skeletal muscle from patients with poorly controlled type 2
diabetes (125853). In diabetic GK rats, they observed that reduced DGKD
protein and DGK kinase activity in skeletal muscle were restored upon
correction of glycemia. Dgkd-haploinsufficient mice had increased
diacylglycerol content and reduced peripheral insulin sensitivity,
insulin signaling, and glucose transport. Dgkd +/- mice displayed
impaired metabolic flexibility by failing to appropriately shift between
lipid and glucose oxidation during fasted and fed conditions, and they
developed age-dependent obesity. Chibalin et al. (2008) concluded that
DGKD deficiency causes hyperglycemia-induced peripheral insulin
resistance and metabolic inflexibility, which may contribute to mild
obesity later in life.
MAPPING
By PCR of a human/rodent hybrid panel, Nagase et al. (1995) mapped the
DGKD gene to chromosome 2.
MOLECULAR GENETICS
Leach et al. (2007) described a female patient with a de novo balanced
translocation, 46,X,t(X;2)(p11.2;q37), who exhibited seizures, capillary
abnormalities, developmental delay, infantile hypotonia, and obesity.
The 2q37 breakpoint associated with the seizure phenotype was of
particular interest, because it lay near loci implicated in epilepsy in
humans and mice. Fluorescence in situ hybridization mapping of the
translocation breakpoints showed that no known genes were disrupted at
Xp11.2, whereas DGKD was disrupted at 2q37. Expression studies in
Drosophila and mouse suggested that DGKD is involved in central nervous
system development and function. Electroencephalographic assessment of
Dgkd mutant mice revealed abnormal epileptic discharges and
electrographic seizures in 3 of 6 homozygotes. At the time of
assessment, the girl with the translocation t(X;2) reported by Leach et
al. (2007) was 12 years old and showed epilepsy, mild hypotonia, and a
history of developmental delay. Congenital capillary abnormalities were
illustrated both on the face and limbs. At 3.5 years of age she had
received the diagnosis of generalized tonic-clonic seizures, which
evolved into drop attacks at age 5 years that eventually subsided; at 11
years of age, she developed staring events with an occasional myoclonic
component, and at the time of evaluation she was having 1 or 2
generalized tonic-clonic seizures per week. She first exhibited
cognitive delay at the age of 18 months and had verbal/auditory
processing difficulties characterized by delayed responses and
perseveration. Seizures in conjunction with behavioral findings were
considered consistent with the Lennox-Gastaut syndrome form of epilepsy.
This patient was part of the Developmental Genome Anatomy Project
(DGAP), a study intended to allow gene discovery related to phenotypic
abnormalities observed in association with balanced chromosomal
rearrangements; such rearrangements can be expected to alter the
expression of a gene(s) residing at or near the chromosomal
breakpoint(s).
ANIMAL MODEL
Crotty et al. (2006) found that Dgkd-null mice were smaller than their
wildtype or heterozygous littermates, were born with open eyelids
similar to Egfr (131550)-knockout mice, and developed respiratory
failure and died within 24 hours after birth. Dgkd knockout increased
diacylglycerol accumulation, increased threonine phosphorylation of
Egfr, enhanced phosphorylation of other protein kinase C (PKC; see PRKCA
176960) substrates, and increased Pkc autophosphorylation. Crotty et al.
(2006) concluded that DGKD regulates EGFR by modulating PKC signaling.
*FIELD* RF
1. Chibalin, A. V.; Leng, Y.; Vieira, E.; Krook, A.; Bjornholm, M.;
Long, Y. C.; Kotova, O.; Zhong, Z.; Sakane, F.; Steiler, T.; Nylen,
C.; Wang, J.; Laakso, M.; Topham, M. K.; Gilbert, M.; Wallberg-Henriksson,
H.; Zierath, J. R.: Downregulation of diacylglycerol kinase delta
contributes to hyperglycemia-induced insulin resistance. Cell 132:
375-386, 2008.
2. Crotty, T.; Cai; J.; Sakane, F.; Taketomi, A.; Prescott, S. M.;
Topham, M. K.: Diacylglycerol kinase-delta regulates protein kinase
C and epidermal growth factor receptor signaling. Proc. Nat. Acad.
Sci. 103: 15485-15490, 2006.
3. Leach, N. T.; Sun, Y.; Michaud, S.; Zheng, Y.; Ligon, K. L.; Ligon,
A. H.; Sander, T.; Korf, B. R.; Lu, W.; Harris, D. J.; Gusella, J.
F.; Maas, R. L.; Quade, B. J.; Cole, A. J.; Kelz, M. B.; Morton, C.
C.: Disruption of diacylglycerol kinase delta (DGKD) associated with
seizures in humans and mice. Am. J. Hum. Genet. 80: 792-799, 2007.
4. Murakami, T.; Sakane, F.; Imai, S.; Houkin, K.; Kanoh, H.: Identification
and characterization of two splice variants of human diacylglycerol
kinase eta. J. Biol. Chem. 278: 34364-34372, 2003.
5. Nagase, T.; Seki, N.; Tanaka, A.; Ishikawa, K.; Nomura, N.: Prediction
of the coding sequences of unidentified human genes. IV. The coding
sequences of 40 new genes (KIAA0121-KIAA0160) deduced by analysis
of cDNA clones from human cell line KG-1. DNA Res. 2: 167-174, 1995.
6. Sakane, F.; Imai, S.; Kai, M.; Wada, I.; Kanoh, H.: Molecular
cloning of a novel diacylglycerol kinase isozyme with a pleckstrin
homology domain and a C-terminal tail similar to those of the EPH
family of protein-tyrosine kinases. J. Biol. Chem. 271: 8394-8401,
1996.
7. Sakane, F.; Imai, S.; Yamada, K.; Murakami, T.; Tsushima, S.; Kanoh,
H.: Alternative splicing of the human diacylglycerol kinase delta
gene generates two isoforms differing in their expression patterns
and in regulatory functions. J. Biol. Chem. 277: 43519-43526, 2002.
*FIELD* CN
Marla J. F. O'Neill - updated: 3/24/2008
Patricia A. Hartz - updated: 4/3/2007
Victor A. McKusick - updated: 3/27/2007
Patricia A. Hartz - updated: 1/26/2007
*FIELD* CD
Jennifer P. Macke: 3/14/1997
*FIELD* ED
ckniffin: 09/09/2013
carol: 3/7/2012
wwang: 3/25/2008
terry: 3/24/2008
wwang: 4/6/2007
terry: 4/3/2007
alopez: 3/28/2007
terry: 3/27/2007
wwang: 1/26/2007
alopez: 10/29/1999
alopez: 10/16/1998
dkim: 7/30/1998
alopez: 6/24/1997
alopez: 6/9/1997
*RECORD*
*FIELD* NO
601826
*FIELD* TI
*601826 DIACYLGLYCEROL KINASE, DELTA, 130-KD; DGKD
;;KIAA0145;;
DGK ISOZYME, 130-KD;;
read moreDGK-DELTA
*FIELD* TX
See 125855 for a general discussion of the diacylglycerol kinases
(DGKs). DAGK4 (DGKQ; 601207) is distinct from this entry.
CLONING
By sequencing clones obtained from an immature myeloid leukemia cell
line cDNA library, Nagase et al. (1995) cloned a partial DGKD cDNA,
which they designated KIAA0145. Northern blot analysis detected highest
expression in skeletal muscle and lower expression in all other tissues
and cell lines examined.
Sakane et al. (1996) used degenerate PCR to isolate a novel DGK
fragment, which they termed DGK-delta, from human testis mRNA. They then
cloned full-length cDNAs from human hepatoma and testis cDNA libraries.
Sequence analysis revealed that this gene encodes a 1,169-amino acid
protein containing, in addition to sequences homologous to other DGKs, a
pleckstrin homology (PH) domain and a C-terminal tail similar to those
of the EPH family of receptor tyrosine kinases. Sakane et al. (1996)
suggested that, because of its different structural features, this novel
DGK belongs to a subfamily of DGKs distinct from the alpha, beta, and
gamma DGK isoforms. Northern blot analysis showed that this gene encodes
a 6.3-kb transcript most abundant in skeletal muscle but undetectable in
brain, thymus, and retina. Sakane et al. (1996) expressed this novel DGK
gene in COS-7 cells and observed DGK activity which was independent of
phosphatidylserine, a common activator of other DGKs.
By 5-prime RACE of a human brain cDNA library, Sakane et al. (2002)
identified a splice variant of DGKD, which they called DGKD2. DGKD2
originates from an upstream first exon relative to that utilized by the
original clone, called DGKD1, and translation of DGKD2 begins at an
alternate upstream initiation methionine. The deduced 1,214-amino acid
protein has a calculated molecular mass of 135 kD, and its N terminus
contains proline-rich and glu/asp-rich sequences not found in DGKD1.
RT-PCR detected DGKD2 in all human normal and tumor tissues and cell
lines examined, with highest expression in testis, peripheral blood
leukocytes, and several tumor tissues. DGKD2 expression was high in
ovary, lower in spleen, and much weaker in tumor tissues and cell lines.
Western blot analysis showed that protein levels reflected the mRNA
levels for the 2 isoforms. The apparent molecular masses of DGKD1 and
DGKD2 in transfected COS-7 cells were 130 and 140 kD, respectively.
GENE FUNCTION
Sakane et al. (2002) found the expression of DGKD2 was induced by
treating cells with epidermal growth factor (131530) and tumor-promoting
phorbol ester. In contrast, the level of DGKD1 mRNA and protein were
suppressed by phorbol ester treatment. DGKD1 was translocated through
its PH domain from the cytoplasm to the plasma membrane in response to
phorbol esters, whereas DGKD2 remained in the cytoplasm after
stimulation. Mutation analysis indicated that the DGKD2-specific
N-terminal sequence blocked the phorbol ester-dependent translocation of
this isoform. Coimmunoprecipitation analysis showed that DGKD1 and DGKD2
were able to form homo- and heterooligomers. Murakami et al. (2003)
found that the DGKH2 isoform of DGKH (604071), which contains a
C-terminal SAM domain, could form higher-order multimers with DGKD1 and
DGKD2.
Chibalin et al. (2008) identified reduced DGKD expression and DGK
activity in skeletal muscle from patients with poorly controlled type 2
diabetes (125853). In diabetic GK rats, they observed that reduced DGKD
protein and DGK kinase activity in skeletal muscle were restored upon
correction of glycemia. Dgkd-haploinsufficient mice had increased
diacylglycerol content and reduced peripheral insulin sensitivity,
insulin signaling, and glucose transport. Dgkd +/- mice displayed
impaired metabolic flexibility by failing to appropriately shift between
lipid and glucose oxidation during fasted and fed conditions, and they
developed age-dependent obesity. Chibalin et al. (2008) concluded that
DGKD deficiency causes hyperglycemia-induced peripheral insulin
resistance and metabolic inflexibility, which may contribute to mild
obesity later in life.
MAPPING
By PCR of a human/rodent hybrid panel, Nagase et al. (1995) mapped the
DGKD gene to chromosome 2.
MOLECULAR GENETICS
Leach et al. (2007) described a female patient with a de novo balanced
translocation, 46,X,t(X;2)(p11.2;q37), who exhibited seizures, capillary
abnormalities, developmental delay, infantile hypotonia, and obesity.
The 2q37 breakpoint associated with the seizure phenotype was of
particular interest, because it lay near loci implicated in epilepsy in
humans and mice. Fluorescence in situ hybridization mapping of the
translocation breakpoints showed that no known genes were disrupted at
Xp11.2, whereas DGKD was disrupted at 2q37. Expression studies in
Drosophila and mouse suggested that DGKD is involved in central nervous
system development and function. Electroencephalographic assessment of
Dgkd mutant mice revealed abnormal epileptic discharges and
electrographic seizures in 3 of 6 homozygotes. At the time of
assessment, the girl with the translocation t(X;2) reported by Leach et
al. (2007) was 12 years old and showed epilepsy, mild hypotonia, and a
history of developmental delay. Congenital capillary abnormalities were
illustrated both on the face and limbs. At 3.5 years of age she had
received the diagnosis of generalized tonic-clonic seizures, which
evolved into drop attacks at age 5 years that eventually subsided; at 11
years of age, she developed staring events with an occasional myoclonic
component, and at the time of evaluation she was having 1 or 2
generalized tonic-clonic seizures per week. She first exhibited
cognitive delay at the age of 18 months and had verbal/auditory
processing difficulties characterized by delayed responses and
perseveration. Seizures in conjunction with behavioral findings were
considered consistent with the Lennox-Gastaut syndrome form of epilepsy.
This patient was part of the Developmental Genome Anatomy Project
(DGAP), a study intended to allow gene discovery related to phenotypic
abnormalities observed in association with balanced chromosomal
rearrangements; such rearrangements can be expected to alter the
expression of a gene(s) residing at or near the chromosomal
breakpoint(s).
ANIMAL MODEL
Crotty et al. (2006) found that Dgkd-null mice were smaller than their
wildtype or heterozygous littermates, were born with open eyelids
similar to Egfr (131550)-knockout mice, and developed respiratory
failure and died within 24 hours after birth. Dgkd knockout increased
diacylglycerol accumulation, increased threonine phosphorylation of
Egfr, enhanced phosphorylation of other protein kinase C (PKC; see PRKCA
176960) substrates, and increased Pkc autophosphorylation. Crotty et al.
(2006) concluded that DGKD regulates EGFR by modulating PKC signaling.
*FIELD* RF
1. Chibalin, A. V.; Leng, Y.; Vieira, E.; Krook, A.; Bjornholm, M.;
Long, Y. C.; Kotova, O.; Zhong, Z.; Sakane, F.; Steiler, T.; Nylen,
C.; Wang, J.; Laakso, M.; Topham, M. K.; Gilbert, M.; Wallberg-Henriksson,
H.; Zierath, J. R.: Downregulation of diacylglycerol kinase delta
contributes to hyperglycemia-induced insulin resistance. Cell 132:
375-386, 2008.
2. Crotty, T.; Cai; J.; Sakane, F.; Taketomi, A.; Prescott, S. M.;
Topham, M. K.: Diacylglycerol kinase-delta regulates protein kinase
C and epidermal growth factor receptor signaling. Proc. Nat. Acad.
Sci. 103: 15485-15490, 2006.
3. Leach, N. T.; Sun, Y.; Michaud, S.; Zheng, Y.; Ligon, K. L.; Ligon,
A. H.; Sander, T.; Korf, B. R.; Lu, W.; Harris, D. J.; Gusella, J.
F.; Maas, R. L.; Quade, B. J.; Cole, A. J.; Kelz, M. B.; Morton, C.
C.: Disruption of diacylglycerol kinase delta (DGKD) associated with
seizures in humans and mice. Am. J. Hum. Genet. 80: 792-799, 2007.
4. Murakami, T.; Sakane, F.; Imai, S.; Houkin, K.; Kanoh, H.: Identification
and characterization of two splice variants of human diacylglycerol
kinase eta. J. Biol. Chem. 278: 34364-34372, 2003.
5. Nagase, T.; Seki, N.; Tanaka, A.; Ishikawa, K.; Nomura, N.: Prediction
of the coding sequences of unidentified human genes. IV. The coding
sequences of 40 new genes (KIAA0121-KIAA0160) deduced by analysis
of cDNA clones from human cell line KG-1. DNA Res. 2: 167-174, 1995.
6. Sakane, F.; Imai, S.; Kai, M.; Wada, I.; Kanoh, H.: Molecular
cloning of a novel diacylglycerol kinase isozyme with a pleckstrin
homology domain and a C-terminal tail similar to those of the EPH
family of protein-tyrosine kinases. J. Biol. Chem. 271: 8394-8401,
1996.
7. Sakane, F.; Imai, S.; Yamada, K.; Murakami, T.; Tsushima, S.; Kanoh,
H.: Alternative splicing of the human diacylglycerol kinase delta
gene generates two isoforms differing in their expression patterns
and in regulatory functions. J. Biol. Chem. 277: 43519-43526, 2002.
*FIELD* CN
Marla J. F. O'Neill - updated: 3/24/2008
Patricia A. Hartz - updated: 4/3/2007
Victor A. McKusick - updated: 3/27/2007
Patricia A. Hartz - updated: 1/26/2007
*FIELD* CD
Jennifer P. Macke: 3/14/1997
*FIELD* ED
ckniffin: 09/09/2013
carol: 3/7/2012
wwang: 3/25/2008
terry: 3/24/2008
wwang: 4/6/2007
terry: 4/3/2007
alopez: 3/28/2007
terry: 3/27/2007
wwang: 1/26/2007
alopez: 10/29/1999
alopez: 10/16/1998
dkim: 7/30/1998
alopez: 6/24/1997
alopez: 6/9/1997