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Information on EC 2.7.11.15 - beta-adrenergic-receptor kinase and Organism(s) Mus musculus and UniProt Accession Q3UYH7
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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).
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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: Mus musculus
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, gpcr kinase, 
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
-
enzymes belong to the GRK family, GRK2 and GRK3, i.e. betaARK1 and betaARK2, form the betaARK subfamily
GRK2
-
-
-
-
GRK2
-
-
GRK3
-
-
-
-
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 + corticotropin-releasing factor receptor type 1
ADP + phosphorylated corticotropin-releasing factor receptor type 1
ATP + insulin receptor substrate-1
ADP + phosphorylated-insulin receptor substrate-1
-
-
-
-
?
ATP + [beta-adrenergic receptor]
ADP + phospho-[beta-adrenergic receptor]
-
-
-
-
?
ATP + [beta2-adrenergic receptor]
ADP + phospho-[beta2-adrenergic receptor]
-
-
-
-
?
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
-
phosphate is incorporated solely into Ser-residues
-
?
ATP + beta-adrenergic receptor
ADP + phospho-beta-adrenergic receptor
-
beta-AR from hamster lung
-
?
ATP + beta-adrenergic receptor
ADP + phospho-beta-adrenergic receptor
-
role of beta-ARK 1 in heart failure, myocardial development and function
-
?
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 + phosphorylated beta-adrenergic receptor
-
-
-
-
?
ATP + beta-adrenergic receptor
ADP + phosphorylated beta-adrenergic receptor
-
betaARK1 is responsible for desensitization and down regulation of beta-adrenergic receptors
-
-
?
ATP + beta-adrenergic receptor
ADP + phosphorylated beta-adrenergic receptor
-
desensitization of the receptor by GRK2 and GRK3
-
-
?
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
-
mapping of S-nitrosylation sites and regulatory locus in GRK2
-
-
?
ATP + corticotropin-releasing factor receptor type 1
ADP + phosphorylated corticotropin-releasing factor receptor type 1
-
-
-
-
?
ATP + corticotropin-releasing factor receptor type 1
ADP + phosphorylated corticotropin-releasing factor receptor type 1
-
i.e. CRFR1, phosphorylation leads to desensitization and downregulation of the receptor
-
-
?
ATP + G protein-coupled receptor
ADP + phosphorylated G protein-coupled receptor
-
-
-
-
?
ATP + G protein-coupled receptor
ADP + phosphorylated G protein-coupled receptor
-
desensitization by GRK2 of the ligand-activated receptor
-
-
?
ATP + G protein-coupled receptor
ADP + phosphorylated G protein-coupled receptor
-
phosphorylation has a regulatory role, regulation of the signal transduction involving GRK2 and beta-arrestin, overview
-
-
?
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 + G protein-coupled receptor
ADP + phosphorylated G protein-coupled receptor
-
the GPCRs possess multiple phosphorylation sites for serine/threonine kinases
-
-
?
ATP + insulin receptor substrate 1
ADP + phosphorylated insulin receptor substrate 1
-
role of GRK2 in insulin receptor IR signaling
-
-
?
ATP + insulin receptor substrate 1
ADP + phosphorylated insulin receptor substrate 1
-
phosphorylation at Ser307 by GRK2
-
-
?
ATP + Nedd4
ADP + phosphorylated Nedd4
-
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
-
-
?
ATP + Nedd4
ADP + phosphorylated Nedd4
-
recombinant GST-tagged wild-type Nedd-4, no activity with Nedd-4 mutant T466A, GRK2 interacts with and phosphorylates the ubiquitin protein ligase Nedd4 at multiple sites, mapping of phosphorylation sites, overview
-
-
?
ATP + Nedd4-2
ADP + phosphorylated Nedd4-2
-
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
-
-
?
ATP + Nedd4-2
ADP + phosphorylated Nedd4-2
-
GRK2 interacts with and phosphorylates the ubiquitin protein ligase Nedd4-2 at multiple sites, mapping of phosphorylation sites, overview
-
-
?
ATP + p38 MAP kinase
ADP + phosphorylated p38 MAP kinase
-
GRK2 inactivates and regulates MAP kinase p38 modulating p38-dependent physiological processes, p38 and GRK2 are localized in a multimolecular complex
-
-
?
ATP + p38 MAP kinase
ADP + phosphorylated p38 MAP kinase
-
phosphorylation at Thr123 located in the docking groove
-
-
?
ATP + protein M33
ADP + phosphorylated protein M33
-
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
-
-
?
ATP + protein M33
ADP + phosphorylated protein M33
-
recombinant FLAG-tagged M33 expressed in HEK-293T cells
-
-
?
ATP + rhodopsin
ADP + phosphorhodopsin
-
light-dependent, actual substrate: light-bleached rhodopsin
-
?
ATP + rhodopsin
ADP + phosphorhodopsin
-
in form of bovine rod outer segments
-
?
additional information
?
-
GRK2 is important for myocardial regulation, and is up-regulated in the dysfunctional heart
-
-
?
additional information
?
-
no activity of GRK2 with alpha1-adrenergic receptor. GRK2 does not show class II histone deacetylase kinase activity or interaction with histone deacetylase kinases in vivo
-
-
?
additional information
?
-
-
involved in the regulation of G protein-coupled receptor function, beta-ARK 1 appears to be the predominant GRK in early embryogenesis and plays a fundamental role in cardiac development, enzyme participates in intracellular signal transduction mechanisms, which regulate cardiogenesis
-
-
?
additional information
?
-
-
betaARK1 binds phosphoinositide 3-kinase, which is by this way targeted to agonist-stimulated beta-adrenergic receptors, where it regulates endocytosis, disruption of the betaARK1-PIK complex leads to restoration of beta-adrenergic receptor signaling and contractile function in heart failure, overview
-
-
?
additional information
?
-
-
G protein-coupled receptors are involved in the regulation of diverse physiological processes, mechanisms of G protein-coupled receptor desensitization, e.g. by phosphorylation or feedback inhibition, overview
-
-
?
additional information
?
-
-
GRK2 regulation mechanism of ERK activation involving interaction with mitogen-activated protein kinase, GRK2 diminishes the level of activating phosphorylation of ERK by CCL2 binding to chemokine receptor CCR2 in endothelial cells
-
-
?
additional information
?
-
-
GRKs are involved in diverse physiological processes and pathologies, overview
-
-
?
additional information
?
-
-
betaARK1 interacts with recombinant phosphoinositide 3-kinase expressed in transgenic mice
-
-
?
additional information
?
-
-
GRK2 functionally ineracts with clathrin, phosphoinositol 3-phosphate kinase-gamma, and G protein-coupled receptor kinase interacting protein, GIT
-
-
?
additional information
?
-
-
the GRKs are specific for GPCRs and arrestins, overview
-
-
?
additional information
?
-
-
adrenal GRK2 upregulation mediates sympathetic overdrive in heart failure, adrenal gland-specific GRK2 inhibition reverses alpha2 beta-adrenergic receptor dysregulation in heart failure, resulting in lowered plasma catecholamine levels, improved cardiac beta-adrenergic signaling and function, and increased sympatholytic efficacy of a alpha2 beta-adrenergic agonist
-
-
?
additional information
?
-
-
GRK2 is essential, and GRK2-deficient mice are embryonically lethal
-
-
?
additional information
?
-
-
GRK2 negatively regulates glycogen synthesis in mouse liver FL83B cells, regulates basal and insulin-stimulated glycogen synthesis via a post-IR signaling mechanism, and GRK2 may contribute to reduced IR expression and function during chronic insulin exposure
-
-
?
additional information
?
-
-
GRK2 plays a role in sodium transport regulation and is involved in the development of essential hypertension, overview
-
-
?
additional information
?
-
-
G protein-coupled receptors and Toll-like receptors play a crucial role in the regulation of macrophage biology and innate immunity, overview
-
-
?
additional information
?
-
-
GRK2 in cardiac myocytes catalyzes phosphorylation and desensitization of different G protein-coupled receptors through specificity controlled by their carboxyl-terminal pleckstrin homology domain, overview
-
-
?
additional information
?
-
-
GRK3 in cardiac myocytes catalyzes phosphorylation and desensitization of different G protein-coupled receptors through specificity controlled by its carboxyl-terminal pleckstrin homology domain. GRK3 controls cardiac alpha1-adrenergic receptor responsiveness, distinct functions of GRK3 in regulation of cardiac contractility and growth, overview
-
-
?
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 + corticotropin-releasing factor receptor type 1
ADP + phosphorylated corticotropin-releasing factor receptor type 1
-
i.e. CRFR1, phosphorylation leads to desensitization and downregulation of the receptor
-
-
?
ATP + insulin receptor substrate 1
ADP + phosphorylated insulin receptor substrate 1
-
role of GRK2 in insulin receptor IR signaling
-
-
?
ATP + insulin receptor substrate-1
ADP + phosphorylated-insulin receptor substrate-1
-
-
-
-
?
ATP + Nedd4
ADP + phosphorylated Nedd4
-
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
-
-
?
ATP + Nedd4-2
ADP + phosphorylated Nedd4-2
-
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
-
-
?
ATP + p38 MAP kinase
ADP + phosphorylated p38 MAP kinase
-
GRK2 inactivates and regulates MAP kinase p38 modulating p38-dependent physiological processes, p38 and GRK2 are localized in a multimolecular complex
-
-
?
ATP + protein M33
ADP + phosphorylated protein M33
-
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
-
-
?
ATP + [beta-adrenergic receptor]
ADP + phospho-[beta-adrenergic receptor]
-
-
-
-
?
ATP + [beta2-adrenergic receptor]
ADP + phospho-[beta2-adrenergic receptor]
-
-
-
-
?
ATP + beta-adrenergic receptor
ADP + phospho-beta-adrenergic receptor
-
role of beta-ARK 1 in heart failure, myocardial development and function
-
?
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 + phosphorylated beta-adrenergic receptor
-
-
-
-
?
ATP + beta-adrenergic receptor
ADP + phosphorylated beta-adrenergic receptor
-
betaARK1 is responsible for desensitization and down regulation of beta-adrenergic receptors
-
-
?
ATP + beta-adrenergic receptor
ADP + phosphorylated beta-adrenergic receptor
-
desensitization of the receptor by GRK2 and GRK3
-
-
?
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
-
desensitization by GRK2 of the ligand-activated receptor
-
-
?
ATP + G protein-coupled receptor
ADP + phosphorylated G protein-coupled receptor
-
phosphorylation has a regulatory role, regulation of the signal transduction involving GRK2 and beta-arrestin, overview
-
-
?
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
?
-
GRK2 is important for myocardial regulation, and is up-regulated in the dysfunctional heart
-
-
?
additional information
?
-
-
involved in the regulation of G protein-coupled receptor function, beta-ARK 1 appears to be the predominant GRK in early embryogenesis and plays a fundamental role in cardiac development, enzyme participates in intracellular signal transduction mechanisms, which regulate cardiogenesis
-
-
?
additional information
?
-
-
betaARK1 binds phosphoinositide 3-kinase, which is by this way targeted to agonist-stimulated beta-adrenergic receptors, where it regulates endocytosis, disruption of the betaARK1-PIK complex leads to restoration of beta-adrenergic receptor signaling and contractile function in heart failure, overview
-
-
?
additional information
?
-
-
G protein-coupled receptors are involved in the regulation of diverse physiological processes, mechanisms of G protein-coupled receptor desensitization, e.g. by phosphorylation or feedback inhibition, overview
-
-
?
additional information
?
-
-
GRK2 regulation mechanism of ERK activation involving interaction with mitogen-activated protein kinase, GRK2 diminishes the level of activating phosphorylation of ERK by CCL2 binding to chemokine receptor CCR2 in endothelial cells
-
-
?
additional information
?
-
-
GRKs are involved in diverse physiological processes and pathologies, overview
-
-
?
additional information
?
-
-
adrenal GRK2 upregulation mediates sympathetic overdrive in heart failure, adrenal gland-specific GRK2 inhibition reverses alpha2 beta-adrenergic receptor dysregulation in heart failure, resulting in lowered plasma catecholamine levels, improved cardiac beta-adrenergic signaling and function, and increased sympatholytic efficacy of a alpha2 beta-adrenergic agonist
-
-
?
additional information
?
-
-
GRK2 is essential, and GRK2-deficient mice are embryonically lethal
-
-
?
additional information
?
-
-
GRK2 negatively regulates glycogen synthesis in mouse liver FL83B cells, regulates basal and insulin-stimulated glycogen synthesis via a post-IR signaling mechanism, and GRK2 may contribute to reduced IR expression and function during chronic insulin exposure
-
-
?
additional information
?
-
-
GRK2 plays a role in sodium transport regulation and is involved in the development of essential hypertension, overview
-
-
?
additional information
?
-
-
G protein-coupled receptors and Toll-like receptors play a crucial role in the regulation of macrophage biology and innate immunity, overview
-
-
?
additional information
?
-
-
GRK2 in cardiac myocytes catalyzes phosphorylation and desensitization of different G protein-coupled receptors through specificity controlled by their carboxyl-terminal pleckstrin homology domain, overview
-
-
?
additional information
?
-
-
GRK3 in cardiac myocytes catalyzes phosphorylation and desensitization of different G protein-coupled receptors through specificity controlled by its carboxyl-terminal pleckstrin homology domain. GRK3 controls cardiac alpha1-adrenergic receptor responsiveness, distinct functions of GRK3 in regulation of cardiac contractility and growth, overview
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Mg2+
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
Ca2+/calmodulin
-
inhibit GRK2 with an IC50 of about 0.002 mM, inhibition mechanism via direct binding
-
corticotropin-releasing factor
-
reduces GRK2 expression in pituitary cells, suppressed by astressin, opposite effect compared to corticotroph tumor cells AtT20
-
nitric oxide
-
inhibits GRK2 by S-nitrosylation at Cys340, regulatory function of S-nitrosylation
S-nitrosothiols
-
inhibit GRK2 by S-nitrosylation at Cys340, regulatory function of S-nitrosylation
-
additional information
-
not inhibited by cAMP, cGMP, cAMP-dependent protein kinase inhibitor, Ca2+/calmodulin, Ca2+/phospholipid, phorbol esters
-
additional information
-
isolated pleckstrin homology domains of GRK2 and GRK3 can act as enzyme inhibitors preventing interaction of the enzymes with the G protein subunits
-
additional information
-
quantitative determination of S-nitrosylation of GRK2 by the biotin-switch assay
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
arrestins
-
arrestins modulate the enzyme activity having a regulatory role, regulation of arrestins, overview
-
corticotropin-releasing factor
-
induces GRK2 expression in pituitary cells, suppressed by astressin, opposite effect compared to pituitary cells
-
G protein betagamma-subunit
-
required for maximum activity, targets beta-ARK 1 to the membrane, which presumably facilitates the precise orchestration of phosphorylation of only activated receptors
-
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
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
-
binding of Gbeta/gamma dimers, activation is required for translocation from cytosol to plasma membrane
-
additional information
-
not activated by cAMP, cGMP, Ca2+/calmodulin, Ca2+/phospholipid, phorbol esters
-
additional information
-
activation of Toll-like receptors significantly increases GRK2 expression in primary macrophages, mechanism, overview
-
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.002
Ca2+/calmodulin
Mus musculus
-
inhibit GRK2 with an IC50 of about 0.002 mM, inhibition mechanism via direct binding
-
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
additional information
-
GRK2 and GRK3 are expressed in a wide variety of tissues, expression patterns, overview
-
peritoneal macrophages, activation of Toll-like receptors significantly increases GRK2 expression in primary macrophages, mechanism, overview
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
-
GRK2 and GRK3, transient translocation upon G protein-coupled receptor activation
-
transient recruitment of GRK2 and GRK3 after GPCR activation, the enzymes bind via pleckstrin homology domains to phosphoinositol-4,5-bisphosphate in the plasma membrane
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
physiological function
malfunction
-
the influence of GRK2 levels is investigated in insulin signaling in myoblasts and adipocytes with experimentally increased or silenced levels of GRK2, as well as in GRK2 hemizygous animals expressing 50% lower levels of this kinase in three different models of insulin resistance: TNF-alpha infusion, aging, and high-fat diet (HFD). GRK2 levels are increased by 2fold in muscle and adipose tissue in the animal models tested. In contrast, hemizygous GRK2 mice show enhanced insulin sensitivity and do not develop insulin resistance by TNF-alpha, aging, or high-fat diet. Reduced GRK2 levels induce a lean phenotype and decrease age-related adiposity
malfunction
-
transgenic mice with cardiac-specific overexpression of GRK2 negatively impact cardiac metabolism by inhibiting glucose uptake and desensitization of insulin signaling, which increases after ischemic injury and precedes heart failure development. Mechanistically, GRK2 interacts with and directly phosphorylates insulin receptor substrate-1 (IRS1) in cardiomyocytes causing insulin-dependent negative signaling feedback including inhibition of membrane translocation of the glucose transporter, GLUT4
malfunction
-
using siRNA-mediated knockdown of GRK2 in mouse embryonic fibroblasts it is shown that GRK2 is required for efficient propagation of viruses from the Flaviviridae family and that a decrease in GRK2 level alters both virus entry and RNA genome amplification
malfunction
-
decreased enzyme expression in endothelial cells accelerates tumor growth in mice by impairing the pericytes ensheathing the vessels, thereby promoting hypoxia and macrophage infiltration
malfunction
-
enzyme ablation leads to marked vascular malformations involving impaired recruitment of mural cells. Enzyme downregulation is a relevant event in the tumoral angiogenic switch
physiological function
-
insulin signaling is regulated by GRK2 levels in adipocytes and myocytes
physiological function
-
G protein-coupled receptor kinase 2 activity in the heart directly correlate with cardiac contractile function. The enzyme plays a role a modulator of contractile properties in skeletal muscle as well as beta2-adrenergic receptor-induced hypertrophy
physiological function
-
G protein-coupled receptor kinase 2 is a key angiogenesis regulator
physiological function
-
the enzyme regulates physiological and tumor vascularization
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). ARBK2_MOUSE
688
0
79657
Swiss-Prot
other Location (Reliability: 2)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
phosphoprotein
additional information
phosphoprotein
-
GRK2 is phosphorylated by c-Src kinase, ERK1 and ERK2, protein kinase C, and PKA, overview
phosphoprotein
-
regulation of GRKs by other kinases, such as PKA, PKC, ERK1 and ERK2, e.g. GRK2 is phosphorylated at Ser670 by ERK1 or ERK2, phosphorylation of the beta-adrenergic receptor-activated GRK2 by c-SRC at tyrosine residues mediated by binding of beta-arrestin, which rapidly activates the GPCR phosphorylation activity of GRK2 and its degradation via the ubiquitine/proteosome pathway, overview
additional information
-
GRK2 is ubiquinated after being tyrosine phosphorylated leading to its proteolytic degradation via the ubiquitine/proteasome pathway, regulation overview
additional information
-
mechanisms of regulation of GRK protein stability and degradation, e.g. via ubiquitination or protease cleavage, overview
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
D110A
-
the point mutation within the RH domain abrogates GRK2 sequestration of activated GTP-boundGalphaq/11
D110A/K220R
-
the mutant, which exhibits no RH or kinase activity, is completely defective in its ability to attenuate M33 signaling
K220R
additional information
K220R
-
the point mutation within the kinase domain inhibits GRK2 catalytic activity
K220R
-
kinase-dead mutant fails to alter Akt activation and GLUT4 membrane translocation in response to insulin
additional information
cardiac GRK2 overexpression does not augments hypertrophy in vivo, phenotype, overview
additional information
-
construction of a phosphorylation-defective CCR2 mutant mice, in the mutant mice GRK2 inhibits ERK activation similar to the wild-type mice, the inhibitory effect is eliminated by co-expression of Galphaq-binding RGS-like RH domain of GRK2 or its Gbetagamma-binding domain
additional information
-
construction of transgenic tissue specific or knockout mice
additional information
-
phenotypes of several GRK and arrestin knockout mice mutants and of transgenic mice overexpressing GRK2 or GRK3, overview
additional information
-
construction of GRK2-deficient cells by expression of siRNA leads to increased insulin-induced glycogen synthesis and basal and insulin-stimulated phosphorylation of Ser21 in glycogen synthase kinase-3'alpha, phosphorylation of insulin receptor substrate 1 ia increased in case of GRK2 depletion
additional information
-
homozygous GRK2-deficient mice are embryonically lethal, heterozygous deficient mice show reduced activity an an altered phenotype, overview
additional information
-
construction of transgenic mice expressing mutant GRK2 or deficient in active GRK2, cardiac phenotype with heart failure, overview
additional information
-
construction of transgenic mice with cardiac-restricted expression of a competitive inhibitor of GRK3, i.e. the carboxyl-terminal plasma membrane targeting domain of GRK3 from Rattus norvegicus, show significantly enhanced agonist-stimulated beta1-adrenergic receptor-mediated activation of ERK1/2, but no alterations of cardiac mass or left ventricular dimensions, versus cardiac myocytes from nontransgenic littermate control mice consistent with inhibition of GRK3, overview
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
cloning and disruption of the beta-ARK 1 gene by homologous recombination, effects of gene disruption on the embryos
-
expression of a dominant negative GRK2 mutant in AtT20 cells showing reduced CRFR1 desensitization
-
expression of Myc-tagged wild-type and mutant GRK2s in HEK-293T cells, co-expression with M33 in wild-type and Galphaq/11-/- mouse embryonic fibroblasts, M33 couples directly to the Gq/11 signaling pathway to induce high levels of total inositol phosphates in an agonist-independent manner
-
transient expression of GRK2 in HEK-293T cells, co-expression with GST-tagged epithelial Na+ channel, and GST-tagged Nedd4 and Nedd4-2
-
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Benovic, J.L.; Strasser, R.H.; Caron, M.G.; Lefkowitz, R.J.
beta-Adrenergic receptor kinase: Identification of a novel protein kinase that phosphorylates the agonist-occupied form of the receptor
Proc. Natl. Acad. Sci. USA
83
2797-2801
1986
Mesocricetus auratus, Mus musculus
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
Jaber, M.; Koch, W.J.; Rockman, H.; Smith, B.; Bond, R.A.; Sulik, K.K.; Ross, J. Jr.; Lefkowitz, R.J.; Caron, M.G.; Giros, B.
Essential role of beta-adrenergic receptor kinase 1 in cardiac development and function
Proc. Natl. Acad. Sci. USA
93
12974-12979
1996
Mus musculus
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
Perrino, C.; Naga Prasad, S.V.; Schroder, J.N.; Hata, J.A.; Milano, C.; Rockman, H.A.
Restoration of beta-adrenergic receptor signaling and contractile function in heart failure by disruption of the betaARK1/phosphoinositide 3-kinase complex
Circulation
111
2579-2587
2005
Mus musculus, Sus scrofa
Kageyama, K.; Hanada, K.; Moriyama, T.; Nigawara, T.; Sakihara, S.; Suda, T.
G protein-coupled receptor kinase 2 involvement in desensitization of corticotropin-releasing factor (CRF) receptor type 1 by CRF in murine corticotrophs
Endocrinology
147
441-450
2006
Mus musculus, Rattus norvegicus
Jimenez-Sainz, M.C.; Murga, C.; Kavelaars, A.; Jurado-Pueyo, M.; Krakstad, B.F.; Heijnen, C.J.; Mayor, F.Jr.; Aragay, A.M.
G protein-coupled receptor kinase 2 negatively regulates chemokine signaling at a level downstream from G protein subunits
Mol. Biol. Cell
17
25-31
2006
Bos taurus, Mus musculus
Kohout, T.A.; Lefkowitz, R.J.
Regulation of G protein-coupled receptor kinases and arrestins during receptor desensitization
Mol. Pharmacol.
63
9-18
2003
Mus musculus
Sanchez-Perez, A.; Kumar, S.; Cook, D.I.
GRK2 interacts with and phosphorylates Nedd4 and Nedd4-2
Biochem. Biophys. Res. Commun.
359
611-615
2007
Mus musculus
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
Peregrin, S.; Jurado-Pueyo, M.; Campos, P.M.; Sanz-Moreno, V.; Ruiz-Gomez, A.; Crespo, P.; Mayor, F.; Murga, C.
Phosphorylation of p38 by GRK2 at the docking groove unveils a novel mechanism for inactivating p38MAPK
Curr. Biol.
16
2042-2047
2006
Mus musculus, Mus musculus C57BL/6
Sherrill, J.D.; Miller, W.E.
G protein-coupled receptor (GPCR) kinase 2 regulates agonist-independent Gq/11 signaling from the mouse cytomegalovirus GPCR M33
J. Biol. Chem.
281
39796-39805
2006
Mus musculus
Shahid, G.; Hussain, T.
GRK2 negatively regulates glycogen synthesis in mouse liver FL83B cells
J. Biol. Chem.
282
20612-20620
2007
Mus musculus
Lymperopoulos, A.; Rengo, G.; Funakoshi, H.; Eckhart, A.D.; Koch, W.J.
Adrenal GRK2 upregulation mediates sympathetic overdrive in heart failure
Nat. Med.
13
315-323
2007
Mus musculus, Rattus norvegicus
Raake, P.W.; Vinge, L.E.; Gao, E.; Boucher, M.; Rengo, G.; Chen, X.; DeGeorge, B.R.; Matkovich, S.; Houser, S.R.; Most, P.; Eckhart, A.D.; Dorn, G.W.; Koch, W.J.
G protein-coupled receptor kinase 2 ablation in cardiac myocytes before or after myocardial infarction prevents heart failure
Circ. Res.
103
413-422
2008
Mus musculus
Vinge, L.E.; von Lueder, T.G.; Aasum, E.; Qvigstad, E.; Gravning, J.A.; How, O.J.; Edvardsen, T.; Bj?rnerheim, R.; Ahmed, M.S.; Mikkelsen, B.W.; Oie, E.; Attramadal, T.; Skomedal, T.; Smiseth, O.A.; Koch, W.J.; Larsen, T.S.; Attramadal, H.
Cardiac-restricted expression of the carboxyl-terminal fragment of GRK3 Uncovers Distinct Functions of GRK3 in regulation of cardiac contractility and growth: GRK3 controls cardiac alpha1-adrenergic receptor responsiveness
J. Biol. Chem.
283
10601-10610
2008
Mus musculus
Loniewski, K.; Shi, Y.; Pestka, J.; Parameswaran, N.
Toll-like receptors differentially regulate GPCR kinases and arrestins in primary macrophages
Mol. Immunol.
45
2312-2322
2008
Mus musculus, Mus musculus C57BL/6
Martini, J.S.; Raake, P.; Vinge, L.E.; DeGeorge, B.; Chuprun, J.K.; Harris, D.M.; Gao, E.; Eckhart, A.D.; Pitcher, J.A.; Koch, W.J.
Uncovering G protein-coupled receptor kinase-5 as a histone deacetylase kinase in the nucleus of cardiomyocytes
Proc. Natl. Acad. Sci. USA
105
12457-12462
2008
Mus musculus (Q3UYH7)
Ciccarelli, M.; Chuprun, J.K.; Rengo, G.; Gao, E.; Wei, Z.; Peroutka, R.J.; Gold, J.I.; Gumpert, A.; Chen, M.; Otis, N.J.; Dorn, G.W.; Trimarco, B.; Iaccarino, G.; Koch, W.J.
G protein-coupled receptor kinase 2 activity impairs cardiac glucose uptake and promotes insulin resistance after myocardial ischemia
Circulation
123
1953-1962
2011
Mus musculus
Garcia-Guerra, L.; Nieto-Vazquez, I.; Vila-Bedmar, R.; Jurado-Pueyo, M.; Zalba, G.; Diez, J.; Murga, C.; Fernandez-Veledo, S.; Mayor, F.; Lorenzo, M.
G protein-coupled receptor kinase 2 plays a relevant role in insulin resistance and obesity
Diabetes
59
2407-2417
2010
Mus musculus
Le Sommer, C.; Barrows, N.; Bradrick, S.; Pearson, J.; Garcia-Blanco, M.
G Protein-coupled receptor kinase 2 promotes flaviviridae entry and replication
PLoS Negl. Trop. Dis.
6
e1820
2012
Mus musculus
Woodall, B.P.; Woodall, M.C.; Luongo, T.S.; Grisanti, L.A.; Tilley, D.G.; Elrod, J.W.; Koch, W.J.
Skeletal muscle-specific G protein-coupled receptor kinase 2 ablation alters isolated skeletal muscle mechanics and enhances clenbuterol-stimulated hypertrophy
J. Biol. Chem.
291
21913-21924
2016
Mus musculus
Rivas, V.; Carmona, R.; Munoz-Chapuli, R.; Mendiola, M.; Nogues, L.; Reglero, C.; Miguel-Martin, M.; Garcia-Escudero, R.; Dorn, G.W.; Hardisson, D.; Mayor, F.; Penela, P.
Developmental and tumoral vascularization is regulated by G protein-coupled receptor kinase 2
J. Clin. Invest.
123
4714-4730
2013
Mus musculus
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