Full text data of GRK6
GRK6
(GPRK6)
[Confidence: low (only semi-automatic identification from reviews)]
G protein-coupled receptor kinase 6; 2.7.11.16 (G protein-coupled receptor kinase GRK6)
G protein-coupled receptor kinase 6; 2.7.11.16 (G protein-coupled receptor kinase GRK6)
UniProt
P43250
ID GRK6_HUMAN Reviewed; 576 AA.
AC P43250; O60541; Q13652;
DT 01-NOV-1995, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2002, sequence version 2.
DT 22-JAN-2014, entry version 146.
DE RecName: Full=G protein-coupled receptor kinase 6;
DE EC=2.7.11.16;
DE AltName: Full=G protein-coupled receptor kinase GRK6;
GN Name=GRK6; Synonyms=GPRK6;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM GRK6A).
RX PubMed=8366096;
RA Benovic J.L., Gomez J.;
RT "Molecular cloning and expression of GRK6. A new member of the G
RT protein-coupled receptor kinase family.";
RL J. Biol. Chem. 268:19521-19527(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS GRK6B AND GRK6C).
RX PubMed=10506199; DOI=10.1074/jbc.274.41.29381;
RA Premont R.T., Macrae A.D., Aparicio S.A., Kendall H.E., Welch J.E.,
RA Lefkowitz R.J.;
RT "The GRK4 subfamily of G protein-coupled receptor kinases. Alternative
RT splicing, gene organization, and sequence conservation.";
RL J. Biol. Chem. 274:29381-29389(1999).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15372022; DOI=10.1038/nature02919;
RA Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S.,
RA Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M.,
RA She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S.,
RA Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M.,
RA Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T.,
RA Gomez M., Gonzales E., Goodstein D., Grigoriev I., Groza M.,
RA Hammon N., Hawkins T., Haydu L., Israni S., Jett J., Kadner K.,
RA Kimball H., Kobayashi A., Lopez F., Lou Y., Martinez D., Medina C.,
RA Morgan J., Nandkeshwar R., Noonan J.P., Pitluck S., Pollard M.,
RA Predki P., Priest J., Ramirez L., Retterer J., Rodriguez A.,
RA Rogers S., Salamov A., Salazar A., Thayer N., Tice H., Tsai M.,
RA Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J., Dickson M.,
RA Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A., Rokhsar D.S.,
RA Richardson P., Lucas S.M., Myers R.M., Rubin E.M.;
RT "The DNA sequence and comparative analysis of human chromosome 5.";
RL Nature 431:268-274(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM GRK6A).
RC TISSUE=Uterus;
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 [5]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 33-576, AND TISSUE SPECIFICITY.
RX PubMed=8415712; DOI=10.1073/pnas.90.20.9398;
RA Haribabu B., Snyderman R.;
RT "Identification of additional members of human G-protein-coupled
RT receptor kinase multigene family.";
RL Proc. Natl. Acad. Sci. U.S.A. 90:9398-9402(1993).
RN [6]
RP PALMITOYLATION AT CYS-561; CYS-562 AND CYS-565, AND MUTAGENESIS OF
RP CYS-561; CYS-562 AND CYS-565.
RX PubMed=7961702;
RA Stoffel R.H., Randall R.R., Premont R.T., Lefkowitz R.J., Inglese J.;
RT "Palmitoylation of G protein-coupled receptor kinase, GRK6. Lipid
RT modification diversity in the GRK family.";
RL J. Biol. Chem. 269:27791-27794(1994).
RN [7]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-484 AND THR-485, AND
RP MASS SPECTROMETRY.
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 [8]
RP FUNCTION IN PHOSPHORYLATION OF LRP6.
RX PubMed=19801552; DOI=10.1074/jbc.M109.047456;
RA Chen M., Philipp M., Wang J., Premont R.T., Garrison T.R., Caron M.G.,
RA Lefkowitz R.J., Chen W.;
RT "G Protein-coupled receptor kinases phosphorylate LRP6 in the Wnt
RT pathway.";
RL J. Biol. Chem. 284:35040-35048(2009).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-484 AND THR-485, AND
RP MASS SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [10]
RP FUNCTION IN PHOSPHORYLATION OF CXCR4.
RX PubMed=20048153; DOI=10.1074/jbc.M109.091173;
RA Busillo J.M., Armando S., Sengupta R., Meucci O., Bouvier M.,
RA Benovic J.L.;
RT "Site-specific phosphorylation of CXCR4 is dynamically regulated by
RT multiple kinases and results in differential modulation of CXCR4
RT signaling.";
RL J. Biol. Chem. 285:7805-7817(2010).
RN [11]
RP X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS).
RX PubMed=16613860; DOI=10.1074/jbc.M601327200;
RA Lodowski D.T., Tesmer V.M., Benovic J.L., Tesmer J.J.;
RT "The structure of G protein-coupled receptor kinase (GRK)-6 defines a
RT second lineage of GRKs.";
RL J. Biol. Chem. 281:16785-16793(2006).
RN [12]
RP X-RAY CRYSTALLOGRAPHY (2.72 ANGSTROMS) IN COMPLEX WITH AMP AND
RP SANGIVAMYCIN, AND MUTAGENESIS OF ILE-6; VAL-7; ASN-9 AND LEU-12.
RX PubMed=20729810; DOI=10.1038/emboj.2010.206;
RA Boguth C.A., Singh P., Huang C.C., Tesmer J.J.;
RT "Molecular basis for activation of G protein-coupled receptor
RT kinases.";
RL EMBO J. 29:3249-3259(2010).
RN [13]
RP VARIANTS [LARGE SCALE ANALYSIS] GLN-31; MET-73 AND MET-275.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C.,
RA Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S.,
RA O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S.,
RA Bhamra G., Buck G., Choudhury B., Clements J., Cole J., Dicks E.,
RA Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J.,
RA Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K.,
RA Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T.,
RA West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P.,
RA Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E.,
RA DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E.,
RA Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T.,
RA Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
CC -!- FUNCTION: Specifically phosphorylates the activated forms of G
CC protein-coupled receptors. Such receptor phosphorylation initiates
CC beta-arrestin-mediated receptor desensitization, internalization,
CC and signaling events leading to their desensitization. Seems to be
CC involved in the desensitization of D2-like dopamine receptors in
CC striatum and chemokine receptor CXCR4 which is critical for
CC CXCL12-induced cell chemotaxis (By similarity). Phosphorylates
CC rhodopsin (RHO) (in vitro) and a non G-protein-coupled receptor:
CC LRP6 during Wnt signaling (in vitro).
CC -!- CATALYTIC ACTIVITY: ATP + [G-protein-coupled receptor] = ADP + [G-
CC protein-coupled receptor] phosphate.
CC -!- INTERACTION:
CC P52205:ROM1 (xeno); NbExp=9; IntAct=EBI-722747, EBI-8176947;
CC -!- SUBCELLULAR LOCATION: Membrane; Lipid-anchor.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=GRK6A;
CC IsoId=P43250-1; Sequence=Displayed;
CC Name=GRK6B;
CC IsoId=P43250-2; Sequence=VSP_004938;
CC Name=GRK6C;
CC IsoId=P43250-3; Sequence=VSP_041813, VSP_041814;
CC -!- TISSUE SPECIFICITY: Widely expressed.
CC -!- PTM: It is uncertain whether palmitoylation is on Cys-561 and/or
CC Cys-562 and/or Cys-565.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. AGC Ser/Thr
CC protein kinase family. GPRK subfamily.
CC -!- SIMILARITY: Contains 1 AGC-kinase C-terminal domain.
CC -!- SIMILARITY: Contains 1 protein kinase domain.
CC -!- SIMILARITY: Contains 1 RGS domain.
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DR EMBL; L16862; AAA60175.1; -; mRNA.
DR EMBL; AF040751; AAC09273.1; -; mRNA.
DR EMBL; AF040752; AAC09274.1; -; mRNA.
DR EMBL; AC145098; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC009277; AAH09277.1; -; mRNA.
DR EMBL; U00686; AAA03565.1; -; mRNA.
DR PIR; A48765; A48765.
DR RefSeq; NP_001004105.1; NM_001004105.2.
DR RefSeq; NP_001004106.1; NM_001004106.2.
DR RefSeq; NP_002073.2; NM_002082.3.
DR UniGene; Hs.235116; -.
DR PDB; 2ACX; X-ray; 2.60 A; A/B=1-576.
DR PDB; 3NYN; X-ray; 2.72 A; A/B=2-576.
DR PDB; 3NYO; X-ray; 2.92 A; A/B=2-576.
DR PDBsum; 2ACX; -.
DR PDBsum; 3NYN; -.
DR PDBsum; 3NYO; -.
DR ProteinModelPortal; P43250; -.
DR SMR; P43250; 2-557.
DR IntAct; P43250; 4.
DR MINT; MINT-1425525; -.
DR STRING; 9606.ENSP00000377204; -.
DR BindingDB; P43250; -.
DR ChEMBL; CHEMBL6144; -.
DR GuidetoPHARMACOLOGY; 1470; -.
DR PhosphoSite; P43250; -.
DR DMDM; 20141386; -.
DR PaxDb; P43250; -.
DR PRIDE; P43250; -.
DR DNASU; 2870; -.
DR Ensembl; ENST00000355472; ENSP00000347655; ENSG00000198055.
DR Ensembl; ENST00000355958; ENSP00000348230; ENSG00000198055.
DR Ensembl; ENST00000528793; ENSP00000433511; ENSG00000198055.
DR GeneID; 2870; -.
DR KEGG; hsa:2870; -.
DR UCSC; uc021yit.1; human.
DR CTD; 2870; -.
DR GeneCards; GC05P176853; -.
DR HGNC; HGNC:4545; GRK6.
DR HPA; HPA015327; -.
DR HPA; HPA018903; -.
DR MIM; 600869; gene.
DR neXtProt; NX_P43250; -.
DR PharmGKB; PA28942; -.
DR eggNOG; COG0515; -.
DR HOGENOM; HOG000006742; -.
DR HOVERGEN; HBG004532; -.
DR KO; K08291; -.
DR OMA; MLEPPFK; -.
DR OrthoDB; EOG7V1FQK; -.
DR BRENDA; 2.7.11.16; 2681.
DR SignaLink; P43250; -.
DR EvolutionaryTrace; P43250; -.
DR GeneWiki; GRK6; -.
DR GenomeRNAi; 2870; -.
DR NextBio; 11323; -.
DR PRO; PR:P43250; -.
DR ArrayExpress; P43250; -.
DR Bgee; P43250; -.
DR CleanEx; HS_GRK6; -.
DR Genevestigator; P43250; -.
DR GO; GO:0016020; C:membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0004703; F:G-protein coupled receptor kinase activity; IEA:UniProtKB-EC.
DR GO; GO:0008277; P:regulation of G-protein coupled receptor protein signaling pathway; TAS:ProtInc.
DR GO; GO:0038032; P:termination of G-protein coupled receptor signaling pathway; IEA:InterPro.
DR GO; GO:0016055; P:Wnt receptor signaling pathway; IEA:UniProtKB-KW.
DR InterPro; IPR000961; AGC-kinase_C.
DR InterPro; IPR000239; GPCR_kinase.
DR InterPro; IPR011009; Kinase-like_dom.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR016137; Regulat_G_prot_signal_superfam.
DR InterPro; IPR000342; RGS_dom.
DR InterPro; IPR002290; Ser/Thr_dual-sp_kinase_dom.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR Pfam; PF00069; Pkinase; 1.
DR Pfam; PF00615; RGS; 1.
DR PRINTS; PR00717; GPCRKINASE.
DR SMART; SM00315; RGS; 1.
DR SMART; SM00133; S_TK_X; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF48097; SSF48097; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS51285; AGC_KINASE_CTER; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
DR PROSITE; PS50132; RGS; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; ATP-binding; Complete proteome;
KW Kinase; Lipoprotein; Membrane; Nucleotide-binding; Palmitate;
KW Phosphoprotein; Polymorphism; Reference proteome;
KW Serine/threonine-protein kinase; Transferase; Wnt signaling pathway.
FT CHAIN 1 576 G protein-coupled receptor kinase 6.
FT /FTId=PRO_0000085974.
FT DOMAIN 53 171 RGS.
FT DOMAIN 186 448 Protein kinase.
FT DOMAIN 449 514 AGC-kinase C-terminal.
FT NP_BIND 192 200 ATP.
FT NP_BIND 264 270 ATP.
FT NP_BIND 315 318 ATP.
FT REGION 1 185 N-terminal.
FT ACT_SITE 311 311 Proton acceptor (By similarity).
FT BINDING 215 215 ATP.
FT MOD_RES 484 484 Phosphoserine.
FT MOD_RES 485 485 Phosphothreonine.
FT LIPID 561 561 S-palmitoyl cysteine (Probable).
FT LIPID 562 562 S-palmitoyl cysteine (Probable).
FT LIPID 565 565 S-palmitoyl cysteine (Probable).
FT VAR_SEQ 560 576 DCCGNCSDSEEELPTRL -> RIAVETAATARKSSPPASSP
FT QPEAPTSSWR (in isoform GRK6B).
FT /FTId=VSP_004938.
FT VAR_SEQ 560 560 D -> R (in isoform GRK6C).
FT /FTId=VSP_041813.
FT VAR_SEQ 561 576 Missing (in isoform GRK6C).
FT /FTId=VSP_041814.
FT VARIANT 31 31 R -> Q (in a gastric adenocarcinoma
FT sample; somatic mutation).
FT /FTId=VAR_040524.
FT VARIANT 73 73 T -> M (in dbSNP:rs56382815).
FT /FTId=VAR_040525.
FT VARIANT 275 275 I -> M (in a breast infiltrating ductal
FT carcinoma sample; somatic mutation).
FT /FTId=VAR_040526.
FT MUTAGEN 6 6 I->A: 12-13 fold defects in kinase
FT activity; 180-fold defects in kinase
FT activity; when associated with A-7.
FT MUTAGEN 7 7 V->A: 12-13 fold defects in kinase
FT activity; 180-fold defects in kinase
FT activity; when associated with A-6.
FT MUTAGEN 9 9 N->A: 140-fold defects in kinase
FT activity.
FT MUTAGEN 12 12 L->A: 1100-fold defects in kinase
FT activity.
FT MUTAGEN 561 561 C->S: Abolishes palmitoylation; when
FT associated with S-562 and S-565.
FT MUTAGEN 562 562 C->S: Abolishes palmitoylation; when
FT associated with S-561 and S-565.
FT MUTAGEN 565 565 C->S: Abolishes palmitoylation; when
FT associated with S-561 and S-562.
FT CONFLICT 60 61 QP -> HA (in Ref. 1; AAA60175).
FT CONFLICT 104 105 QL -> HV (in Ref. 1; AAA60175).
FT HELIX 3 18
FT STRAND 23 25
FT HELIX 30 33
FT HELIX 40 42
FT HELIX 43 48
FT HELIX 53 57
FT HELIX 61 71
FT HELIX 75 91
FT TURN 95 97
FT HELIX 98 109
FT STRAND 112 114
FT STRAND 117 120
FT HELIX 123 135
FT TURN 139 142
FT HELIX 143 153
FT HELIX 156 162
FT HELIX 165 177
FT HELIX 183 185
FT STRAND 186 195
FT STRAND 198 205
FT TURN 206 208
FT STRAND 211 218
FT HELIX 219 224
FT HELIX 228 240
FT STRAND 249 254
FT STRAND 256 263
FT HELIX 271 276
FT STRAND 277 280
FT HELIX 285 304
FT HELIX 314 316
FT STRAND 317 319
FT STRAND 325 327
FT HELIX 349 351
FT HELIX 354 357
FT STRAND 361 364
FT HELIX 365 380
FT STRAND 384 386
FT STRAND 388 390
FT HELIX 394 403
FT STRAND 410 412
FT HELIX 414 423
FT HELIX 428 430
FT STRAND 435 437
FT HELIX 438 443
FT HELIX 446 448
FT HELIX 453 457
FT HELIX 477 479
FT HELIX 493 502
FT HELIX 508 517
FT HELIX 520 525
FT STRAND 527 530
FT HELIX 549 555
SQ SEQUENCE 576 AA; 65991 MW; 3BF8C3B1CDE2BD74 CRC64;
MELENIVANT VLLKAREGGG GNRKGKSKKW RQMLQFPHIS QCEELRLSLE RDYHSLCERQ
PIGRLLFREF CATRPELSRC VAFLDGVAEY EVTPDDKRKA CGRQLTQNFL SHTGPDLIPE
VPRQLVTNCT QRLEQGPCKD LFQELTRLTH EYLSVAPFAD YLDSIYFNRF LQWKWLERQP
VTKNTFRQYR VLGKGGFGEV CACQVRATGK MYACKKLEKK RIKKRKGEAM ALNEKQILEK
VNSRFVVSLA YAYETKDALC LVLTLMNGGD LKFHIYHMGQ AGFPEARAVF YAAEICCGLE
DLHRERIVYR DLKPENILLD DHGHIRISDL GLAVHVPEGQ TIKGRVGTVG YMAPEVVKNE
RYTFSPDWWA LGCLLYEMIA GQSPFQQRKK KIKREEVERL VKEVPEEYSE RFSPQARSLC
SQLLCKDPAE RLGCRGGSAR EVKEHPLFKK LNFKRLGAGM LEPPFKPDPQ AIYCKDVLDI
EQFSTVKGVE LEPTDQDFYQ KFATGSVPIP WQNEMVETEC FQELNVFGLD GSVPPDLDWK
GQPPAPPKKG LLQRLFSRQD CCGNCSDSEE ELPTRL
//
ID GRK6_HUMAN Reviewed; 576 AA.
AC P43250; O60541; Q13652;
DT 01-NOV-1995, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2002, sequence version 2.
DT 22-JAN-2014, entry version 146.
DE RecName: Full=G protein-coupled receptor kinase 6;
DE EC=2.7.11.16;
DE AltName: Full=G protein-coupled receptor kinase GRK6;
GN Name=GRK6; Synonyms=GPRK6;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM GRK6A).
RX PubMed=8366096;
RA Benovic J.L., Gomez J.;
RT "Molecular cloning and expression of GRK6. A new member of the G
RT protein-coupled receptor kinase family.";
RL J. Biol. Chem. 268:19521-19527(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS GRK6B AND GRK6C).
RX PubMed=10506199; DOI=10.1074/jbc.274.41.29381;
RA Premont R.T., Macrae A.D., Aparicio S.A., Kendall H.E., Welch J.E.,
RA Lefkowitz R.J.;
RT "The GRK4 subfamily of G protein-coupled receptor kinases. Alternative
RT splicing, gene organization, and sequence conservation.";
RL J. Biol. Chem. 274:29381-29389(1999).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15372022; DOI=10.1038/nature02919;
RA Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S.,
RA Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M.,
RA She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S.,
RA Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M.,
RA Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T.,
RA Gomez M., Gonzales E., Goodstein D., Grigoriev I., Groza M.,
RA Hammon N., Hawkins T., Haydu L., Israni S., Jett J., Kadner K.,
RA Kimball H., Kobayashi A., Lopez F., Lou Y., Martinez D., Medina C.,
RA Morgan J., Nandkeshwar R., Noonan J.P., Pitluck S., Pollard M.,
RA Predki P., Priest J., Ramirez L., Retterer J., Rodriguez A.,
RA Rogers S., Salamov A., Salazar A., Thayer N., Tice H., Tsai M.,
RA Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J., Dickson M.,
RA Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A., Rokhsar D.S.,
RA Richardson P., Lucas S.M., Myers R.M., Rubin E.M.;
RT "The DNA sequence and comparative analysis of human chromosome 5.";
RL Nature 431:268-274(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM GRK6A).
RC TISSUE=Uterus;
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 [5]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 33-576, AND TISSUE SPECIFICITY.
RX PubMed=8415712; DOI=10.1073/pnas.90.20.9398;
RA Haribabu B., Snyderman R.;
RT "Identification of additional members of human G-protein-coupled
RT receptor kinase multigene family.";
RL Proc. Natl. Acad. Sci. U.S.A. 90:9398-9402(1993).
RN [6]
RP PALMITOYLATION AT CYS-561; CYS-562 AND CYS-565, AND MUTAGENESIS OF
RP CYS-561; CYS-562 AND CYS-565.
RX PubMed=7961702;
RA Stoffel R.H., Randall R.R., Premont R.T., Lefkowitz R.J., Inglese J.;
RT "Palmitoylation of G protein-coupled receptor kinase, GRK6. Lipid
RT modification diversity in the GRK family.";
RL J. Biol. Chem. 269:27791-27794(1994).
RN [7]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-484 AND THR-485, AND
RP MASS SPECTROMETRY.
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 [8]
RP FUNCTION IN PHOSPHORYLATION OF LRP6.
RX PubMed=19801552; DOI=10.1074/jbc.M109.047456;
RA Chen M., Philipp M., Wang J., Premont R.T., Garrison T.R., Caron M.G.,
RA Lefkowitz R.J., Chen W.;
RT "G Protein-coupled receptor kinases phosphorylate LRP6 in the Wnt
RT pathway.";
RL J. Biol. Chem. 284:35040-35048(2009).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-484 AND THR-485, AND
RP MASS SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [10]
RP FUNCTION IN PHOSPHORYLATION OF CXCR4.
RX PubMed=20048153; DOI=10.1074/jbc.M109.091173;
RA Busillo J.M., Armando S., Sengupta R., Meucci O., Bouvier M.,
RA Benovic J.L.;
RT "Site-specific phosphorylation of CXCR4 is dynamically regulated by
RT multiple kinases and results in differential modulation of CXCR4
RT signaling.";
RL J. Biol. Chem. 285:7805-7817(2010).
RN [11]
RP X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS).
RX PubMed=16613860; DOI=10.1074/jbc.M601327200;
RA Lodowski D.T., Tesmer V.M., Benovic J.L., Tesmer J.J.;
RT "The structure of G protein-coupled receptor kinase (GRK)-6 defines a
RT second lineage of GRKs.";
RL J. Biol. Chem. 281:16785-16793(2006).
RN [12]
RP X-RAY CRYSTALLOGRAPHY (2.72 ANGSTROMS) IN COMPLEX WITH AMP AND
RP SANGIVAMYCIN, AND MUTAGENESIS OF ILE-6; VAL-7; ASN-9 AND LEU-12.
RX PubMed=20729810; DOI=10.1038/emboj.2010.206;
RA Boguth C.A., Singh P., Huang C.C., Tesmer J.J.;
RT "Molecular basis for activation of G protein-coupled receptor
RT kinases.";
RL EMBO J. 29:3249-3259(2010).
RN [13]
RP VARIANTS [LARGE SCALE ANALYSIS] GLN-31; MET-73 AND MET-275.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C.,
RA Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S.,
RA O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S.,
RA Bhamra G., Buck G., Choudhury B., Clements J., Cole J., Dicks E.,
RA Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J.,
RA Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K.,
RA Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T.,
RA West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P.,
RA Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E.,
RA DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E.,
RA Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T.,
RA Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
CC -!- FUNCTION: Specifically phosphorylates the activated forms of G
CC protein-coupled receptors. Such receptor phosphorylation initiates
CC beta-arrestin-mediated receptor desensitization, internalization,
CC and signaling events leading to their desensitization. Seems to be
CC involved in the desensitization of D2-like dopamine receptors in
CC striatum and chemokine receptor CXCR4 which is critical for
CC CXCL12-induced cell chemotaxis (By similarity). Phosphorylates
CC rhodopsin (RHO) (in vitro) and a non G-protein-coupled receptor:
CC LRP6 during Wnt signaling (in vitro).
CC -!- CATALYTIC ACTIVITY: ATP + [G-protein-coupled receptor] = ADP + [G-
CC protein-coupled receptor] phosphate.
CC -!- INTERACTION:
CC P52205:ROM1 (xeno); NbExp=9; IntAct=EBI-722747, EBI-8176947;
CC -!- SUBCELLULAR LOCATION: Membrane; Lipid-anchor.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=GRK6A;
CC IsoId=P43250-1; Sequence=Displayed;
CC Name=GRK6B;
CC IsoId=P43250-2; Sequence=VSP_004938;
CC Name=GRK6C;
CC IsoId=P43250-3; Sequence=VSP_041813, VSP_041814;
CC -!- TISSUE SPECIFICITY: Widely expressed.
CC -!- PTM: It is uncertain whether palmitoylation is on Cys-561 and/or
CC Cys-562 and/or Cys-565.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. AGC Ser/Thr
CC protein kinase family. GPRK subfamily.
CC -!- SIMILARITY: Contains 1 AGC-kinase C-terminal domain.
CC -!- SIMILARITY: Contains 1 protein kinase domain.
CC -!- SIMILARITY: Contains 1 RGS domain.
CC -----------------------------------------------------------------------
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DR EMBL; L16862; AAA60175.1; -; mRNA.
DR EMBL; AF040751; AAC09273.1; -; mRNA.
DR EMBL; AF040752; AAC09274.1; -; mRNA.
DR EMBL; AC145098; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC009277; AAH09277.1; -; mRNA.
DR EMBL; U00686; AAA03565.1; -; mRNA.
DR PIR; A48765; A48765.
DR RefSeq; NP_001004105.1; NM_001004105.2.
DR RefSeq; NP_001004106.1; NM_001004106.2.
DR RefSeq; NP_002073.2; NM_002082.3.
DR UniGene; Hs.235116; -.
DR PDB; 2ACX; X-ray; 2.60 A; A/B=1-576.
DR PDB; 3NYN; X-ray; 2.72 A; A/B=2-576.
DR PDB; 3NYO; X-ray; 2.92 A; A/B=2-576.
DR PDBsum; 2ACX; -.
DR PDBsum; 3NYN; -.
DR PDBsum; 3NYO; -.
DR ProteinModelPortal; P43250; -.
DR SMR; P43250; 2-557.
DR IntAct; P43250; 4.
DR MINT; MINT-1425525; -.
DR STRING; 9606.ENSP00000377204; -.
DR BindingDB; P43250; -.
DR ChEMBL; CHEMBL6144; -.
DR GuidetoPHARMACOLOGY; 1470; -.
DR PhosphoSite; P43250; -.
DR DMDM; 20141386; -.
DR PaxDb; P43250; -.
DR PRIDE; P43250; -.
DR DNASU; 2870; -.
DR Ensembl; ENST00000355472; ENSP00000347655; ENSG00000198055.
DR Ensembl; ENST00000355958; ENSP00000348230; ENSG00000198055.
DR Ensembl; ENST00000528793; ENSP00000433511; ENSG00000198055.
DR GeneID; 2870; -.
DR KEGG; hsa:2870; -.
DR UCSC; uc021yit.1; human.
DR CTD; 2870; -.
DR GeneCards; GC05P176853; -.
DR HGNC; HGNC:4545; GRK6.
DR HPA; HPA015327; -.
DR HPA; HPA018903; -.
DR MIM; 600869; gene.
DR neXtProt; NX_P43250; -.
DR PharmGKB; PA28942; -.
DR eggNOG; COG0515; -.
DR HOGENOM; HOG000006742; -.
DR HOVERGEN; HBG004532; -.
DR KO; K08291; -.
DR OMA; MLEPPFK; -.
DR OrthoDB; EOG7V1FQK; -.
DR BRENDA; 2.7.11.16; 2681.
DR SignaLink; P43250; -.
DR EvolutionaryTrace; P43250; -.
DR GeneWiki; GRK6; -.
DR GenomeRNAi; 2870; -.
DR NextBio; 11323; -.
DR PRO; PR:P43250; -.
DR ArrayExpress; P43250; -.
DR Bgee; P43250; -.
DR CleanEx; HS_GRK6; -.
DR Genevestigator; P43250; -.
DR GO; GO:0016020; C:membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0004703; F:G-protein coupled receptor kinase activity; IEA:UniProtKB-EC.
DR GO; GO:0008277; P:regulation of G-protein coupled receptor protein signaling pathway; TAS:ProtInc.
DR GO; GO:0038032; P:termination of G-protein coupled receptor signaling pathway; IEA:InterPro.
DR GO; GO:0016055; P:Wnt receptor signaling pathway; IEA:UniProtKB-KW.
DR InterPro; IPR000961; AGC-kinase_C.
DR InterPro; IPR000239; GPCR_kinase.
DR InterPro; IPR011009; Kinase-like_dom.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR016137; Regulat_G_prot_signal_superfam.
DR InterPro; IPR000342; RGS_dom.
DR InterPro; IPR002290; Ser/Thr_dual-sp_kinase_dom.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR Pfam; PF00069; Pkinase; 1.
DR Pfam; PF00615; RGS; 1.
DR PRINTS; PR00717; GPCRKINASE.
DR SMART; SM00315; RGS; 1.
DR SMART; SM00133; S_TK_X; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF48097; SSF48097; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS51285; AGC_KINASE_CTER; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
DR PROSITE; PS50132; RGS; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; ATP-binding; Complete proteome;
KW Kinase; Lipoprotein; Membrane; Nucleotide-binding; Palmitate;
KW Phosphoprotein; Polymorphism; Reference proteome;
KW Serine/threonine-protein kinase; Transferase; Wnt signaling pathway.
FT CHAIN 1 576 G protein-coupled receptor kinase 6.
FT /FTId=PRO_0000085974.
FT DOMAIN 53 171 RGS.
FT DOMAIN 186 448 Protein kinase.
FT DOMAIN 449 514 AGC-kinase C-terminal.
FT NP_BIND 192 200 ATP.
FT NP_BIND 264 270 ATP.
FT NP_BIND 315 318 ATP.
FT REGION 1 185 N-terminal.
FT ACT_SITE 311 311 Proton acceptor (By similarity).
FT BINDING 215 215 ATP.
FT MOD_RES 484 484 Phosphoserine.
FT MOD_RES 485 485 Phosphothreonine.
FT LIPID 561 561 S-palmitoyl cysteine (Probable).
FT LIPID 562 562 S-palmitoyl cysteine (Probable).
FT LIPID 565 565 S-palmitoyl cysteine (Probable).
FT VAR_SEQ 560 576 DCCGNCSDSEEELPTRL -> RIAVETAATARKSSPPASSP
FT QPEAPTSSWR (in isoform GRK6B).
FT /FTId=VSP_004938.
FT VAR_SEQ 560 560 D -> R (in isoform GRK6C).
FT /FTId=VSP_041813.
FT VAR_SEQ 561 576 Missing (in isoform GRK6C).
FT /FTId=VSP_041814.
FT VARIANT 31 31 R -> Q (in a gastric adenocarcinoma
FT sample; somatic mutation).
FT /FTId=VAR_040524.
FT VARIANT 73 73 T -> M (in dbSNP:rs56382815).
FT /FTId=VAR_040525.
FT VARIANT 275 275 I -> M (in a breast infiltrating ductal
FT carcinoma sample; somatic mutation).
FT /FTId=VAR_040526.
FT MUTAGEN 6 6 I->A: 12-13 fold defects in kinase
FT activity; 180-fold defects in kinase
FT activity; when associated with A-7.
FT MUTAGEN 7 7 V->A: 12-13 fold defects in kinase
FT activity; 180-fold defects in kinase
FT activity; when associated with A-6.
FT MUTAGEN 9 9 N->A: 140-fold defects in kinase
FT activity.
FT MUTAGEN 12 12 L->A: 1100-fold defects in kinase
FT activity.
FT MUTAGEN 561 561 C->S: Abolishes palmitoylation; when
FT associated with S-562 and S-565.
FT MUTAGEN 562 562 C->S: Abolishes palmitoylation; when
FT associated with S-561 and S-565.
FT MUTAGEN 565 565 C->S: Abolishes palmitoylation; when
FT associated with S-561 and S-562.
FT CONFLICT 60 61 QP -> HA (in Ref. 1; AAA60175).
FT CONFLICT 104 105 QL -> HV (in Ref. 1; AAA60175).
FT HELIX 3 18
FT STRAND 23 25
FT HELIX 30 33
FT HELIX 40 42
FT HELIX 43 48
FT HELIX 53 57
FT HELIX 61 71
FT HELIX 75 91
FT TURN 95 97
FT HELIX 98 109
FT STRAND 112 114
FT STRAND 117 120
FT HELIX 123 135
FT TURN 139 142
FT HELIX 143 153
FT HELIX 156 162
FT HELIX 165 177
FT HELIX 183 185
FT STRAND 186 195
FT STRAND 198 205
FT TURN 206 208
FT STRAND 211 218
FT HELIX 219 224
FT HELIX 228 240
FT STRAND 249 254
FT STRAND 256 263
FT HELIX 271 276
FT STRAND 277 280
FT HELIX 285 304
FT HELIX 314 316
FT STRAND 317 319
FT STRAND 325 327
FT HELIX 349 351
FT HELIX 354 357
FT STRAND 361 364
FT HELIX 365 380
FT STRAND 384 386
FT STRAND 388 390
FT HELIX 394 403
FT STRAND 410 412
FT HELIX 414 423
FT HELIX 428 430
FT STRAND 435 437
FT HELIX 438 443
FT HELIX 446 448
FT HELIX 453 457
FT HELIX 477 479
FT HELIX 493 502
FT HELIX 508 517
FT HELIX 520 525
FT STRAND 527 530
FT HELIX 549 555
SQ SEQUENCE 576 AA; 65991 MW; 3BF8C3B1CDE2BD74 CRC64;
MELENIVANT VLLKAREGGG GNRKGKSKKW RQMLQFPHIS QCEELRLSLE RDYHSLCERQ
PIGRLLFREF CATRPELSRC VAFLDGVAEY EVTPDDKRKA CGRQLTQNFL SHTGPDLIPE
VPRQLVTNCT QRLEQGPCKD LFQELTRLTH EYLSVAPFAD YLDSIYFNRF LQWKWLERQP
VTKNTFRQYR VLGKGGFGEV CACQVRATGK MYACKKLEKK RIKKRKGEAM ALNEKQILEK
VNSRFVVSLA YAYETKDALC LVLTLMNGGD LKFHIYHMGQ AGFPEARAVF YAAEICCGLE
DLHRERIVYR DLKPENILLD DHGHIRISDL GLAVHVPEGQ TIKGRVGTVG YMAPEVVKNE
RYTFSPDWWA LGCLLYEMIA GQSPFQQRKK KIKREEVERL VKEVPEEYSE RFSPQARSLC
SQLLCKDPAE RLGCRGGSAR EVKEHPLFKK LNFKRLGAGM LEPPFKPDPQ AIYCKDVLDI
EQFSTVKGVE LEPTDQDFYQ KFATGSVPIP WQNEMVETEC FQELNVFGLD GSVPPDLDWK
GQPPAPPKKG LLQRLFSRQD CCGNCSDSEE ELPTRL
//
MIM
600869
*RECORD*
*FIELD* NO
600869
*FIELD* TI
*600869 G PROTEIN-COUPLED RECEPTOR KINASE 6; GRK6
;;GPRK6
*FIELD* TX
CLONING
By PCR on neutrophil cDNA using primers based on sequences of known
read morereceptor kinases, Haribabu and Snyderman (1993) identified GPRK5
(600870) and GPRK6 sequences. Using a fragment of the GPRK6 PCR clone to
screen a cDNA library, they isolated a cDNA encoding GPRK6. Sequence
analysis predicted that the 544-amino acid GPRK6 protein contains the
conserved DLG (asp-leu-gly) and ENIL (glu-asn-ile-leu) motifs. Northern
blot analysis detected 2.1- and 2.9-kb GPRK6 transcripts in all tissues
tested, with strongest expression in placenta and skeletal muscle.
By screening a heart cDNA with the catalytic domains of BARK (ADRBK1;
109635), Benovic and Gomez (1993) isolated a cDNA encoding GRK6. The
576-amino acid GRK6 protein is 70% identical to GRK5. PAGE analysis
showed expression of a 66-kD protein from an insect cell line.
GENE FUNCTION
Benovic and Gomez (1993) found that GRK6 could phosphorylate rhodopsin
(RHO; 180380) in a light-dependent manner and ADRB2 (109690) in an
agonist-dependent manner. However, GRK6 was significantly less active
than BARK or GRK5 on these substrates.
Gaudreau et al. (2002) identified the leukotriene B4 receptor, BLT1
(LTB4R; 601531), as a substrate for GRK6. Thr308 in the BLT1 cytoplasmic
tail was critical for inositol phosphate production and GRK6-mediated
phosphorylation and desensitization of BLT1 signaling.
MAPPING
By somatic cell hybrid analysis, Haribabu and Snyderman (1993) mapped
the GPRK6 gene and a closely related gene to chromosomes 5 and 13,
respectively. Bullrich et al. (1995) mapped GPRK6 to 5q35 by analysis of
a rodent human hybrid panel. The GPRK6-related locus was found to map to
13pter-q21.
ANIMAL MODEL
Gainetdinov et al. (2003) noted that some GRKs have been shown to
phosphorylate G protein-coupled dopamine receptors, thereby regulating
their activity and mediating desensitization of the receptors. Using
immunohistochemistry, Gainetdinov et al. (2003) found that GRK6 is
expressed in striatal neurons receiving dopaminergic input, and that
postsynaptic D2/D3 dopamine receptors are physiologic targets of this
kinase. GRK6 knockout mice showed supersensitivity to the
locomotor-stimulating effects of psychostimulants, including cocaine and
amphetamine. In addition, these mice demonstrated an enhanced coupling
of striatal D2-like dopamine receptors to G proteins and augmented
response to direct dopamine agonists. Gainetdinov et al. (2003) noted
that supersensitivity of dopamine signaling has been postulated to be
involved in several brain disorders, including addiction.
Kavelaars et al. (2003) found that application of arachidonic acid to
the ears of Grk6 -/- mice induced significantly increased inflammatory
responses compared with wildtype mice. Neutrophils from Grk6 -/- mice
responded to leukotriene B4 with a prolonged increase in intracellular
calcium and actin polymerization. Kavelaars et al. (2003) concluded that
GRK6 deficiency leads to prolonged BLT1 signaling and increased
neutrophil migration.
*FIELD* RF
1. Benovic, J. L.; Gomez, J.: Molecular cloning and expression of
GRK6: a new member of the G protein-coupled receptor kinase family. J.
Biol. Chem. 268: 19521-19527, 1993.
2. Bullrich, F.; Druck, T.; Kunapuli, P.; Gomez, J.; Gripp, K. W.;
Schlegelberger, B.; Lasota, J.; Aronson, M.; Cannizzaro, L. A.; Huebner,
K.; Benovic, J. L.: Chromosomal mapping of the genes GPRK5 and GPRK6
encoding G protein-coupled receptor kinases GRK5 and GRK6. Cytogenet.
Cell Genet. 70: 250-254, 1995.
3. Gainetdinov, R. R.; Bohn, L. M.; Sotnikova, T. D.; Cyr, M.; Laakso,
A.; Macrae, A. D.; Torres, G. E.; Kim, K.-M.; Lefkowitz, R. J.; Caron,
M. G.; Premont, R. T.: Dopaminergic supersensitivity in G protein-coupled
receptor kinase 6-deficient mice. Neuron 38: 291-303, 2003.
4. Gaudreau, R.; Le Gouill, C.; Venne, M. H.; Stankova, J.; Rola-Pleszczynski,
M.: Threonine 308 within a putative casein kinase 2 site of the cytoplasmic
tail of leukotriene B(4) receptor (BLT1) is crucial for ligand-induced,
G-protein-coupled receptor-specific kinase 6-mediated desensitization. J.
Biol. Chem. 277: 31567-31576, 2002.
5. Haribabu, B.; Snyderman, R.: Identification of additional members
of human G-protein-coupled receptor kinase multigene family. Proc.
Nat. Acad. Sci. 90: 9398-9402, 1993.
6. Kavelaars, A.; Vroon, A.; Raatgever, R. P.; Fong, A. M.; Premont,
R. T.; Patel, D. D.; Lefkowitz, R. J.; Heijnen, C. J.: Increased
acute inflammation, leukotriene B4-induced chemotaxis, and signaling
in mice deficient for G protein-coupled receptor kinase 6. J. Immun. 171:
6128-6134, 2003.
*FIELD* CN
Paul J. Converse - updated: 3/31/2006
Cassandra L. Kniffin - updated: 10/10/2003
Paul J. Converse - updated: 6/22/2000
*FIELD* CD
Victor A. McKusick: 10/16/1995
*FIELD* ED
mgross: 05/18/2012
mgross: 4/3/2006
terry: 3/31/2006
carol: 10/13/2003
ckniffin: 10/10/2003
carol: 7/1/2002
carol: 5/24/2002
mgross: 6/22/2000
mark: 10/16/1995
*RECORD*
*FIELD* NO
600869
*FIELD* TI
*600869 G PROTEIN-COUPLED RECEPTOR KINASE 6; GRK6
;;GPRK6
*FIELD* TX
CLONING
By PCR on neutrophil cDNA using primers based on sequences of known
read morereceptor kinases, Haribabu and Snyderman (1993) identified GPRK5
(600870) and GPRK6 sequences. Using a fragment of the GPRK6 PCR clone to
screen a cDNA library, they isolated a cDNA encoding GPRK6. Sequence
analysis predicted that the 544-amino acid GPRK6 protein contains the
conserved DLG (asp-leu-gly) and ENIL (glu-asn-ile-leu) motifs. Northern
blot analysis detected 2.1- and 2.9-kb GPRK6 transcripts in all tissues
tested, with strongest expression in placenta and skeletal muscle.
By screening a heart cDNA with the catalytic domains of BARK (ADRBK1;
109635), Benovic and Gomez (1993) isolated a cDNA encoding GRK6. The
576-amino acid GRK6 protein is 70% identical to GRK5. PAGE analysis
showed expression of a 66-kD protein from an insect cell line.
GENE FUNCTION
Benovic and Gomez (1993) found that GRK6 could phosphorylate rhodopsin
(RHO; 180380) in a light-dependent manner and ADRB2 (109690) in an
agonist-dependent manner. However, GRK6 was significantly less active
than BARK or GRK5 on these substrates.
Gaudreau et al. (2002) identified the leukotriene B4 receptor, BLT1
(LTB4R; 601531), as a substrate for GRK6. Thr308 in the BLT1 cytoplasmic
tail was critical for inositol phosphate production and GRK6-mediated
phosphorylation and desensitization of BLT1 signaling.
MAPPING
By somatic cell hybrid analysis, Haribabu and Snyderman (1993) mapped
the GPRK6 gene and a closely related gene to chromosomes 5 and 13,
respectively. Bullrich et al. (1995) mapped GPRK6 to 5q35 by analysis of
a rodent human hybrid panel. The GPRK6-related locus was found to map to
13pter-q21.
ANIMAL MODEL
Gainetdinov et al. (2003) noted that some GRKs have been shown to
phosphorylate G protein-coupled dopamine receptors, thereby regulating
their activity and mediating desensitization of the receptors. Using
immunohistochemistry, Gainetdinov et al. (2003) found that GRK6 is
expressed in striatal neurons receiving dopaminergic input, and that
postsynaptic D2/D3 dopamine receptors are physiologic targets of this
kinase. GRK6 knockout mice showed supersensitivity to the
locomotor-stimulating effects of psychostimulants, including cocaine and
amphetamine. In addition, these mice demonstrated an enhanced coupling
of striatal D2-like dopamine receptors to G proteins and augmented
response to direct dopamine agonists. Gainetdinov et al. (2003) noted
that supersensitivity of dopamine signaling has been postulated to be
involved in several brain disorders, including addiction.
Kavelaars et al. (2003) found that application of arachidonic acid to
the ears of Grk6 -/- mice induced significantly increased inflammatory
responses compared with wildtype mice. Neutrophils from Grk6 -/- mice
responded to leukotriene B4 with a prolonged increase in intracellular
calcium and actin polymerization. Kavelaars et al. (2003) concluded that
GRK6 deficiency leads to prolonged BLT1 signaling and increased
neutrophil migration.
*FIELD* RF
1. Benovic, J. L.; Gomez, J.: Molecular cloning and expression of
GRK6: a new member of the G protein-coupled receptor kinase family. J.
Biol. Chem. 268: 19521-19527, 1993.
2. Bullrich, F.; Druck, T.; Kunapuli, P.; Gomez, J.; Gripp, K. W.;
Schlegelberger, B.; Lasota, J.; Aronson, M.; Cannizzaro, L. A.; Huebner,
K.; Benovic, J. L.: Chromosomal mapping of the genes GPRK5 and GPRK6
encoding G protein-coupled receptor kinases GRK5 and GRK6. Cytogenet.
Cell Genet. 70: 250-254, 1995.
3. Gainetdinov, R. R.; Bohn, L. M.; Sotnikova, T. D.; Cyr, M.; Laakso,
A.; Macrae, A. D.; Torres, G. E.; Kim, K.-M.; Lefkowitz, R. J.; Caron,
M. G.; Premont, R. T.: Dopaminergic supersensitivity in G protein-coupled
receptor kinase 6-deficient mice. Neuron 38: 291-303, 2003.
4. Gaudreau, R.; Le Gouill, C.; Venne, M. H.; Stankova, J.; Rola-Pleszczynski,
M.: Threonine 308 within a putative casein kinase 2 site of the cytoplasmic
tail of leukotriene B(4) receptor (BLT1) is crucial for ligand-induced,
G-protein-coupled receptor-specific kinase 6-mediated desensitization. J.
Biol. Chem. 277: 31567-31576, 2002.
5. Haribabu, B.; Snyderman, R.: Identification of additional members
of human G-protein-coupled receptor kinase multigene family. Proc.
Nat. Acad. Sci. 90: 9398-9402, 1993.
6. Kavelaars, A.; Vroon, A.; Raatgever, R. P.; Fong, A. M.; Premont,
R. T.; Patel, D. D.; Lefkowitz, R. J.; Heijnen, C. J.: Increased
acute inflammation, leukotriene B4-induced chemotaxis, and signaling
in mice deficient for G protein-coupled receptor kinase 6. J. Immun. 171:
6128-6134, 2003.
*FIELD* CN
Paul J. Converse - updated: 3/31/2006
Cassandra L. Kniffin - updated: 10/10/2003
Paul J. Converse - updated: 6/22/2000
*FIELD* CD
Victor A. McKusick: 10/16/1995
*FIELD* ED
mgross: 05/18/2012
mgross: 4/3/2006
terry: 3/31/2006
carol: 10/13/2003
ckniffin: 10/10/2003
carol: 7/1/2002
carol: 5/24/2002
mgross: 6/22/2000
mark: 10/16/1995