Any feedback?
Information on EC 2.7.11.15 - beta-adrenergic-receptor kinase and Organism(s) Homo sapiens and UniProt Accession P25098
for references in articles please use BRENDA:EC2.7.11.15Please wait a moment until all data is loaded. This message will disappear when all data is loaded.
EC Tree
2.7.11.15 beta-adrenergic-receptor kinaseIUBMB Comments
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).
Specify your search results
Word Map
- 2.7.11.15
-
desensitization
- agonist
- cardiac
- myocardial
- cyclase
-
gpcrs
- g-proteins
-
adenylyl
- ventricular
- camp
-
agonist-induced
-
heterotrimeric
- rhodopsin
-
contractility
- gbetagamma
- beta-arrestins
-
myocytes
- pkc
-
agonist-dependent
-
2-adrenergic
-
beta2-adrenergic
- isoproterenol
- pertussis
-
muscarinic
-
agonist-occupied
- arrestins
-
pleckstrin
-
betaars
-
cardiac-specific
-
grk-mediated
-
phosphorylation-independent
-
agonist-promoted
- paroxetine
- galphaq
-
agonist-stimulated
- rgs
-
inotropic
- smoothened
-
agonist-specific
-
mu-opioid
-
agonist-mediated
- phosducin
- biotechnology
-
galphaq/11
-
gamma-mediated
-
machrs
- diagnostics
- medicine
-
agonist-activated
-
gi-coupled
-
receptor-stimulated
-
gbeta
- rkip
The taxonomic range for the selected organisms is: Homo sapiens
The expected taxonomic range for this enzyme is: Eukaryota, Archaea, Bacteria
The expected taxonomic range for this enzyme is: Eukaryota, Archaea, Bacteria
Synonyms
g protein-coupled receptor kinase 2, beta-adrenergic receptor kinase, betaark1, betaark, g-protein-coupled receptor kinase 2, gprk2, g protein-coupled receptor kinase-2, beta-adrenergic receptor kinase 1, g protein coupled receptor kinase, beta-ark, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
beta-adrenergic receptor kinase
beta-adrenergic receptor-specific kinase
-
-
-
-
beta-AR kinase
-
-
-
-
beta-ARK
-
-
-
-
beta-ARK 1
-
-
-
-
beta-ARK 2
-
-
-
-
beta-receptor kinase
-
-
-
-
G protein-coupled receptor kinase 2
-
-
GRK2
GRK3
kinase (phosphorylating), beta-adrenergic-receptor
-
-
-
-
additional information
beta-adrenergic receptor kinase
-
-
-
-
GRK2
-
-
-
-
GRK2
-
-
GRK3
-
-
-
-
additional information
-
enzymes belong to the GRK family, GRK2 and GRK3, i.e. betaARK1 and betaARK2, form the betaARK subfamily
additional information
-
the enzyme belongs to the beta-adrenergic receptor kinase subfamily
additional information
-
the enzyme belongs to the betaARK subfamily of the GRK family
additional information
-
the enzyme belongs to the G-protein-coupled receptor kinase family
additional information
-
the enzyme belongs to the GRK2 subfamily, consisting of GRK2, beta-ARK1, GRK3, and beta-ARK2
additional information
-
the enzyme belongs to the serine/threonine kinase family
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
ATP + [beta-adrenergic receptor] = ADP + phospho-[beta-adrenergic receptor]
regulation mechanism
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
phospho group transfer
-
-
-
-
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
102925-39-3
-
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
ATP + Ac-DEMEFTEAESNMN-NH2
ADP + Ac-DEMEFpTEAESNMN-NH2
-
highly specific substrate with phosphorylation sites at Thr409 and Ser413
-
-
?
ATP + beta2-adrenergic receptor
ADP + phosphorylated beta2-adrenergic receptor
-
-
-
-
?
ATP + epidermal growth factor receptor
ADP + phosphorylated epidermal growth factor receptor
-
-
-
-
?
ATP + histone deacetylase 6
ADP + phosphorylated histone deacetylase 6
-
phosphorylation at Ser-670
-
-
?
ATP + insulin receptor substrate-1
ADP + phosphorylated insulin receptor substrate-1
-
phosphorylation at Ser-307
-
-
?
ATP + p38 mitogen-activated protein kinase
ADP + phosphorylated p38 mitogen-activated protein kinase
-
-
-
-
?
ATP + phosphodiesterase gamma
ADP + phosphorylated phosphodiesterase gamma
-
-
-
-
?
ATP + platelet-activating factor receptor
ADP + phospho-platelet-activating factor receptor
PAF receptor acts as substrate
-
-
?
ATP + platelet-derived growth factor receptor-beta protein
ADP + phosphorylated platelet-derived growth factor receptor
-
-
-
-
?
ATP + rhodopsin
ADP + phosphorylated rhodopsin
-
-
-
-
?
ATP + rhodopsin
ADP + rhodopsin phosphate
-
cf. EC 2.7.11.14, rhodopsin is also a substrate of GRK2
-
-
?
ATP + [beta-adrenergic receptor]
ADP + phospho-[beta-adrenergic receptor]
-
-
-
-
?
ATP + [neurotensin receptor]
ADP + phospho-[neurotensin receptor]
-
the enzyme phosphorylates only the C-terminal serine residues
-
-
?
ATP + alpha1D-adrenergic receptor
ADP + alpha1D-adrenergic receptor phosphate
-
-
-
?
ATP + alpha1D-adrenergic receptor
ADP + alpha1D-adrenergic receptor phosphate
inhibition of vascular smooth muscle G protein-coupled receptor kinase 2 enhances alpha1D-adrenergic receptor constriction and signalling, overview
-
-
?
ATP + protein
ADP + phosphoprotein
specifically phosphorylates the agonist-occupied forms of the beta 2-adrenergic receptor and related G protein-coupled receptors
-
-
?
ATP + protein
ADP + phosphoprotein
the enzyme mediates agonist-dependent phosphorylation of the beta 2-adrenergic and related G protein-coupled receptors
-
-
?
ATP + [beta-adrenergic receptor]
ADP + phospho-[beta-adrenergic receptor]
-
-
-
?
ATP + [beta-adrenergic receptor]
ADP + phospho-[beta-adrenergic receptor]
-
-
-
-
?
ATP + [beta-adrenergic receptor]
ADP + phospho-[beta-adrenergic receptor]
-
-
-
?
ATP + alpha-synuclein
ADP + phosphorylated alpha-synuclein
-
colocalization of GRK2, GRK5, alpha-synuclein, and tau in neurodegenerative disorders characterized by fibrillary tau inclusions and/or alpha-synuclein-enriched Lewy bodies, overview
-
-
?
ATP + alpha-synuclein
ADP + phosphorylated alpha-synuclein
-
phosphorylation at Ser129
-
-
?
ATP + angiotensin receptor
ADP + phosphorylated angiotensin receptor
-
phosphorylation by GRK2 preceeds the binding of arrestins, which inhibits the seven-transmembrane receptor, but initiates internalization, overview
-
-
?
ATP + beta-adrenergic receptor
ADP + beta-adrenergic receptor phosphate
-
-
-
-
?
ATP + beta-adrenergic receptor
ADP + beta-adrenergic receptor phosphate
-
the mechanism of myocardial beta-adrenergic receptor desensitization during cardiac surgery involves GRK2, overview
-
-
?
ATP + beta-adrenergic receptor
ADP + phospho-beta-adrenergic receptor
-
-
-
?
ATP + beta-adrenergic receptor
ADP + phospho-beta-adrenergic receptor
specifically phosphorylates the agonist-occupied form of the receptor
-
?
ATP + beta-adrenergic receptor
ADP + phospho-beta-adrenergic receptor
-
specifically phosphorylates the agonist-occupied form of the receptor
-
?
ATP + beta-adrenergic receptor
ADP + phospho-beta-adrenergic receptor
-
specifically phosphorylates the agonist-occupied form of the receptor
-
?
ATP + beta-adrenergic receptor
ADP + phospho-beta-adrenergic receptor
-
specifically phosphorylates the agonist-occupied form of the receptor
-
?
ATP + beta-adrenergic receptor
ADP + phospho-beta-adrenergic receptor
specifically phosphorylates the agonist-occupied form of the receptor
-
?
ATP + beta-adrenergic receptor
ADP + phospho-beta-adrenergic receptor
-
human beta2-adrenergic receptor
-
?
ATP + beta-adrenergic receptor
ADP + phospho-beta-adrenergic receptor
-
human beta2-adrenergic receptor
-
?
ATP + beta-adrenergic receptor
ADP + phospho-beta-adrenergic receptor
-
incorporation of up to 5 mol phosphate/mol receptor
-
?
ATP + beta-adrenergic receptor
ADP + phospho-beta-adrenergic receptor
-
beta-AR from Sf9 cells
-
?
ATP + beta-adrenergic receptor
ADP + phospho-beta-adrenergic receptor
-
beta-ARK 1: substrate recognition mechanism, consensus sequence required for substrates, 3-dimensional model structure of the catalytic domain, potential phosphorylation sites of human beta2-adrenergic receptor
-
?
ATP + beta-adrenergic receptor
ADP + phospho-beta-adrenergic receptor
presumably modulates some receptor-mediated immune functions
-
?
ATP + beta-adrenergic receptor
ADP + phospho-beta-adrenergic receptor
-
natural substrate: beta2-adrenergic receptor
-
?
ATP + beta-adrenergic receptor
ADP + phospho-beta-adrenergic receptor
agonist-occupied form of the receptor
-
?
ATP + beta-adrenergic receptor
ADP + phospho-beta-adrenergic receptor
-
agonist-occupied form of the receptor
-
?
ATP + beta-adrenergic receptor
ADP + phospho-beta-adrenergic receptor
agonist-occupied form of the receptor
-
?
ATP + beta-adrenergic receptor
ADP + phospho-beta-adrenergic receptor
involved in homologous desensitization of beta-adrenergic receptor
-
?
ATP + beta-adrenergic receptor
ADP + phospho-beta-adrenergic receptor
-
involved in homologous desensitization of beta-adrenergic receptor
-
?
ATP + beta-adrenergic receptor
ADP + phospho-beta-adrenergic receptor
-
involved in homologous desensitization of beta-adrenergic receptor
-
?
ATP + beta-adrenergic receptor
ADP + phospho-beta-adrenergic receptor
functional role of the beta-ARK/beta-arrestin mechanism of receptor desensitization in immune cells
-
?
ATP + beta-adrenergic receptor
ADP + phosphorylated beta-adrenergic receptor
-
-
-
-
?
ATP + beta-adrenergic receptor
ADP + phosphorylated beta-adrenergic receptor
-
G protein-coupled receptor kinase phosphorylation mediates beta-1 adrenergic receptor endocytosis via clathrin-coated pits
-
-
?
ATP + beta-adrenergic receptor
ADP + phosphorylated beta-adrenergic receptor
-
mouse wild-type receptor, cytosolic phosphorylation domain of the substrate, overview
-
-
?
ATP + beta-adrenergic receptor
ADP + phosphorylated beta-adrenergic receptor
-
GRK3 and GRK2 are involved in down-regulation of the alpha2B-adrenoceptor, regulation of the pathway, overview
-
-
?
ATP + beta-adrenergic receptor
ADP + phosphorylated beta-adrenergic receptor
-
in human heart failure, impaired beta-adrenergic receptor signaling compromises cardiac sensitivity to inotropic stimulation, overview
-
-
?
ATP + beta-adrenergic receptor
ADP + phosphorylated beta-adrenergic receptor
-
phosphorylation by GRK2 preceeds the binding of arrestins, which inhibits the seven-transmembrane receptor, but initiates internalization, overview
-
-
?
ATP + beta-adrenergic receptor
ADP + phosphorylated beta-adrenergic receptor
-
the enzyme is involved in regulation of the beta-adrenergic receptor signaling by inhibiting arrestin recruitment to the receptor and subsequent desensitization and internalization, regulation of GRK2 by S-nitrosylation, molecular mechanism, overview
-
-
?
ATP + beta-adrenergic receptor
ADP + phosphorylated beta-adrenergic receptor
-
recombinantly expressed beta-adrenergic receptor in U2-OS cells, mapping of S-nitrosylation sites and regulatory locus in GRK2
-
-
?
ATP + beta2-adrenergic receptor
ADP + beta2-adrenergic receptor phosphate
-
-
-
-
?
ATP + beta2-adrenergic receptor
ADP + beta2-adrenergic receptor phosphate
-
role of GRK activity in the regulation of beta2 adrenergic signaling, feedback mechanism, overview
-
-
?
ATP + calcium-sensing receptor
ADP + calcium-sensing receptor phosphate
GRK2
-
-
?
ATP + calcium-sensing receptor
ADP + calcium-sensing receptor phosphate
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
-
-
?
ATP + dephospho-beta-tubulin
ADP + phosphorylated beta-tubulin
-
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
-
-
?
ATP + DREAM
ADP + phosphorylated DREAM
-
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
-
-
?
ATP + DREAM
ADP + phosphorylated DREAM
-
i.e. downstream regulatory element antagonist modulator protein, GRK2 phosphorylates Ser95
-
-
?
ATP + epithelial Na+ channel
ADP + phosphorylated epithelial Na+ channel
-
-
-
-
?
ATP + epithelial Na+ channel
ADP + phosphorylated epithelial Na+ channel
-
channel inactivation
-
-
?
ATP + ezrin
ADP + phosphorylated ezrin
-
phosphorylation of ezrin affects the 7TM receptor mediated cytoskeletal reorganization
-
-
?
ATP + G protein-coupled receptor
ADP + phosphorylated G protein-coupled receptor
-
-
-
-
?
ATP + G protein-coupled receptor
ADP + phosphorylated G protein-coupled receptor
-
regulation mechanism of GRK2, overview, regulation by phosphorylation at specific sites via distinct specific kinases, overview
-
-
?
ATP + PDEgamma
ADP + phosphorylated PDEgamma
-
phosphorylation of PDEgamma possibly stimulates EGFR-mediated ERK activation
-
-
?
ATP + phosducin
ADP + phosphorylated phosducin
-
phosducin is activated to inhibit Gbetagamma protein
-
-
?
ATP + rhodopsin
ADP + phosphorhodopsin
light-dependent, actual substrate: light-bleached rhodopsin
-
?
ATP + rhodopsin
ADP + phosphorhodopsin
in form of bovine rod outer segments
-
?
ATP + rhodopsin
ADP + phosphorhodopsin
-
in form of bovine rod outer segments
-
?
ATP + rhodopsin
ADP + phosphorhodopsin
-
in form of bovine rod outer segments
-
?
ATP + rhodopsin
ADP + phosphorhodopsin
in form of bovine rod outer segments
-
?
ATP + rhodopsin
ADP + phosphorhodopsin
recombinant beta-ARK 2: 40% of efficiency of beta-ARK 1 in phosphorylating rhodopsin
-
?
ATP + ribosomal protein P2
ADP + phosphorylated ribosomal protein P2
-
-
-
-
?
ATP + ribosomal protein P2
ADP + phosphorylated ribosomal protein P2
-
activation of P2
-
-
?
ATP + ribosomal protein P2
ADP + phosphorylated ribosomal protein P2
-
GRK2
-
-
?
ATP + [beta2-adrenergic receptor]
ADP + [beta2-adrenergic receptor] phosphate
-
-
-
-
?
ATP + [beta2-adrenergic receptor]
ADP + [beta2-adrenergic receptor] phosphate
-
recombinant FLAG-tagged beta2-adrenergic receptor stably expressed in HEK-293 cells
-
-
?
ATP + [TSH receptor]
ADP + [TSH receptor]phosphate
-
GRK2 and GRK3, receptor activation
-
-
?
additional information
?
-
-
role for beta ARK in modulating some receptor-mediated immune functions
-
-
?
additional information
?
-
role for beta ARK in modulating some receptor-mediated immune functions
-
-
?
additional information
?
-
-
beta-ARK 1 phosphorylates beta2-AR and other G protein-coupled receptors, substrate recognition mechanism, consensus sequence required for substrates, 3-dimensional model structure of the catalytic domain, residues 188-436
-
-
?
additional information
?
-
-
betaARK enhances the contractility in heart myocardium via inhibition of Gbetagamma subunits
-
-
?
additional information
?
-
-
betaARK1 inhibition improves beta-adrenergic signaling and contractile function in failing human myocytes
-
-
?
additional information
?
-
-
GRK2 and GRK3 are involved in methacholine-stimulated inositol 3-phosphate production
-
-
?
additional information
?
-
-
GRK2 mediates endothelin-1-induced insulin resistance via the inhibition of both Galphaq/11 and insulin receptor substrate-1 pathways in 3T3-L1 adipocytes, GRK2 does not affect insulin receptor tyrosine phosphorylation
-
-
?
additional information
?
-
-
GRKs are involved in diverse physiological processes and pathologies, overview
-
-
?
additional information
?
-
-
the enzyme is involved in G protein-coupled receptor signal transduction pathways and desensitization, GRK2 is a multiple domain kinase regulating by multiple mechanisms, overview
-
-
?
additional information
?
-
-
GRK2 functionally ineracts with clathrin, phosphoinositol 3-phosphate kinase-gamma, and G protein-coupled receptor kinase interacting protein, GIT
-
-
?
additional information
?
-
-
GRK2 interacts by direct binding with Galphaq/11, phosphorylation of agonist-activated seven-transmembrane receptors by GRK2
-
-
?
additional information
?
-
-
GRK2 interacts with calmodulin, substrate specificity, GRK2 phosphorylates serine and threonine residues with preceeding acidic amino acid residues
-
-
?
additional information
?
-
-
GRK2 prefers acidic protein sequences for phosphorylation
-
-
?
additional information
?
-
-
the M3 muscarinic acetylcholine receptor is no substrate for GRK2 and GRK3
-
-
?
additional information
?
-
-
GPCR-dependent kinases play a major role in agonist-induced phosphorylation and desensitization of G-protein coupled receptors, GRK2 is a component of neuronal and glial fibrillary tau deposits with no preference in tau isoform binding, GRK2 may play a role in hyperphosphorylation of tau in tauopathies
-
-
?
additional information
?
-
-
GRK activity is regulated by phosphorylation through several kinases and by interactions with several cellular proteins, e.g. calmodulin, caveolin or RKIP, GRK also interacts with PI3K, Akt, GIT or MEK, the interactions occur at the RH and PH domains, overview, the GRK interactome: role of GRKs in GPCR regulation and signaling, detailed overview
-
-
?
additional information
?
-
-
GRK-mediated receptor phosphorylation rapidly initiates profound impairment of receptor signaling and desensitization, beta-arrestin-mediated receptor internalization, activity of GRKs and subcellular targeting is tightly regulated by interaction with receptor domains, G protein subunits, lipids, anchoring proteins and calcium-sensitive proteins, selective binding of activated Galphaq and Galpha-11 to RH domains of GRK2 and GRK3 selectively inhibits Gq signaling
-
-
?
additional information
?
-
-
GRK2 interacts with multiple signaling proteins and is involved in several cellular processes, e.g. expression and regulation of key cardiac seven-transmembrane receptors, 7TM receptors, such as the beta-adrenergic and angiotensin receptors, GRK2 interacts with NCS-1, mechanism, overview, GRK2 inhibition can ameliorate heart failure, molecular mechanism of GRK2 activity regulation, GRK2 is probably involved in regulation of hypertension, overview
-
-
?
additional information
?
-
-
GRK2 binds to and inhibits Galphaq protein via its N-terminal RGS domain, GRK2 interacts with NCS-1
-
-
?
additional information
?
-
-
GRK2 interacts with a component of the MAPK pathway, as well as with the PI-3K substrate AKT, GRK2 and GRK3 bind the Gbetagamma subunit complex, a process that induces activation of the GRKs
-
-
?
additional information
?
-
-
GRK-mediated desensitization of beta2-adrenergic receptors is sufficient to cause declines in cAMP signals. GRK-mediated desensitization is primarily responsible for a sustained suppression of beta2AR signaling, overview
-
-
?
additional information
?
-
-
GRK2 also phosphorylates rhodopsin, cf. EC 2.7.11.14
-
-
?
additional information
?
-
-
GRK2 is also active with rhodopsin, cf. EC 2.7.11.14
-
-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
ATP + alpha1D-adrenergic receptor
ADP + alpha1D-adrenergic receptor phosphate
inhibition of vascular smooth muscle G protein-coupled receptor kinase 2 enhances alpha1D-adrenergic receptor constriction and signalling, overview
-
-
?
ATP + alpha-synuclein
ADP + phosphorylated alpha-synuclein
-
colocalization of GRK2, GRK5, alpha-synuclein, and tau in neurodegenerative disorders characterized by fibrillary tau inclusions and/or alpha-synuclein-enriched Lewy bodies, overview
-
-
?
ATP + angiotensin receptor
ADP + phosphorylated angiotensin receptor
-
phosphorylation by GRK2 preceeds the binding of arrestins, which inhibits the seven-transmembrane receptor, but initiates internalization, overview
-
-
?
ATP + beta-adrenergic receptor
ADP + beta-adrenergic receptor phosphate
-
the mechanism of myocardial beta-adrenergic receptor desensitization during cardiac surgery involves GRK2, overview
-
-
?
ATP + beta2-adrenergic receptor
ADP + beta2-adrenergic receptor phosphate
-
role of GRK activity in the regulation of beta2 adrenergic signaling, feedback mechanism, overview
-
-
?
ATP + beta2-adrenergic receptor
ADP + phosphorylated beta2-adrenergic receptor
-
-
-
-
?
ATP + calcium-sensing receptor
ADP + calcium-sensing receptor phosphate
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
-
-
?
ATP + DREAM
ADP + phosphorylated DREAM
-
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
-
-
?
ATP + epithelial Na+ channel
ADP + phosphorylated epithelial Na+ channel
-
channel inactivation
-
-
?
ATP + ezrin
ADP + phosphorylated ezrin
-
phosphorylation of ezrin affects the 7TM receptor mediated cytoskeletal reorganization
-
-
?
ATP + PDEgamma
ADP + phosphorylated PDEgamma
-
phosphorylation of PDEgamma possibly stimulates EGFR-mediated ERK activation
-
-
?
ATP + phosducin
ADP + phosphorylated phosducin
-
phosducin is activated to inhibit Gbetagamma protein
-
-
?
ATP + ribosomal protein P2
ADP + phosphorylated ribosomal protein P2
-
activation of P2
-
-
?
ATP + [beta-adrenergic receptor]
ADP + phospho-[beta-adrenergic receptor]
-
-
-
-
?
ATP + [beta2-adrenergic receptor]
ADP + [beta2-adrenergic receptor] phosphate
-
-
-
-
?
ATP + [neurotensin receptor]
ADP + phospho-[neurotensin receptor]
-
the enzyme phosphorylates only the C-terminal serine residues
-
-
?
ATP + [TSH receptor]
ADP + [TSH receptor]phosphate
-
GRK2 and GRK3, receptor activation
-
-
?
ATP + protein
ADP + phosphoprotein
specifically phosphorylates the agonist-occupied forms of the beta 2-adrenergic receptor and related G protein-coupled receptors
-
-
?
ATP + protein
ADP + phosphoprotein
the enzyme mediates agonist-dependent phosphorylation of the beta 2-adrenergic and related G protein-coupled receptors
-
-
?
ATP + [beta-adrenergic receptor]
ADP + phospho-[beta-adrenergic receptor]
-
-
-
?
ATP + [beta-adrenergic receptor]
ADP + phospho-[beta-adrenergic receptor]
-
-
-
-
?
ATP + [beta-adrenergic receptor]
ADP + phospho-[beta-adrenergic receptor]
-
-
-
?
ATP + beta-adrenergic receptor
ADP + phospho-beta-adrenergic receptor
presumably modulates some receptor-mediated immune functions
-
?
ATP + beta-adrenergic receptor
ADP + phospho-beta-adrenergic receptor
-
natural substrate: beta2-adrenergic receptor
-
?
ATP + beta-adrenergic receptor
ADP + phospho-beta-adrenergic receptor
agonist-occupied form of the receptor
-
?
ATP + beta-adrenergic receptor
ADP + phospho-beta-adrenergic receptor
-
agonist-occupied form of the receptor
-
?
ATP + beta-adrenergic receptor
ADP + phospho-beta-adrenergic receptor
agonist-occupied form of the receptor
-
?
ATP + beta-adrenergic receptor
ADP + phospho-beta-adrenergic receptor
involved in homologous desensitization of beta-adrenergic receptor
-
?
ATP + beta-adrenergic receptor
ADP + phospho-beta-adrenergic receptor
-
involved in homologous desensitization of beta-adrenergic receptor
-
?
ATP + beta-adrenergic receptor
ADP + phospho-beta-adrenergic receptor
-
involved in homologous desensitization of beta-adrenergic receptor
-
?
ATP + beta-adrenergic receptor
ADP + phospho-beta-adrenergic receptor
functional role of the beta-ARK/beta-arrestin mechanism of receptor desensitization in immune cells
-
?
ATP + beta-adrenergic receptor
ADP + phosphorylated beta-adrenergic receptor
-
G protein-coupled receptor kinase phosphorylation mediates beta-1 adrenergic receptor endocytosis via clathrin-coated pits
-
-
?
ATP + beta-adrenergic receptor
ADP + phosphorylated beta-adrenergic receptor
-
GRK3 and GRK2 are involved in down-regulation of the alpha2B-adrenoceptor, regulation of the pathway, overview
-
-
?
ATP + beta-adrenergic receptor
ADP + phosphorylated beta-adrenergic receptor
-
in human heart failure, impaired beta-adrenergic receptor signaling compromises cardiac sensitivity to inotropic stimulation, overview
-
-
?
ATP + beta-adrenergic receptor
ADP + phosphorylated beta-adrenergic receptor
-
phosphorylation by GRK2 preceeds the binding of arrestins, which inhibits the seven-transmembrane receptor, but initiates internalization, overview
-
-
?
ATP + beta-adrenergic receptor
ADP + phosphorylated beta-adrenergic receptor
-
the enzyme is involved in regulation of the beta-adrenergic receptor signaling by inhibiting arrestin recruitment to the receptor and subsequent desensitization and internalization, regulation of GRK2 by S-nitrosylation, molecular mechanism, overview
-
-
?
ATP + G protein-coupled receptor
ADP + phosphorylated G protein-coupled receptor
-
-
-
-
?
ATP + G protein-coupled receptor
ADP + phosphorylated G protein-coupled receptor
-
regulation mechanism of GRK2, overview, regulation by phosphorylation at specific sites via distinct specific kinases, overview
-
-
?
additional information
?
-
-
role for beta ARK in modulating some receptor-mediated immune functions
-
-
?
additional information
?
-
role for beta ARK in modulating some receptor-mediated immune functions
-
-
?
additional information
?
-
-
betaARK enhances the contractility in heart myocardium via inhibition of Gbetagamma subunits
-
-
?
additional information
?
-
-
betaARK1 inhibition improves beta-adrenergic signaling and contractile function in failing human myocytes
-
-
?
additional information
?
-
-
GRK2 and GRK3 are involved in methacholine-stimulated inositol 3-phosphate production
-
-
?
additional information
?
-
-
GRK2 mediates endothelin-1-induced insulin resistance via the inhibition of both Galphaq/11 and insulin receptor substrate-1 pathways in 3T3-L1 adipocytes, GRK2 does not affect insulin receptor tyrosine phosphorylation
-
-
?
additional information
?
-
-
GRKs are involved in diverse physiological processes and pathologies, overview
-
-
?
additional information
?
-
-
the enzyme is involved in G protein-coupled receptor signal transduction pathways and desensitization, GRK2 is a multiple domain kinase regulating by multiple mechanisms, overview
-
-
?
additional information
?
-
-
GPCR-dependent kinases play a major role in agonist-induced phosphorylation and desensitization of G-protein coupled receptors, GRK2 is a component of neuronal and glial fibrillary tau deposits with no preference in tau isoform binding, GRK2 may play a role in hyperphosphorylation of tau in tauopathies
-
-
?
additional information
?
-
-
GRK activity is regulated by phosphorylation through several kinases and by interactions with several cellular proteins, e.g. calmodulin, caveolin or RKIP, GRK also interacts with PI3K, Akt, GIT or MEK, the interactions occur at the RH and PH domains, overview, the GRK interactome: role of GRKs in GPCR regulation and signaling, detailed overview
-
-
?
additional information
?
-
-
GRK-mediated receptor phosphorylation rapidly initiates profound impairment of receptor signaling and desensitization, beta-arrestin-mediated receptor internalization, activity of GRKs and subcellular targeting is tightly regulated by interaction with receptor domains, G protein subunits, lipids, anchoring proteins and calcium-sensitive proteins, selective binding of activated Galphaq and Galpha-11 to RH domains of GRK2 and GRK3 selectively inhibits Gq signaling
-
-
?
additional information
?
-
-
GRK2 interacts with multiple signaling proteins and is involved in several cellular processes, e.g. expression and regulation of key cardiac seven-transmembrane receptors, 7TM receptors, such as the beta-adrenergic and angiotensin receptors, GRK2 interacts with NCS-1, mechanism, overview, GRK2 inhibition can ameliorate heart failure, molecular mechanism of GRK2 activity regulation, GRK2 is probably involved in regulation of hypertension, overview
-
-
?
additional information
?
-
-
GRK-mediated desensitization of beta2-adrenergic receptors is sufficient to cause declines in cAMP signals. GRK-mediated desensitization is primarily responsible for a sustained suppression of beta2AR signaling, overview
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Mg2+
Mg2+
-
-
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
(6R)-6-([[(1S)-1-(5-fluoro-2-methoxyphenyl)ethyl]amino]methyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide
-
1-[(3R)-1-benzylpyrrolidin-3-yl]-3-[(3,5-dimethyl-1,2-oxazol-4-yl)methyl]urea
-
2-[(2-amino-2-oxoethyl)(propan-2-yl)amino]-N-[(1S)-1-(naphthalen-2-yl)ethyl]acetamide
-
2-[(3S)-3-[(phenylsulfanyl)methyl]pyrrolidin-1-yl]-N-(pyridin-3-ylmethyl)acetamide
-
3-cyano-N-[[(3R)-1-(thiophen-2-ylmethyl)piperidin-3-yl]methyl]benzamide
-
3-[(1R)-1-(3-methoxyphenyl)ethyl]-6-(1H-pyrazol-4-yl)quinazolin-4(3H)-one
-
3-[(1S)-1-(3-methoxyphenyl)ethyl]-6-(1H-pyrazol-4-yl)quinazolin-4(3H)-one
-
3-[1-(3-methoxyphenyl)-3-(methylamino)propyl]-6-(1H-pyrazol-4-yl)quinazolin-4(3H)-one
-
4-acetyl-N-[(2S)-2-(dimethylamino)-2-(4-methoxyphenyl)ethyl]-1H-pyrrole-2-carboxamide
-
4-acetyl-N-[2-(3,4-dihydroisoquinolin-2(1H)-yl)-2-methylpropyl]-1H-pyrrole-2-carboxamide
-
4-acetyl-N-[[(3R)-1-benzylpiperidin-3-yl]methyl]-1H-pyrrole-2-carboxamide
-
5-(4-fluorophenyl)-N-[[(3S,5R,8aR)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-yl]methyl]-5-oxopentanamide
-
N-(4-cyanophenyl)-3-[4-(4-hydroxyphenyl)-3,6-dihydropyridin-1(2H)-yl]propanamide
-
N-(4-fluorophenyl)-3-[[4-oxo-6-(1H-pyrazol-4-yl)quinazolin-3(4H)-yl]methyl]benzamide
-
N-[(2,6-difluorocyclohexa-1,5-dien-1-yl)methyl]-4-[[4-oxo-6-(1H-pyrazol-4-yl)quinazolin-3(4H)-yl]methyl]benzamide
-
N-[(2,6-difluorophenyl)methyl]-3-[[4-oxo-6-(1H-pyrazol-4-yl)quinazolin-3(4H)-yl]methyl]benzamide
-
N-[(2R)-2-(3,4-dihydroisoquinolin-2(1H)-yl)butyl]-N'-(1-ethyl-1H-pyrazol-4-yl)urea
-
N-[(2R)-2-(3,4-dihydroisoquinolin-2(1H)-yl)propyl]-N'-[(2S)-1-(1H-pyrrol-1-yl)propan-2-yl]urea
-
N-[(4-fluorophenyl)methyl]-3-[[4-oxo-6-(1H-pyrazol-4-yl)quinazolin-3(4H)-yl]methyl]benzamide
-
N-[1-[benzyl(methyl)amino]-2-methylpropan-2-yl]-6-methyl-4-oxo-1,4-dihydropyridine-3-carboxamide
-
N2-methyl-N2-[[4-(methylsulfanyl)phenyl]methyl]-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)-L-alaninamide
-
N3-[(6-fluoroquinolin-8-yl)methyl]-N-[(pyridin-3-yl)methyl]-beta-alaninamide
-
betaARKct
-
the isolated C-terminal sequence of the enzyme acts as a peptide inhibitor
-
GRK2ct
-
GRK2 inhibitor GRK2ct corresponding to the carboxyl-terminal 194 amino acids of GRK2 is expressed in failing cardiac fibroblasts using an adenoviral-mediated approach driven by the CMV promoter. Inhibition restores beta-agonist stimulated inhibition of collagen synthesis and decreases collagen synthesis in response to TGF beta stimulation
-
nitric oxide
-
inhibits GRK2 by S-nitrosylation at Cys340, regulatory function of S-nitrosylation
RNA aptamer C13
-
development and synthesis of a highly specific RNA aptamer C13 that potently inhibits GRK2 by binding to it kinase domain, binding kinetics, inhibitor secondary structure, overview
-
S-nitrosothiols
-
inhibit GRK2 by S-nitrosylation at Cys340, regulatory function of S-nitrosylation
-
CMPD101
-
specific inhibitor, i.e. 3-[(4-methyl-5-pyridin-4-yl-1,2,4-triazol-3-yl)methylamino]-N-[[2-(trifluoromethyl)phenyl]methyl]benzamide hydrochloride
-
additional information
-
clathrin inhibitors inhibit the internalization of the beta-adrenergic receptor by GRK
-
additional information
-
deletion mutants of the enzyme, comprising parts of the C-terminus or the N-terminus, are able to inhibit the full-length wild-type enzyme, overview
-
additional information
-
ERK phosphorylates and inhibits GRK2, protein kinase C phosphorylated GRK2 at Ser685 and induces RKIP binding, RKIP binds to GRK2 and inhibits it after it has been phosphorylated by protein kinase C
-
additional information
-
quantitative determination of S-nitrosylation of GRK2 by the biotin-switch assay
-
additional information
-
S-nitrosylation at Cys-340 inhibits isoform GRK2 activity
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
beta-arrestin
-
required for phosphorylation activity and receptor substrate endocytosis
-
G protein betagamma-subunit
-
from brain, stimulates the phosphorylation of rhodopsin, but not of the peptide RRREEEEESAAA, an intact N-terminus of the gamma subunit is required for stimulation, but not for kinase binding, endoprotease Lys-C blocks stimulation, Gbetagamma binds to the C-terminal region of beta-ARK containing the pleckstrin homology domain, role of the G protein gamma-subunit
-
G protein Gbetagamma subunits
-
required for activity, 20fold stimulation with substrate rhodopsin, 2 regulatory Gbetagamma binding sites: one N-terminal domain of GRK2, and one C-terminal within the pleckstrin homology domain, both sites are functionally different, overview
-
isoproterenol
requirement, beta-agonist, beta-adrenergic receptor as substrate
phosphatidylinositol 4,5-bisphosphate
-
binding of GRK2 and GRK3 via their pleckstrin homology domains, activate the phosphorylation activity
phosphatidylserine
-
binding of GRK2 and GRK3 via their pleckstrin homology domains, activate the phosphorylation activity
platelet activating factor
requirement, agonist, beta-adrenergic receptor as substrate
G protein
-
binding and modulation of GRK2 and GRK3, Gbetagamma subunits bind GRK2 required for lipid association and G protein-coupled receptor phosphorylation and are released afterwards
-
G protein
-
interaction via GRK2 N-terminal RGS domain, binding of free Gbetagamma subunits initiates GRK2 translocation from cytosol to the plasma membrane and its activation for receptor phosphorylation
-
additional information
-
GRK2 is activated by phosphorylation through c-Src in a positive feedback reaction, Hsp90 secures proper folding and maturation and protects GRK2 from ubiquitination and proteasomal degradation, it induces GRK2 expression, phosphoinositol kinase 3 binds GRK2 and enhances receptor internalization
-
additional information
-
GRK3 bind the Gbetagamma subunit complex, a process that induces activation of the GRKs by phosphorylation
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0324
DEMEFTEAESNMNDLVSEYQ
-
pH and temperature not specified in the publication
-
0.1
GEGMDEMEFTEAESNMN
-
Km above 0.1 mM, pH and temperature not specified in the publication
-
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.000019
2-(3-methoxybenzyl)-7-(1H-pyrazol-4-yl)phthalazin-1(2H)-one
Homo sapiens
pH and temperature not specified in the publication
0.00275
3-(3-fluoro-4-methoxybenzyl)-6-(1H-pyrazol-4-yl)quinazolin-4(3H)-one
Homo sapiens
pH and temperature not specified in the publication
0.000006
3-(3-methoxybenzyl)-6-(1H-pyrazol-4-yl)quinazolin-4(3H)-one
Homo sapiens
pH and temperature not specified in the publication
0.000018
3-(4-fluoro-3-methoxybenzyl)-6-(1H-pyrazol-4-yl)quinazolin-4(3H)-one
Homo sapiens
pH and temperature not specified in the publication
0.000095
3-benzyl-6-(1H-pyrazol-4-yl)quinazolin-4(3H)-one
Homo sapiens
pH and temperature not specified in the publication
0.1
3-benzyl-6-(1H-pyrazol-5-yl)quinazolin-4(3H)-one
Homo sapiens
IC50 above 0.1 mM, pH and temperature not specified in the publication
0.025
3-benzyl-6-(pyridin-4-yl)quinazolin-4(3H)-one
Homo sapiens
pH and temperature not specified in the publication
0.1
3-benzyl-6-(pyrimidin-5-yl)quinazolin-4(3H)-one
Homo sapiens
IC50 above 0.1 mM, pH and temperature not specified in the publication
0.0041
3-benzyl-7-(1H-pyrazol-4-yl)quinazolin-4(3H)-one
Homo sapiens
pH and temperature not specified in the publication
0.000278
3-benzyl-7-fluoro-6-(1H-pyrazol-4-yl)quinazolin-4(3H)-one
Homo sapiens
pH and temperature not specified in the publication
0.000472
3-benzyl-8-fluoro-6-(1H-pyrazol-4-yl)quinazolin-4(3H)-one
Homo sapiens
pH and temperature not specified in the publication
0.000013
3-[(1R)-1-(3-methoxyphenyl)ethyl]-6-(1H-pyrazol-4-yl)quinazolin-4(3H)-one
Homo sapiens
pH and temperature not specified in the publication
0.00211
3-[(1S)-1-(3-methoxyphenyl)ethyl]-6-(1H-pyrazol-4-yl)quinazolin-4(3H)-one
Homo sapiens
pH and temperature not specified in the publication
0.000012
3-[1-(3-methoxyphenyl)-3-(methylamino)propyl]-6-(1H-pyrazol-4-yl)quinazolin-4(3H)-one
Homo sapiens
pH and temperature not specified in the publication
0.000078
3-[3-(4-fluorophenoxy)benzyl]-6-(1H-pyrazol-4-yl)quinazolin-4(3H)-one
Homo sapiens
pH and temperature not specified in the publication
0.000206
3-[3-(difluoromethoxy)benzyl]-6-(1H-pyrazol-4-yl)quinazolin-4(3H)-one
Homo sapiens
pH and temperature not specified in the publication
0.000009
N-(4-fluorophenyl)-3-[[4-oxo-6-(1H-pyrazol-4-yl)quinazolin-3(4H)-yl]methyl]benzamide
Homo sapiens
pH and temperature not specified in the publication
0.02
N-[(2,6-difluorocyclohexa-1,5-dien-1-yl)methyl]-4-[[4-oxo-6-(1H-pyrazol-4-yl)quinazolin-3(4H)-yl]methyl]benzamide
Homo sapiens
pH and temperature not specified in the publication
0.00001
N-[(2,6-difluorophenyl)methyl]-3-[[4-oxo-6-(1H-pyrazol-4-yl)quinazolin-3(4H)-yl]methyl]benzamide
Homo sapiens
IC50 below 0.00001 mM, pH and temperature not specified in the publication
0.00001
N-[(4-fluorophenyl)methyl]-3-[[4-oxo-6-(1H-pyrazol-4-yl)quinazolin-3(4H)-yl]methyl]benzamide
Homo sapiens
IC50 below 0.00001 mM, pH and temperature not specified in the publication
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
7.4
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
30
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
-
40-50% co-localization of GRK2 with neurofibrillary tangles in Alzheimer's disease
myeloid and lymphoid leukemia cell lines, high expression of beta-ARK 1
-
primary isolated from hearts of patients in the end-stage of heart failure undergoing heart transplantation
-
colocalization of GRK2 and tau in intracellular neurofibrillary tangles and isolated paired helical filaments
-
prepared without lymphocytic infiltrations in the tumor, GRKs expression patterns, low expression of GRK2, and high expression level of GRK3
additional information
-
myocardial G protein-coupled receptor kinase expression and activity, overview
additional information
-
GRK2 and GRK3 are expressed in a wide variety of tissues, expression patterns, overview
additional information
-
Lewy bodies were negative for both GRK2 and GRK5 in Lewy body disease
additional information
-
the enzyme is ubiquitously expressed, developmental regulation of GRK2 expression, overview
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
cytosolic enzyme, isoproterenol and platelet-activating factor induce translocation of beta-ARK from cytosol to membrane
isoproterenol and platelet-activating factor induce translocation of beta-ARK from cytosol to membrane
-
GRK2 and GRK3, transient translocation upon G protein-coupled receptor activation
-
recruitment of GRk2 to the plasma membrane is assisted by phospholipids and Gbetagamma proteins binding to the PH domain and another N-terminal site
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
physiological function
malfunction
-
overexpression of GRK2 in normal cardiac fibroblasts recapitulates a heart failure phenotype with minimal inhibition of collagen synthesis following beta-agonist stimulation. Knockdown of GRK2 expression in normal cardiac fibroblasts enhances cAMP production and leads to greater beta-agonist-mediated inhibition of basal and TGF beta-stimulated collagen synthesis versus control. Inhibition of GRK2 activity in failing cardiac fibroblasts by expression of the GRK2 inhibitor, GRK2ct, or siRNA-mediated knockdown restores beta-agonist stimulated inhibition of collagen synthesis and decreases collagen synthesis in response to TGF beta stimulation
malfunction
-
RNA silencing of GRK5 in HeLa cells impairs NF-kappaB reporter activity
physiological function
-
GRK2 plays a significant role in regulating collagen synthesis in adult human cardiac fibroblasts
physiological function
-
GRK2 regulates membrane protrusion and collective migration of a cell sheet during wound closure in MDCK cell monolayers at least partly through phosphorylation of ezrin/radixin/moesin (ERM) proteins, in particular radixin
physiological function
-
the enzyme mediates epidermal growth factorpromoted centrosomal separation
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). ARBK1_HUMAN
689
0
79574
Swiss-Prot
other Location (Reliability: 2)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
-
beta-ARK 1: amino acid sequence, 689 amino acids protein
additional information
amino acid sequences of human and bovine beta-ARK 1 and 2
additional information
-
amino acid sequences of human and bovine beta-ARK 1 and 2
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
-
GRK family domain structure, the N-terminal RGS domain of GRK2 has regulatory function on G protein binding and receptor phosphorylation and activity, overview
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
phosphoprotein
additional information
-
mechanisms of regulation of GRK protein stability and degradation, e.g. via ubiquitination or protease cleavage, overview
phosphoprotein
-
GRK2 is phosphorylated by c-Src kinase, ERK1 and ERK2, protein kinase C, and PKA, overview
phosphoprotein
-
GRK2 is activated by phosphorylation through c-Src, while phosphorylation by ERK inhibits GRK2
phosphoprotein
-
phosphorylation, e.g. by PKA, PKC, ERK1/2 or c-SRC, activates the enzyme
phosphoprotein
-
enzyme phosphorylation at Tyr-13, Try-86, and Try-92 by c-Src and phosphorylation at Ser-685 by protein kinase A are associated with increased enzyme activity, whereas phosphorylation at Ser-670 by CDK2/ERK1/2 negatively regulates enzyme activity
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
crystal structures of human GRK2 in complex with Gbetagamma in the presence and absence of the AGC (protein kinase A, kinase G, and kinase C subfamily) kinase inhibitor balanol is determined. Balanol stabilizes the kinase domain of GRK2 in a slightly more closed conformation distinct from that of the protein kinase A balanol complex
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
D110A
the Galphaq binding site mutant of GRK 2 inhibits the inositol phosphate signal significantly less than wild-type GRK2, the mutant GRK 2 D110A still inhibitS inositol phosphate formation by 22.35
D110A/K220R
the mutant inhibits the inositol phosphate signal significantly less than wild-type GRK2, but does not differ significantly from wild-type GRK2 in its ability to inhibit calcium-sensing receptor signaling
K220R
S670A
additional information
K220R
-
site-directed mutagenesis, inactive, dominant negative mutants of GRK3 and GRK2, overexpression in SH-SY5Y cells does not influence endogenous M3 muscarinic acetylcholine receptor phosphorylation and desensitization by the endogenous wild-type GRK6, but inhibits methacholine-stimulated inositol 3-phosphate production by 75%
K220R
-
site-directed mutagenesis, kinase-dead GRK2 mutant, overexpression in HEK-293 cells leads to partially desensitization of G protein-coupled receptor
K220R
a catalytic site mutant of GRK2, the mutant does not differ significantly from wild-type GRK2 in its ability to inhibit calcium-sensing receptor signaling
K220R
-
kinase-dead mutant shows no phosphorylation of ezrin/radixin/moesin (ERM) proteins
S670A
-
the GRK2 mutant shows reduced phosphorylation by ERK and is less degraded
additional information
-
construction and expression of a mouse mutant beta-adrenergic receptor lacking the GRK phosphorylation sites in HEK-293 cells, and coexpression of murine GFP-tagged beta-arrestin
additional information
-
construction of betaARKct mutant comprising the C-terminus of the enzyme
additional information
-
construction of deletion mutants comprising residues 1-485, 1-185, 561-689, 1-53, 1-200, or 54-185, analysis of activity with rhodopsin and binding of G protein betagamma subunits, overview
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant GRK2 from insect Sf9 cells by ammonium sulfate fractionation, hydrophobic interaction and heparin affinity chromatography
-
recombinant GST-tagged GRK2 and GRK2 C-terminal or N-terminal domains from insect Sf9 cells by ion exchange and heparin affinity chromatography
-
recombinant GST-tagged wild-type and truncation mutant GRK2s from Escherichia coli by glutathione affinity chromatography, recombinant wild-type GRK2 from Sf9 insect cells by heparin affinity chromatography and gel filtration
-
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
beta ARK locus segregated with the long arm of chromosome 11, centromeric to 11q13
expression of GRK2, with or without inhibitor GRK2ct, in vascular smooth emuscle of transgenic mice, phenotypes, overview
adenovirus-mediated gene transfer and expression of inhibitor betaARKct in primary myocytes isolated from hearts of patients in the end-stage of heart failure undergoing heart transplantation, betaARK1 activity is inhibited but beta-adrenergic signaling and contractile function are improved
-
beta-ARK 1 is cloned and expressed in SF9 cells using the baculovirus expression system
-
cDNA encoding beta-ARK 1 is cloned and sequenced, very similar sequences of bovine and human kinases
cDNA encoding beta-ARK 2 is cloned, expressed in COS-7 cells and sequenced
co-expression of rat thyrotropin receptor with GRK2 and GRK3 in HEK-293 cells, receptor phosphorylation occurs with both enzymes
-
DNAs encoding the C-terminal domains Gly556-Ser670 and Pro466-Leu689 are cloned and expressed in Escherichia coli
-
expression of GST-tagged GRK2 and GRK2 C-terminal or N-terminal domains in Spodoptera frugiperda Sf9 cells using the baculovirus transfection method
-
expression of GST-tagged wild-type and truncation mutant GRK2s in Escherichia coli, expression of wild-type GRK2 in Spodoptera frugiperda Sf9 cells using the baculovirus infection system, expression of wild-type and truncation mutant GRK2s in HEK-293 cells
-
expression of kinase-dead GRK2 mutant and of the N-terminal region of GRK2, residues Ala2-Thr187, in HEK-293 cells
-
overexpression of the C-terminus of betaARK in ventricular cardiomyocytes and in the myocardium of rabbits suffering heart failure by adenoviral gene transfer, co-expression of N-terminal deletion mutant of phosducin, leading to increase in contractility of the cells due to inhibition of Gbetagamma subunits rather than to beta-adrenergic receptor resensitization, betaARK additionally stimulates cAMP production
-
overexpression of wild-type and kinase-dead mutant GRK2 in murine 3T3-L1 adipocytes via adenovirus infection system leading to inhibition of Galphaq/11 signaling, including tyrosine phosphorylation of Galphaq11 and cdc42-associated phosphatidylinositol 3-kinase activity, overexpression of the inactive muant, but not of wild-type enzyme, inhibits endothelin-1-induced Ser612 phosphorylation of insulin receptor substrate-1, and restores activation of the pathway
-
stable overexpression of GFP-fusion K220R mutant GRK2 and GFP-fusion K220R mutant GRK3 in SH-SY5Y neuroblastoma cells via adenovirus infection system
-
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
a 4fold increase in GRK2 expression in the failing cardiac fibroblasts is detected compared with normal controls
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
diagnostics
-
GRK2 levels in heart and peripheral lymphocytes correlate well, therefore the lymphocytic enzyme level might be a very suitable marker for determination for the sympathetic drive to heart failure during clinical course and treatment of human congestive heart failure patients
medicine
medicine
-
heart failure: therapeutic strategy by manipulating beta-AR signaling, specifically through the inhibition of beta-ARK 1, elevated levels of beta-ARK 1 are an early ubiquitous consequence of myocardial injury
medicine
-
effectiveness of in vivo applications of beta-ARK 1-targeted gene therapy at ameliorating heart failure, beta-ARK 1 upregulation often precedes the development of measurable heart failure and may represent an indicator for cardiac injury and potential therapeutic intervention prior to clinical dysfunction
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Benovic, J.L.; Stone, W.C.; Huebner, K.; Croce, C.; Caron, M.G.; Lefkowitz, R.J.
cDNA cloning and chromosomal localization of the human beta-adrenergic receptor kinase
FEBS Lett.
283
122-126
1991
Homo sapiens (P25098), Homo sapiens
Chuang, T.T.; Sallese, M.; Ambrosini, G.; Parruti, G.; De Blasi, A.
High expression of beta-adrenergic receptor kinase in human peripheral blood leukocytes. Isoproterenol and platelet activating factor can induce kinase translocation
J. Biol. Chem.
267
6886-6892
1992
Bos taurus, Homo sapiens, Homo sapiens (P25098)
Fushman, D.; Najmabadi-Haske, T.; Cahill, S.; Zheng, J.; LeVine, H.; Cowburn, D.
The solution structure and dynamics of the pleckstrin homology domain of G protein-coupled receptor kinase 2 (beta-adrenergic receptor kinase 1). A binding partner of Gbetagamma subunits
J. Biol. Chem.
273
2835-2843
1998
Homo sapiens (P25098)
Penn, R.B.; Benovic, J.L.
Structure of the human gene encoding the beta-adrenergic receptor kinase
J. Biol. Chem.
269
14924-14930
1994
Homo sapiens (P25098), Homo sapiens
Dunham, I.; Shimizu, N.; Roe, B.A.; Chissoe, S.; Hunt, A.R.; Collins, J.E.; Bruskiewich, R.; Beare, D.M.; Clamp, M.; Smink, L.J.; Ainscough, R.; Almeida, J.P.; Babbage, A.; Bagguley, C.; Bailey, J.; Barlow, K.; Bates, K.N.; Beasley, O.; Bird, C.P.; Blakey, S.; Bridgeman, A.M.; Buck, D.; Burgess, J.; Burrill, W.D.; O'Brien, K.P.; et al.
The DNA sequence of human chromosome 22
Nature
402
489-495
1999
Homo sapiens (P35626)
Parruti, G.; Ambrosini, G.; Sallese, M.; De Blasi, A.
Molecular cloning, functional expression and mRNA analysis of human beta-adrenergic receptor kinase 2
Biochem. Biophys. Res. Commun.
190
475-481
1993
Bos taurus, Homo sapiens (P35626), Homo sapiens
Shlemann, P.; Hekman, M.; Buchen, C.; Elce, J.S.; Lohse, M.J.
Purification and functional characterization of beta-adrenergic receptor kinase expressed in insect cells
FEBS Lett.
324
59-62
1993
Bos taurus, Homo sapiens
Petrofski, J.A.; Koch, W.J.
The beta-adrenergic receptor kinase in heart failure
J. Mol. Cell. Cardiol.
35
1167-1174
2003
Homo sapiens, Mus musculus
Iino, M.; Shibano, T.
Substrate recognition mechanism of human beta-adrenergic receptor kinase 1 based on a three-dimensional model structure
Drug Des. Discov.
14
145-155
1996
Homo sapiens
Haske, T.N.; DeBlasi, A.; LeVine, H.
An intact N terminus of the gamma subunit is required for the Gbetagamma stimulation of rhodopsin phosphorylation by human beta-adrenergic receptor kinase-1 but not for kinase binding
J. Biol. Chem.
271
2941-2948
1996
Homo sapiens
Penela, P.; Ribas, C.; Mayor, F.
Mechanisms of regulation of the expression and function of G protein-coupled receptor kinases
Cell. Signal.
15
973-981
2003
Homo sapiens, Mus musculus, Rattus norvegicus
Oyama, N.; Urasawa, K.; Kaneta, S.; Sakai, H.; Saito, T.; Takagi, C.; Yoshida, I.; Kitabatake, A.; Tsutsui, H.
Chronic beta-adrenergic receptor stimulation enhances the expression of G-protein coupled receptor kinases, GRK2 and GRK5, in both the heart and peripheral lymphocytes
Circ. J.
69
987-990
2005
Homo sapiens, Rattus norvegicus
Williams, M.L.; Hata, J.A.; Schroder, J.; Rampersaud, E.; Petrofski, J.; Jakoi, A.; Milano, C.A.; Koch, W.J.
Targeted beta-adrenergic receptor kinase (betaARK1) inhibition by gene transfer in failing human hearts
Circulation
109
1590-1593
2004
Homo sapiens
Yoshida, N.; Haga, K.; Haga, T.
Identification of sites of phosphorylation by G-protein-coupled receptor kinase 2 in beta-tubulin
Eur. J. Biochem.
270
1154-1163
2003
Homo sapiens
Voigt, C.; Holzapfel, H.P.; Paschke, R.
Decreased expression of G-protein coupled receptor kinase 2 in cold thyroid nodules
Exp. Clin. Endocrinol. Diabetes
113
102-106
2005
Homo sapiens
Li, Z.; Laugwitz, K.L.; Pinkernell, K.; Pragst, I.; Baumgartner, C.; Hoffmann, E.; Rosport, K.; Munch, G.; Moretti, A.; Humrich, J.; Lohse, M.J.; Ungerer, M.
Effects of two Gbetagamma-binding proteins - N-terminally truncated phosducin and beta-adrenergic receptor kinase C terminus (betaARKct)--in heart failure
Gene Ther.
10
1354-1361
2003
Homo sapiens
Rapacciuolo, A.; Suvarna, S.; Barki-Harrington, L.; Luttrell, L.M.; Cong, M.; Lefkowitz, R.J.; Rockman, H.A.
Protein kinase A and G protein-coupled receptor kinase phosphorylation mediates beta-1 adrenergic receptor endocytosis through different pathways
J. Biol. Chem.
278
35403-35411
2003
Homo sapiens
Eichmann, T.; Lorenz, K.; Hoffmann, M.; Brockmann, J.; Krasel, C.; Lohse, M.J.; Quitterer, U.
The amino-terminal domain of G-protein-coupled receptor kinase 2 is a regulatory Gbeta gamma binding site
J. Biol. Chem.
278
8052-8057
2003
Homo sapiens
Picascia, A.; Capobianco, L.; Iacovelli, L.; De Blasi, A.
Analysis of differential modulatory activities of GRK2 and GRK4 on Galphaq-coupled receptor signaling
Methods Enzymol.
390
337-353
2004
Homo sapiens
Usui, I.; Imamura, T.; Babendure, J.L.; Satoh, H.; Lu, J.C.; Hupfeld, C.J.; Olefsky, J.M.
G protein-coupled receptor kinase 2 mediates endothelin-1-induced insulin resistance via the inhibition of both Galphaq/11 and insulin receptor substrate-1 pathways in 3T3-L1 adipocytes
Mol. Endocrinol.
19
2760-2768
2005
Homo sapiens
Willets, J.M.; Mistry, R.; Nahorski, S.R.; Challiss, R.A.
Specificity of G protein-coupled receptor kinase 6-mediated phosphorylation and regulation of single-cell M3 muscarinic acetylcholine receptor signaling
Mol. Pharmacol.
64
1059-1068
2003
Homo sapiens
Ribas, C.; Penela, P.; Murga, C.; Salcedo, A.; Garcia-Hoz, C.; Jurado-Pueyo, M.; Aymerich, I.; Mayor, F.
The G protein-coupled receptor kinase (GRK) interactome: Role of GRKs in GPCR regulation and signaling
Biochim. Biophys. Acta
1768
913-922
2007
Homo sapiens, Mammalia
Whalen, E.J.; Foster, M.W.; Matsumoto, A.; Ozawa, K.; Violin, J.D.; Que, L.G.; Nelson, C.D.; Benhar, M.; Keys, J.R.; Rockman, H.A.; Koch, W.J.; Daaka, Y.; Lefkowitz, R.J.; Stamler, J.S.
Regulation of beta-adrenergic receptor signaling by S-nitrosylation of G-protein-coupled receptor kinase 2
Cell
129
511-522
2007
Homo sapiens, Mus musculus
Ruiz-Gomez, A.; Mellstroem, B.; Tornero, D.; Morato, E.; Savignac, M.; Holguin, H.; Aurrekoetxea, K.; Gonzalez, P.; Gonzalez-Garcia, C.; Cena, V.; Mayor, F.; Naranjo, J.R.
G protein-coupled receptor kinase 2-mediated phosphorylation of downstream regulatory element antagonist modulator regulates membrane trafficking of Kv4.2 potassium channel
J. Biol. Chem.
282
1205-1215
2007
Homo sapiens
Takahashi, M.; Uchikado, H.; Caprotti, D.; Weidenheim, K.M.; Dickson, D.W.; Ksiezak-Reding, H.; Pasinetti, G.M.
Identification of G-protein coupled receptor kinase 2 in paired helical filaments and neurofibrillary tangles
J. Neuropathol. Exp. Neurol.
65
1157-1169
2006
Homo sapiens
Desai, A.N.; Salim, S.; Standifer, K.M.; Eikenburg, D.C.
Involvement of G protein-coupled receptor kinase (GRK) 3 and GRK2 in down-regulation of the alpha2B-adrenoceptor
J. Pharmacol. Exp. Ther.
317
1027-1035
2006
Homo sapiens
Hansen, J.L.; Theilade, J.; Aplin, M.; Sheikh, S.P.
Role of G-protein-coupled receptor kinase 2 in the heart--do regulatory mechanisms open novel therapeutic perspectives?
Trends Cardiovasc. Med.
16
169-177
2006
Homo sapiens
Yang, W.; Xia, S.
Mechanisms of regulation and function of G-protein-coupled receptor kinases
World J. Gastroenterol.
12
7753-7757
2006
Homo sapiens
Cohn, H.I.; Harris, D.M.; Pesant, S.; Pfeiffer, M.; Zhou, R.H.; Koch, W.J.; Dorn, G.W.; Eckhart, A.D.
Inhibition of vascular smooth muscle G protein-coupled receptor kinase 2 enhances alpha1D-adrenergic receptor constriction
Am. J. Physiol. Heart Circ. Physiol.
295
H1695-H1704
2008
Homo sapiens (P25098), Homo sapiens
Bulcao, C.F.; Pandalai, P.K.; DSouza, K.M.; Merrill, W.H.; Akhter, S.A.
Uncoupling of myocardial beta-adrenergic receptor signaling during coronary artery bypass grafting: the role of GRK2
Ann. Thorac. Surg.
86
1189-1194
2008
Homo sapiens
Tran, T.M.; Jorgensen, R.; Clark, R.B.
Phosphorylation of the beta2-adrenergic receptor in plasma membranes by intrinsic GRK5
Biochemistry
46
14438-14449
2007
Homo sapiens
Lorenz, S.; Frenzel, R.; Paschke, R.; Breitwieser, G.E.; Miedlich, S.U.
Functional desensitization of the extracellular calcium-sensing receptor is regulated via distinct mechanisms: role of G protein-coupled receptor kinases, protein kinase C and beta-arrestins
Endocrinology
148
2398-2404
2007
Homo sapiens (P35626)
Xin, W.; Tran, T.M.; Richter, W.; Clark, R.B.; Rich, T.C.
Roles of GRK and PDE4 activities in the regulation of beta2 adrenergic signaling
J. Gen. Physiol.
131
349-364
2008
Homo sapiens
Mayer, G.; Wulffen, B.; Huber, C.; Brockmann, J.; Flicke, B.; Neumann, L.; Hafenbradl, D.; Klebl, B.M.; Lohse, M.J.; Krasel, C.; Blind, M.
An RNA molecule that specifically inhibits G-protein-coupled receptor kinase 2 in vitro
RNA
14
524-534
2008
Homo sapiens
Kahsai, A.; Zhu, S.; Fenteany, G.
G protein-coupled receptor kinase 2 activates radixin, regulating membrane protrusion and motility in epithelial cells
Biochim. Biophys. Acta
1803
300-310
2010
Homo sapiens
DSouza, K.M.; Malhotra, R.; Philip, J.L.; Staron, M.L.; Theccanat, T.; Jeevanandam, V.; Akhter, S.A.
G protein-coupled receptor kinase-2 is a novel regulator of collagen synthesis in adult human cardiac fibroblasts
J. Biol. Chem.
286
15507-15516
2011
Homo sapiens
Valanne, S.; Myllymaeki, H.; Kallio, J.; Schmid, M.R.; Kleino, A.; Murumaegi, A.; Airaksinen, L.; Kotipelto, T.; Kaustio, M.; Ulvila, J.; Esfahani, S.S.; Engstroem, Y.; Silvennoinen, O.; Hultmark, D.; Parikka, M.; Raemet, M.
Genome-wide RNA interference in Drosophila cells identifies G protein-coupled receptor kinase 2 as a conserved regulator of NF-kappaB signaling
J. Immunol.
184
6188-6198
2010
Danio rerio, Drosophila melanogaster, Homo sapiens
Tesmer, J.J.; Tesmer, V.M.; Lodowski, D.T.; Steinhagen, H.; Huber, J.
Structure of human G protein-coupled receptor kinase 2 in complex with the kinase inhibitor balanol
J. Med. Chem.
53
1867-1870
2010
Homo sapiens (P25098), Homo sapiens
Asai, D.; Murata, M.; Toita, R.; Kawano, T.; Nakashima, H.; Kang, J.H.
Role of amino acid residues surrounding the phosphorylation site in peptide substrates of G protein-coupled receptor kinase 2 (GRK2)
Amino Acids
48
2875-2880
2016
Homo sapiens
Inagaki, S.; Ghirlando, R.; Vishnivetskiy, S.A.; Homan, K.T.; White, J.F.; Tesmer, J.J.; Gurevich, V.V.; Grisshammer, R.
G protein-coupled receptor kinase 2 (GRK2) and 5 (GRK5) exhibit selective phosphorylation of the neurotensin receptor in vitro
Biochemistry
54
4320-4329
2015
Homo sapiens
Asai, D.; Toita, R.; Murata, M.; Katayama, Y.; Nakashima, H.; Kang, J.H.
Peptide substrates for G protein-coupled receptor kinase 2
FEBS Lett.
588
2129-2132
2014
Homo sapiens
So, C.H.; Michal, A.; Komolov, K.E.; Luo, J.; Benovic, J.L.
G protein-coupled receptor kinase 2 (GRK2) is localized to centrosomes and mediates epidermal growth factor-promoted centrosomal separation
Mol. Biol. Cell
24
2795-2806
2013
Homo sapiens
Asai, D.; Murata, M.; Toita, R.; Kawano, T.; Nakashima, H.; Kang, J.
A high-affinity peptide substrate for G protein-coupled receptor kinase 2 (GRK2)
Amino Acids
51
973-976
2019
Homo sapiens
Kang, J.H.; Toita, R.; Kawano, T.; Murata, M.; Asai, D.
Design of substrates and inhibitors of G protein-coupled receptor kinase 2 (GRK2) based on its phosphorylation reaction
Amino Acids
52
863-870
2020
Homo sapiens
Kuwasako, K.; Sekiguchi, T.; Nagata, S.; Jiang, D.; Hayashi, H.; Murakami, M.; Hattori, Y.; Kitamura, K.; Kato, J.
Inhibitory effects of two G protein-coupled receptor kinases on the cell surface expression and signaling of the human adrenomedullin receptor
Biochem. Biophys. Res. Commun.
470
894-899
2016
Homo sapiens (P25098)
Xu, G.; Gaul, M.D.; Liu, Z.; DesJarlais, R.L.; Qi, J.; Wang, W.; Krosky, D.; Petrounia, I.; Milligan, C.M.; Hermans, A.; Lu, H.R.; Huang, D.Z.; Xu, J.Z.; Spurlino, J.C.
Hit-to-lead optimization and discovery of a potent, and orally bioavailable G protein coupled receptor kinase 2 (GRK2) inhibitor
Bioorg. Med. Chem. Lett.
30
127602
2020
Homo sapiens (P25098), Homo sapiens
Ye, W.; Yang, S.; Zhang, L.; Deng, Z.; Li, W.; Zhang, J.; Zhang, L.; Yun, Y.; Chen, A.; Cao, D.
Multistep virtual screening for rapid identification of G protein-coupled receptors kinase 2 inhibitors for heart failure treatment
Chemometr. Intell. Lab. Syst.
185
32-40
2019
Homo sapiens (P25098)
-
EXTERNAL LINKS (specific for EC-Number 2.7.11.15)
Use of this online version of BRENDA is free under the CC BY 4.0 license. See terms of use for full details.
Release 2023.1 (January 2023)
Legal
Curated at
Member of
