ID   ARBK1_RAT               Reviewed;         689 AA.
AC   P26817;
DT   01-AUG-1992, integrated into UniProtKB/Swiss-Prot.
DT   01-AUG-1992, sequence version 1.
DT   08-NOV-2023, entry version 181.
DE   RecName: Full=Beta-adrenergic receptor kinase 1 {ECO:0000305};
DE            Short=Beta-ARK-1;
DE            EC=2.7.11.15 {ECO:0000269|PubMed:1403099};
DE   AltName: Full=G-protein-coupled receptor kinase 2 {ECO:0000312|RGD:2062};
GN   Name=Grk2 {ECO:0000312|RGD:2062}; Synonyms=Adrbk1;
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], TISSUE SPECIFICITY, SUBCELLULAR LOCATION, AND
RP   CATALYTIC ACTIVITY.
RC   TISSUE=Brain;
RX   PubMed=1403099; DOI=10.1523/jneurosci.12-10-04045.1992;
RA   Arriza J.L., Dawson T.M., Simerly R.B., Martin L.J., Caron M.G.,
RA   Snyder S.H., Lefkowitz R.J.;
RT   "The G-protein-coupled receptor kinases beta ARK1 and beta ARK2 are widely
RT   distributed at synapses in rat brain.";
RL   J. Neurosci. 12:4045-4055(1992).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RC   TISSUE=Brain;
RX   PubMed=1436718; DOI=10.1016/0304-3940(92)90704-b;
RA   Owada Y., Watanabe M., Kondo H.;
RT   "Localization of mRNA for beta-adrenergic receptor kinase in the brain of
RT   adult rats.";
RL   Neurosci. Lett. 144:9-13(1992).
RN   [3]
RP   INTERACTION WITH GIT1.
RX   PubMed=9826657; DOI=10.1073/pnas.95.24.14082;
RA   Premont R.T., Claing A., Vitale N., Freeman J.L.R., Pitcher J.A.,
RA   Patton W.A., Moss J., Vaughan M., Lefkowitz R.J.;
RT   "Beta2-adrenergic receptor regulation by GIT1, a G protein-coupled receptor
RT   kinase-associated ADP ribosylation factor GTPase-activating protein.";
RL   Proc. Natl. Acad. Sci. U.S.A. 95:14082-14087(1998).
RN   [4]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-670, 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: Specifically phosphorylates the agonist-occupied form of the
CC       beta-adrenergic and closely related receptors, probably inducing a
CC       desensitization of them (PubMed:1403099). Key regulator of LPAR1
CC       signaling (By similarity). Competes with RALA for binding to LPAR1 thus
CC       affecting the signaling properties of the receptor (By similarity).
CC       Desensitizes LPAR1 and LPAR2 in a phosphorylation-independent manner
CC       (By similarity). Positively regulates ciliary smoothened (SMO)-
CC       dependent Hedgehog (Hh) signaling pathway by facilitating the
CC       trafficking of SMO into the cilium and the stimulation of SMO activity
CC       (By similarity). Inhibits relaxation of airway smooth muscle in
CC       response to blue light (By similarity). {ECO:0000250|UniProtKB:P21146,
CC       ECO:0000250|UniProtKB:P25098, ECO:0000250|UniProtKB:Q99MK8,
CC       ECO:0000269|PubMed:1403099}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=[beta-adrenergic receptor] + ATP = [beta-adrenergic receptor]-
CC         phosphate + ADP + H(+); Xref=Rhea:RHEA:19429, Rhea:RHEA-COMP:11222,
CC         Rhea:RHEA-COMP:11223, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616,
CC         ChEBI:CHEBI:43176, ChEBI:CHEBI:68546, ChEBI:CHEBI:456216;
CC         EC=2.7.11.15; Evidence={ECO:0000269|PubMed:1403099};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:19430;
CC         Evidence={ECO:0000269|PubMed:1403099};
CC   -!- ACTIVITY REGULATION: In contrast to other AGC family kinases, the
CC       catalytic activity is solely regulated by the binding of substrates and
CC       ligands, not by phosphorylation of the kinase domain.
CC       {ECO:0000250|UniProtKB:P21146}.
CC   -!- SUBUNIT: Interacts with the heterodimer formed by GNB1 and GNG2 (By
CC       similarity). Interacts with GIT1 (PubMed:9826657). Interacts with, and
CC       phosphorylates chemokine-stimulated CCR5 (By similarity). Interacts
CC       with ARRB1 (By similarity). Interacts with LPAR1 and LPAR2 (By
CC       similarity). Interacts with RALA in response to LPAR1 activation (By
CC       similarity). ADRBK1 and RALA mutually inhibit each other's binding to
CC       LPAR1 (By similarity). Interacts with ADRB2 (By similarity).
CC       {ECO:0000250|UniProtKB:P21146, ECO:0000250|UniProtKB:P25098,
CC       ECO:0000269|PubMed:9826657}.
CC   -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:1403099}. Cell
CC       membrane {ECO:0000250|UniProtKB:P21146}. Postsynapse
CC       {ECO:0000269|PubMed:1403099}. Presynapse {ECO:0000269|PubMed:1403099}.
CC   -!- TISSUE SPECIFICITY: Expressed at low levels in brain cortex,
CC       hippocampus, striatum, hypothalamus, cerebellum and brainstem (at
CC       protein level). {ECO:0000269|PubMed:1403099}.
CC   -!- DOMAIN: The PH domain binds anionic phospholipids and helps recruiting
CC       ADRBK1 from the cytoplasm to plasma membrane close to activated
CC       receptors. It mediates binding to G protein beta and gamma subunits,
CC       competing with G-alpha subunits and other G-betagamma effectors.
CC       {ECO:0000250|UniProtKB:P21146}.
CC   -!- SIMILARITY: Belongs to the protein kinase superfamily. AGC Ser/Thr
CC       protein kinase family. GPRK subfamily. {ECO:0000305}.
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DR   EMBL; M87854; AAA40802.1; -; mRNA.
DR   EMBL; S48813; AAB24228.1; -; mRNA.
DR   PIR; I56531; I56531.
DR   RefSeq; NP_036908.1; NM_012776.1.
DR   AlphaFoldDB; P26817; -.
DR   SMR; P26817; -.
DR   BioGRID; 247278; 3.
DR   STRING; 10116.ENSRNOP00000025847; -.
DR   ChEMBL; CHEMBL4105719; -.
DR   iPTMnet; P26817; -.
DR   PhosphoSitePlus; P26817; -.
DR   SwissPalm; P26817; -.
DR   jPOST; P26817; -.
DR   PaxDb; 10116-ENSRNOP00000025847; -.
DR   GeneID; 25238; -.
DR   KEGG; rno:25238; -.
DR   UCSC; RGD:2062; rat.
DR   AGR; RGD:2062; -.
DR   CTD; 156; -.
DR   RGD; 2062; Grk2.
DR   eggNOG; KOG0986; Eukaryota.
DR   InParanoid; P26817; -.
DR   OrthoDB; 3415459at2759; -.
DR   PhylomeDB; P26817; -.
DR   BRENDA; 2.7.11.15; 5301.
DR   Reactome; R-RNO-111933; Calmodulin induced events.
DR   Reactome; R-RNO-416476; G alpha (q) signalling events.
DR   Reactome; R-RNO-418555; G alpha (s) signalling events.
DR   Reactome; R-RNO-5635838; Activation of SMO.
DR   Reactome; R-RNO-8856825; Cargo recognition for clathrin-mediated endocytosis.
DR   PRO; PR:P26817; -.
DR   Proteomes; UP000002494; Unplaced.
DR   GO; GO:0016324; C:apical plasma membrane; IDA:RGD.
DR   GO; GO:0030424; C:axon; IDA:RGD.
DR   GO; GO:0016323; C:basolateral plasma membrane; IDA:RGD.
DR   GO; GO:0005901; C:caveola; IDA:RGD.
DR   GO; GO:0005737; C:cytoplasm; ISO:RGD.
DR   GO; GO:0043198; C:dendritic shaft; IDA:RGD.
DR   GO; GO:0043197; C:dendritic spine; IDA:RGD.
DR   GO; GO:0098978; C:glutamatergic synapse; IDA:SynGO.
DR   GO; GO:0016020; C:membrane; ISO:RGD.
DR   GO; GO:0005634; C:nucleus; IEA:GOC.
DR   GO; GO:0014069; C:postsynaptic density; IDA:SynGO.
DR   GO; GO:0098793; C:presynapse; IDA:SynGO.
DR   GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR   GO; GO:0047696; F:beta-adrenergic receptor kinase activity; IDA:RGD.
DR   GO; GO:0031850; F:delta-type opioid receptor binding; IPI:RGD.
DR   GO; GO:0031755; F:Edg-2 lysophosphatidic acid receptor binding; ISO:RGD.
DR   GO; GO:0001664; F:G protein-coupled receptor binding; IPI:RGD.
DR   GO; GO:0004703; F:G protein-coupled receptor kinase activity; IDA:RGD.
DR   GO; GO:0031851; F:kappa-type opioid receptor binding; IPI:RGD.
DR   GO; GO:0004672; F:protein kinase activity; ISO:RGD.
DR   GO; GO:0004674; F:protein serine/threonine kinase activity; ISO:RGD.
DR   GO; GO:0097110; F:scaffold protein binding; IPI:RGD.
DR   GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:RGD.
DR   GO; GO:0060048; P:cardiac muscle contraction; ISO:RGD.
DR   GO; GO:0071870; P:cellular response to catecholamine stimulus; IEP:RGD.
DR   GO; GO:1990869; P:cellular response to chemokine; IDA:RGD.
DR   GO; GO:0071364; P:cellular response to epidermal growth factor stimulus; IMP:RGD.
DR   GO; GO:0071333; P:cellular response to glucose stimulus; IDA:RGD.
DR   GO; GO:0071407; P:cellular response to organic cyclic compound; IEP:RGD.
DR   GO; GO:1904628; P:cellular response to phorbol 13-acetate 12-myristate; IEP:RGD.
DR   GO; GO:0072752; P:cellular response to rapamycin; IEP:RGD.
DR   GO; GO:0002029; P:desensitization of G protein-coupled receptor signaling pathway; IDA:BHF-UCL.
DR   GO; GO:0042699; P:follicle-stimulating hormone signaling pathway; IDA:RGD.
DR   GO; GO:0007186; P:G protein-coupled receptor signaling pathway; IDA:RGD.
DR   GO; GO:0007507; P:heart development; ISO:RGD.
DR   GO; GO:0051457; P:maintenance of protein location in nucleus; IMP:RGD.
DR   GO; GO:0106072; P:negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway; IMP:RGD.
DR   GO; GO:0043066; P:negative regulation of apoptotic process; IMP:RGD.
DR   GO; GO:1900077; P:negative regulation of cellular response to insulin stimulus; IMP:RGD.
DR   GO; GO:0045744; P:negative regulation of G protein-coupled receptor signaling pathway; IDA:RGD.
DR   GO; GO:0046325; P:negative regulation of glucose import; IMP:RGD.
DR   GO; GO:0033137; P:negative regulation of peptidyl-serine phosphorylation; IMP:RGD.
DR   GO; GO:0010801; P:negative regulation of peptidyl-threonine phosphorylation; IMP:RGD.
DR   GO; GO:1901081; P:negative regulation of relaxation of smooth muscle; ISS:UniProtKB.
DR   GO; GO:0045988; P:negative regulation of striated muscle contraction; ISO:RGD.
DR   GO; GO:0003108; P:negative regulation of the force of heart contraction by chemical signal; ISO:RGD.
DR   GO; GO:0048709; P:oligodendrocyte differentiation; IMP:RGD.
DR   GO; GO:0016310; P:phosphorylation; IEA:UniProtKB-KW.
DR   GO; GO:0033605; P:positive regulation of catecholamine secretion; IDA:BHF-UCL.
DR   GO; GO:2000463; P:positive regulation of excitatory postsynaptic potential; IMP:RGD.
DR   GO; GO:0048146; P:positive regulation of fibroblast proliferation; IMP:RGD.
DR   GO; GO:0032755; P:positive regulation of interleukin-6 production; IMP:RGD.
DR   GO; GO:0010661; P:positive regulation of muscle cell apoptotic process; IMP:RGD.
DR   GO; GO:1904707; P:positive regulation of vascular associated smooth muscle cell proliferation; IMP:RGD.
DR   GO; GO:0045907; P:positive regulation of vasoconstriction; IMP:RGD.
DR   GO; GO:0031623; P:receptor internalization; ISO:RGD.
DR   GO; GO:0002026; P:regulation of the force of heart contraction; ISO:RGD.
DR   GO; GO:0061771; P:response to caloric restriction; IEP:RGD.
DR   GO; GO:0042542; P:response to hydrogen peroxide; IEP:RGD.
DR   GO; GO:0044321; P:response to leptin; IEP:RGD.
DR   GO; GO:0014850; P:response to muscle activity; IEP:RGD.
DR   GO; GO:0014070; P:response to organic cyclic compound; IDA:RGD.
DR   GO; GO:0006979; P:response to oxidative stress; IDA:RGD.
DR   GO; GO:0007217; P:tachykinin receptor signaling pathway; ISO:RGD.
DR   GO; GO:0042311; P:vasodilation; IMP:RGD.
DR   GO; GO:0046718; P:viral entry into host cell; ISO:RGD.
DR   GO; GO:0019079; P:viral genome replication; ISO:RGD.
DR   CDD; cd01240; PH_GRK2_subgroup; 1.
DR   CDD; cd08747; RGS_GRK2_GRK3; 1.
DR   CDD; cd14223; STKc_GRK2; 1.
DR   Gene3D; 2.30.29.30; Pleckstrin-homology domain (PH domain)/Phosphotyrosine-binding domain (PTB); 1.
DR   Gene3D; 1.10.167.10; Regulator of G-protein Signalling 4, domain 2; 1.
DR   Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1.
DR   InterPro; IPR000961; AGC-kinase_C.
DR   InterPro; IPR000239; GPCR_kinase.
DR   InterPro; IPR011009; Kinase-like_dom_sf.
DR   InterPro; IPR011993; PH-like_dom_sf.
DR   InterPro; IPR001849; PH_domain.
DR   InterPro; IPR000719; Prot_kinase_dom.
DR   InterPro; IPR017441; Protein_kinase_ATP_BS.
DR   InterPro; IPR016137; RGS.
DR   InterPro; IPR036305; RGS_sf.
DR   InterPro; IPR044926; RGS_subdomain_2.
DR   InterPro; IPR008271; Ser/Thr_kinase_AS.
DR   PANTHER; PTHR24355:SF22; BETA-ADRENERGIC RECEPTOR KINASE 1; 1.
DR   PANTHER; PTHR24355; G PROTEIN-COUPLED RECEPTOR KINASE/RIBOSOMAL PROTEIN S6 KINASE; 1.
DR   Pfam; PF00169; PH; 1.
DR   Pfam; PF00069; Pkinase; 1.
DR   Pfam; PF00615; RGS; 1.
DR   PRINTS; PR00717; GPCRKINASE.
DR   SMART; SM00233; PH; 1.
DR   SMART; SM00315; RGS; 1.
DR   SMART; SM00133; S_TK_X; 1.
DR   SMART; SM00220; S_TKc; 1.
DR   SUPFAM; SSF50729; PH domain-like; 1.
DR   SUPFAM; SSF56112; Protein kinase-like (PK-like); 1.
DR   SUPFAM; SSF48097; Regulator of G-protein signaling, RGS; 1.
DR   PROSITE; PS51285; AGC_KINASE_CTER; 1.
DR   PROSITE; PS50003; PH_DOMAIN; 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   ATP-binding; Cell membrane; Cell projection; Cytoplasm; Kinase; Membrane;
KW   Nucleotide-binding; Phosphoprotein; Reference proteome;
KW   Serine/threonine-protein kinase; Synapse; Transferase.
FT   CHAIN           1..689
FT                   /note="Beta-adrenergic receptor kinase 1"
FT                   /id="PRO_0000085630"
FT   DOMAIN          54..175
FT                   /note="RGS"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00171"
FT   DOMAIN          191..453
FT                   /note="Protein kinase"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   DOMAIN          454..521
FT                   /note="AGC-kinase C-terminal"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00618"
FT   DOMAIN          558..652
FT                   /note="PH"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00145"
FT   REGION          1..190
FT                   /note="N-terminal"
FT   ACT_SITE        317
FT                   /note="Proton acceptor"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT                   ECO:0000255|PROSITE-ProRule:PRU10027"
FT   BINDING         197..205
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   BINDING         220
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   SITE            3
FT                   /note="Required for receptor phosphorylation"
FT                   /evidence="ECO:0000250|UniProtKB:P25098"
FT   SITE            4
FT                   /note="Required for receptor phosphorylation"
FT                   /evidence="ECO:0000250|UniProtKB:P25098"
FT   SITE            10
FT                   /note="Required for receptor phosphorylation"
FT                   /evidence="ECO:0000250|UniProtKB:P25098"
FT   MOD_RES         670
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:22673903"
FT   CONFLICT        24..25
FT                   /note="PA -> RR (in Ref. 2; AAB24228)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        46
FT                   /note="Y -> N (in Ref. 2; AAB24228)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        72
FT                   /note="Y -> C (in Ref. 2; AAB24228)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        90
FT                   /note="E -> K (in Ref. 2; AAB24228)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        249
FT                   /note="G -> V (in Ref. 2; AAB24228)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        270
FT                   /note="I -> S (in Ref. 2; AAB24228)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        296
FT                   /note="F -> Y (in Ref. 2; AAB24228)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        447
FT                   /note="I -> V (in Ref. 2; AAB24228)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        594
FT                   /note="D -> G (in Ref. 2; AAB24228)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   689 AA;  79785 MW;  426A3335ACEB5A34 CRC64;
     MADLEAVLAD VSYLMAMEKS KATPAARASK KILLPEPSIR SVMQKYLEDR GEVTFEKIFS
     QKLGYLLFRD FYLNHLEEAK PLVEFYEEIE KYEKLETEEE RVVRSREIFD SYIMKELLAC
     SHPFSKNATE HVQGHLVKKQ VPPDLFQPYI EEICQNLRGD VFHKFIESDK FTRFCQWKNV
     ELNIHLTMND FSVHRIIGRG GFGEVYGCRK ADTGKMYAMK CLDKKRIKMK QGETLALNER
     IMLSLVSTGD CPFIVCMSYA FHTPDKLSFI LDLMNGGDLH YHLSQHGVFS EADMRFYAAE
     IILGLEHMHN RFVVYRDLKP ANILLDEHGH VRISDLGLAC DFSKKKPHAS VGTHGYMAPE
     VLQKGVAYDS SADWFSLGCM LFKLLRGHSP FRQHKTKDKH EIDRMTLTMA VELPDSFSPE
     LRSLLEGLLQ RDVNRRLGCL GRGAQEIKES PFFRSLDWQM VFLQKYPPPL IPPRGEVNAA
     DAFDIGSFDE EDTKGIKLLD SDQELYRNFP LTISERWQQE VAETVFDTIN AETDRLEARK
     KAKNKQLGHE EDYALGKDCI MHGYMSKMGN PFLTQWQRRY FYLFPNRLEW RGEDEAPQSL
     LTMEEIQSVE ETQIKERKCL LLKIRGGKQF VLQCDSDPEL VQWKKELRDA YREAQQLVQR
     VPKMKNKPRS PVVELSKVPL IQRGSANGL
//