Information on EC 2.7.11.15 - beta-adrenergic-receptor kinase

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The expected taxonomic range for this enzyme is: Coelomata

EC NUMBER
COMMENTARY hide
2.7.11.15
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RECOMMENDED NAME
GeneOntology No.
beta-adrenergic-receptor kinase
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
ATP + [beta-adrenergic receptor] = ADP + phospho-[beta-adrenergic receptor]
show the reaction diagram
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
phospho group transfer
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SYSTEMATIC NAME
IUBMB Comments
ATP:[beta-adrenergic receptor] phosphotransferase
Requires G-protein for activation and therefore belongs to the family of G-protein-dependent receptor kinases (GRKs). Acts on the agonist-occupied form of the receptor; also phosphorylates rhodopsin, but more slowly. Does not act on casein or histones. The enzyme is inhibited by Zn2+ and digitonin but is unaffected by cyclic-AMP (cf. EC 2.7.11.14, rhodopsin kinase and EC 2.7.11.16, G-protein-coupled receptor kinase).
CAS REGISTRY NUMBER
COMMENTARY hide
102925-39-3
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ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
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Manually annotated by BRENDA team
North American opossum, gene GRK2
SwissProt
Manually annotated by BRENDA team
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Manually annotated by BRENDA team
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Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
malfunction
physiological function
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
ATP + a protein
ADP + a phosphoprotein
show the reaction diagram
ATP + alpha-synuclein
ADP + phosphorylated alpha-synuclein
show the reaction diagram
ATP + alpha1 beta-adrenergic receptor
ADP + phosphorylated alpha1 beta-adrenergic receptor
show the reaction diagram
ATP + alpha1-adrenergic receptor
ADP + alpha1-adrenergic receptor phosphate
show the reaction diagram
-
-
-
?
ATP + alpha1D-adrenergic receptor
ADP + alpha1D-adrenergic receptor phosphate
show the reaction diagram
ATP + alpha2-adrenergic receptor
ADP + phospho-alpha2-adrenergic receptor
show the reaction diagram
ATP + alpha2A-adrenergic receptor
ADP + phosphorylated alpha2A-adrenergic receptor
show the reaction diagram
ATP + angiotensin receptor
ADP + phosphorylated angiotensin receptor
show the reaction diagram
ATP + beta-adrenergic receptor
ADP + beta-adrenergic receptor phosphate
show the reaction diagram
ATP + beta-adrenergic receptor
ADP + phospho-beta-adrenergic receptor
show the reaction diagram
ATP + beta-adrenergic receptor
ADP + phosphorylated beta-adrenergic receptor
show the reaction diagram
ATP + beta-casein
ADP + phosphorylated beta-casein
show the reaction diagram
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recombinant HA-tagged wild-type and mutant GRK3
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?
ATP + beta-tubulin
ADP + phosphorylated beta-tubulin
show the reaction diagram
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purified substrate from porcine brain or human GST-tagged protein recombinantly expressed in Escherichia coli, phosphorylation of betaI- and betaIII-tubulin at Thr409, Ser420, and, in betaIII-tubulin, also at Ser420 of the C-terminal outer surface of the substrate protein
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?
ATP + beta1-adrenergic receptor
ADP + beta1-adrenergic receptor phosphate
show the reaction diagram
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-
?
ATP + beta2-adrenergic receptor
ADP + beta2-adrenergic receptor phosphate
show the reaction diagram
ATP + beta2-adrenergic receptor
ADP + phosphorylated beta2-adrenergic receptor
show the reaction diagram
ATP + calcium-sensing receptor
ADP + calcium-sensing receptor phosphate
show the reaction diagram
ATP + corticotropin-releasing factor receptor type 1
ADP + phosphorylated corticotropin-releasing factor receptor type 1
show the reaction diagram
ATP + dopamine D1 receptor
ADP + phosphorylated dopamine D1 receptor
show the reaction diagram
ATP + dopamine D3 receptor
ADP + phosphorylated dopamine D3 receptor
show the reaction diagram
ATP + DREAM
ADP + phosphorylated DREAM
show the reaction diagram
ATP + epidermal growth factor receptor
ADP + phosphorylated epidermal growth factor receptor
show the reaction diagram
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-
-
?
ATP + epithelial Na+ channel
ADP + phosphorylated epithelial Na+ channel
show the reaction diagram
ATP + ezrin
ADP + phosphorylated ezrin
show the reaction diagram
ATP + G protein-coupled receptor
ADP + phosphorylated G protein-coupled receptor
show the reaction diagram
ATP + insulin receptor substrate 1
ADP + phosphorylated insulin receptor substrate 1
show the reaction diagram
ATP + insulin receptor substrate-1
ADP + phosphorylated-insulin receptor substrate-1
show the reaction diagram
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-
?
ATP + LEESSSSDHAERPPG
?
show the reaction diagram
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-
?
ATP + M1 muscarinic acetylcholine receptor
ADP + phosphorylated M1 muscarinic acetylcholine receptor
show the reaction diagram
ATP + micro-opioid receptor
ADP + phosphorylated micro-opioid receptor
show the reaction diagram
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mutant C221V GRK2 shows slightly higher effect on morphine-induced internalization of the micro-opioid receptor compared to the wild-type GRK2, while the effects of mutants L271G, L273Y, and L336F are reduced, overview
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?
ATP + muscarinic acetylcholine receptor
ADP + phospho-muscarinic acetylcholine receptor
show the reaction diagram
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agonist-dependent phosphorylation, subtype 2
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?
ATP + muscarinic cholinergic receptor
ADP + phospho-muscarinic cholinergic receptor
show the reaction diagram
ATP + myelin basic protein
ADP + phosphorylated myelin basic protein
show the reaction diagram
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recombinant HA-tagged wild-type and mutant GRK3
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?
ATP + Nedd4
ADP + phosphorylated Nedd4
show the reaction diagram
ATP + Nedd4-2
ADP + phosphorylated Nedd4-2
show the reaction diagram
ATP + p38 MAP kinase
ADP + phosphorylated p38 MAP kinase
show the reaction diagram
ATP + PDEgamma
ADP + phosphorylated PDEgamma
show the reaction diagram
ATP + PDGFRbeta
ADP + phosphorylated PDGFRbeta
show the reaction diagram
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?
ATP + peptide
ADP + phosphopeptide
show the reaction diagram
ATP + phosducin
ADP + phosphorylated phosducin
show the reaction diagram
ATP + platelet-activating factor receptor
ADP + phospho-platelet-activating factor receptor
show the reaction diagram
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PAF receptor acts as substrate
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?
ATP + platelet-derived growth factor receptor-beta
ADP + phosphorylated platelet-derived growth factor receptor-beta
show the reaction diagram
ATP + protein
ADP + phosphoprotein
show the reaction diagram
ATP + protein
ATP + phosphoprotein
show the reaction diagram
ATP + protein M33
ADP + phosphorylated protein M33
show the reaction diagram
ATP + R-smad
ADP + phosphorylated R-smad
show the reaction diagram
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GRK2
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?
ATP + rhodopsin
ADP + phosphorhodopsin
show the reaction diagram
ATP + rhodopsin
ADP + phosphorylated rhodopsin
show the reaction diagram
ATP + rhodopsin
ADP + rhodopsin phosphate
show the reaction diagram
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cf. EC 2.7.11.14, rhodopsin is also a substrate of GRK2
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?
ATP + ribosomal protein P2
ADP + phosphorylated ribosomal protein P2
show the reaction diagram
ATP + RRRAEAAASAAA
ADP + RRRAEAAApSAAA
show the reaction diagram
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?
ATP + RRRAEASAA
ADP + RRRAEApSAA
show the reaction diagram
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poor peptide substrate
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?
ATP + RRRASAAASAA
?
show the reaction diagram
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poor peptide substrate
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?
ATP + RRRASASAA
?
show the reaction diagram
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poor peptide substrate
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?
ATP + RRRASpAAASAA
ADP + RRRASpAAASpAA
show the reaction diagram
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poor peptide substrate, higher catalytic efficiency than RRRASAAASAA
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?
ATP + RRRASpASAA
?
show the reaction diagram
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poor peptide substrate
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?
ATP + RRREEEEESAAA
?
show the reaction diagram
ATP + Smo
ADP + phosphorylated Smo
show the reaction diagram
ATP + Smoothened protein
ADP + phopshorylated Smoothened
show the reaction diagram
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a seven-transmembrane signaling protein
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?
ATP + Smoothened protein
ADP + phosphorylated Smoothened
show the reaction diagram
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GRK2 promotes smoothened signal transduction involved in regulation of cellular proliferation and differentiation through activation of the transcription factor Gli, overview
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?
ATP + synuclein
ADP + phosphorylated synuclein
show the reaction diagram
ATP + tubulin
ADP + phosphorylated tubulin
show the reaction diagram
ATP + [beta2-adrenergic receptor]
ADP + [beta2-adrenergic receptor] phosphate
show the reaction diagram
ATP + [TSH receptor]
ADP + [TSH receptor]phosphate
show the reaction diagram
ezrin + ATP
phosphorylated ezrin + ADP
show the reaction diagram
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-
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?
GTP + beta-adrenergic receptor
GDP + phospho-beta-adrenergic receptor
show the reaction diagram
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agonist-occupied form of beta-AR from hamster lung, GTP can substitute ATP, 2% as effective as ATP
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?
histamine H2 receptor + ATP
phosphorylated histamine H2 receptor + ADP
show the reaction diagram
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?
moesin + ATP
phosphorylated moesin + ADP
show the reaction diagram
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?
radixin + ATP
phosphorylated radixin + ADP
show the reaction diagram
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?
tubulin + ATP
phosphorylated-tubulin + ADP
show the reaction diagram
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?
additional information
?
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NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
ATP + a protein
ADP + a phosphoprotein
show the reaction diagram
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?
ATP + alpha-synuclein
ADP + phosphorylated alpha-synuclein
show the reaction diagram
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colocalization of GRK2, GRK5, alpha-synuclein, and tau in neurodegenerative disorders characterized by fibrillary tau inclusions and/or alpha-synuclein-enriched Lewy bodies, overview
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?
ATP + alpha1 beta-adrenergic receptor
ADP + phosphorylated alpha1 beta-adrenergic receptor
show the reaction diagram
P26819
substrate specificities of GRK2 and GRK3 in cardiac myocytes, overview
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?
ATP + alpha1-adrenergic receptor
ADP + alpha1-adrenergic receptor phosphate
show the reaction diagram
P26819
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?
ATP + alpha1D-adrenergic receptor
ADP + alpha1D-adrenergic receptor phosphate
show the reaction diagram
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inhibition of vascular smooth muscle G protein-coupled receptor kinase 2 enhances alpha1D-adrenergic receptor constriction and signalling, overview
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?
ATP + alpha2A-adrenergic receptor
ADP + phosphorylated alpha2A-adrenergic receptor
show the reaction diagram
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?
ATP + angiotensin receptor
ADP + phosphorylated angiotensin receptor
show the reaction diagram
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phosphorylation by GRK2 preceeds the binding of arrestins, which inhibits the seven-transmembrane receptor, but initiates internalization, overview
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?
ATP + beta-adrenergic receptor
ADP + beta-adrenergic receptor phosphate
show the reaction diagram
ATP + beta-adrenergic receptor
ADP + phospho-beta-adrenergic receptor
show the reaction diagram
ATP + beta-adrenergic receptor
ADP + phosphorylated beta-adrenergic receptor
show the reaction diagram
ATP + beta1-adrenergic receptor
ADP + beta1-adrenergic receptor phosphate
show the reaction diagram
P26819
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?
ATP + beta2-adrenergic receptor
ADP + beta2-adrenergic receptor phosphate
show the reaction diagram
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role of GRK activity in the regulation of beta2 adrenergic signaling, feedback mechanism, overview
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?
ATP + beta2-adrenergic receptor
ADP + phosphorylated beta2-adrenergic receptor
show the reaction diagram
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desensitization of the receptor with subsequent decline in the stimulatory effects of beta2-adrenergic agonists over time, the receptor is involved in alveolar Na+ and water clearance
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?
ATP + calcium-sensing receptor
ADP + calcium-sensing receptor phosphate
show the reaction diagram
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homologous desensitization of G protein-coupled receptors is generally mediated by GRKs through phosphorylation-dependent and independent mechanisms, GRK2 can phosphorylate calcium-sensing receptor and, along with beta-arrestins, can attenuate calcium-sensing receptor-mediated signaling, mechanism, overview
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?
ATP + corticotropin-releasing factor receptor type 1
ADP + phosphorylated corticotropin-releasing factor receptor type 1
show the reaction diagram
ATP + dopamine D1 receptor
ADP + phosphorylated dopamine D1 receptor
show the reaction diagram
O97627
phosphorylation by GRK2 has a regulatory role as part of the PI3K-PKC-GRK2 cascade
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?
ATP + dopamine D3 receptor
ADP + phosphorylated dopamine D3 receptor
show the reaction diagram
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the receptor is activated by GRK2 and GRK3 phosphorylation involving beta-arrestins, GRK-mediated regulation of receptor-filamin complex stability and receptor-G protein signaling potential, GRK2 reduces the dopamine D3 receptor signaling, overview
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?
ATP + DREAM
ADP + phosphorylated DREAM
show the reaction diagram
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i.e. downstream regulatory element antagonist modulator protein, GRK2 mediates phosphorylation of DREAM/potassium channel interacting protein KChIP3, a multifunctional protein of the neuronal calcium sensor subfamily of Ca2+-binding proteins with specific roles in different cell compartments, regulating membrane trafficking of Kv4.2 potassium channel, phosphorylation of Ser95 affects cell surface localization, but not Kv4 channel tetramerization, overview
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?
ATP + epithelial Na+ channel
ADP + phosphorylated epithelial Na+ channel
show the reaction diagram
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channel inactivation
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?
ATP + ezrin
ADP + phosphorylated ezrin
show the reaction diagram
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phosphorylation of ezrin affects the 7TM receptor mediated cytoskeletal reorganization
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?
ATP + G protein-coupled receptor
ADP + phosphorylated G protein-coupled receptor
show the reaction diagram
ATP + insulin receptor substrate 1
ADP + phosphorylated insulin receptor substrate 1
show the reaction diagram
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role of GRK2 in insulin receptor IR signaling
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?
ATP + insulin receptor substrate-1
ADP + phosphorylated-insulin receptor substrate-1
show the reaction diagram
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?
ATP + M1 muscarinic acetylcholine receptor
ADP + phosphorylated M1 muscarinic acetylcholine receptor
show the reaction diagram
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phosphorylation-dependent and -independent mechanisms in the regulation of M1 muscarinic acetylcholine receptors by G protein-coupled receptor kinase 2 in hippocampal neurons, GRK2 can inhibit the receptor-dependent signaling via phospholipase C, overview
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?
ATP + Nedd4
ADP + phosphorylated Nedd4
show the reaction diagram
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GRK2 interacts with and phosphorylates the ubiquitin protein ligase Nedd4 preventing the binding to proline-rich motifs present in the C-termini of epithelial Na+ channel subunits and inhibition of the channels, overview
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?
ATP + Nedd4-2
ADP + phosphorylated Nedd4-2
show the reaction diagram
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GRK2 interacts with and phosphorylates the ubiquitin protein ligase Nedd4-2 preventing the binding to proline-rich motifs present in the C-termini of epithelial Na+ channel subunits and inhibition of the channels, overview
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?
ATP + p38 MAP kinase
ADP + phosphorylated p38 MAP kinase
show the reaction diagram
ATP + PDEgamma
ADP + phosphorylated PDEgamma
show the reaction diagram
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phosphorylation of PDEgamma possibly stimulates EGFR-mediated ERK activation
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?
ATP + PDGFRbeta
ADP + phosphorylated PDGFRbeta
show the reaction diagram
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-
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?
ATP + phosducin
ADP + phosphorylated phosducin
show the reaction diagram
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phosducin is activated to inhibit Gbetagamma protein
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?
ATP + platelet-derived growth factor receptor-beta
ADP + phosphorylated platelet-derived growth factor receptor-beta
show the reaction diagram
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feedback inhibition mechanism, overview
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?
ATP + protein
ATP + phosphoprotein
show the reaction diagram
ATP + protein M33
ADP + phosphorylated protein M33
show the reaction diagram
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GRK2 is a potent regulator of the mouse cytomegalovirus GPCR protein M33-induced Gq/11 signaling through its ability to phosphorylate M33 and sequester Galphaq/11 proteins dependent on an intact RH domain, the protein M33 is able to induce inositol phosphate accumulation, activate NF-kappaB, and promote smooth muscle cell migration, viral GPCRs like M33 play a role in viral dissemination in vivo, M33 is required for efficient murine cytomegalovirus replication in the mouse, and induces several signlaing pathways, overview
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?
ATP + rhodopsin
ADP + phosphorylated rhodopsin
show the reaction diagram
ATP + ribosomal protein P2
ADP + phosphorylated ribosomal protein P2
show the reaction diagram
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activation of P2
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?
ATP + Smo
ADP + phosphorylated Smo
show the reaction diagram
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GPRK2 participates in Hedgehog signaling in Drosophila melanogaster, and plays a key role in the Smo signal transduction pathway, when Gprk2 levels are lowered, Smo still accumulates at the cell membrane, but its activation is reduced, overview
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?
ATP + Smoothened protein
ADP + phosphorylated Smoothened
show the reaction diagram
-
GRK2 promotes smoothened signal transduction involved in regulation of cellular proliferation and differentiation through activation of the transcription factor Gli, overview
-
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?
ATP + synuclein
ADP + phosphorylated synuclein
show the reaction diagram
-
-
-
-
?
ATP + [beta2-adrenergic receptor]
ADP + [beta2-adrenergic receptor] phosphate
show the reaction diagram
-
-
-
-
?
ATP + [TSH receptor]
ADP + [TSH receptor]phosphate
show the reaction diagram
-
GRK2 and GRK3, receptor activation
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?
ezrin + ATP
phosphorylated ezrin + ADP
show the reaction diagram
-
-
-
-
?
histamine H2 receptor + ATP
phosphorylated histamine H2 receptor + ADP
show the reaction diagram
-
-
-
-
?
moesin + ATP
phosphorylated moesin + ADP
show the reaction diagram
-
-
-
-
?
radixin + ATP
phosphorylated radixin + ADP
show the reaction diagram
-
-
-
-
?
additional information
?
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
additional information
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
2,3-diphosphoglycerate
4-amino-1-tert-butyl-3-(1'-naphthyl)pyrrazolo[3,4-d]pyrimidine
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i.e. 1-Na-PP1, inhibits mutant C221V mediated morphine-induced internalization of the micro-opioid receptor, but not wild-type GRK2 and mutant L271G activities
59-74E
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actin
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actinin
alpha-actinin
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alpha2-adrenergic antagonist
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co-incubation completely blocks phosphorylation of alpha2-adrenergic receptor
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Alprenolol
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beta-adrenergic antagonist, blocks phosphorylation
atropine
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receptor antagonist
balanol
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betaARKct
C-terminus of beta-ARK
Ca2+
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inhibits GRK2
Ca2+/calmodulin
Calmodulin
calveolin
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caveolin
Chloropromazine
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IC50: 0.043 mM
chondroitin sulfate B
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weak
chondroitin sulfate C
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less inhibitory than heparin
concanavalin A
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inhibitor of clathrin-mediated receptor endocytosis via clathrin binding domain of beta-arrestin-2, inhibitor reduces the GRK3/beta-arrestin-2 induction activity of germinal vesicle breakdown
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corticotropin-releasing factor
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reduces GRK2 expression in pituitary cells, suppressed by astressin, opposite effect compared to corticotroph tumor cells AtT20
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D-glucosamine 2,6-disulfate
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inhibits in the millimolar range, weak, IC50: 7.3 mM with rhodopsin as substrate
D-Sphingosine
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IC50: 0.027 mM
Dextran sulfate
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strong, IC50: 0.00015 mM with rhodopsin as substrate
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Digitonin
EDTA
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GRK2ct
heparan sulfate
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less inhibitory than heparin