Information on EC 2.7.11.16 - G-protein-coupled receptor kinase

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The expected taxonomic range for this enzyme is: Mammalia

EC NUMBER
COMMENTARY
2.7.11.16
-
RECOMMENDED NAME
GeneOntology No.
G-protein-coupled receptor kinase
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
ATP + [G protein-coupled receptor] = ADP + [G protein-coupled receptor]phosphate
show the reaction diagram
regulation mechanism
-
ATP + [G-protein-coupled receptor] = ADP + [G-protein-coupled receptor] phosphate
show the reaction diagram
-
-
-
-
SYSTEMATIC NAME
IUBMB Comments
ATP:[G-protein-coupled receptor] phosphotransferase
Requires G-protein for activation and therefore belongs to the family of G-protein-dependent receptor kinases (GRKs). All members of this enzyme subfamily possess a highly conserved binding site for 1-phosphatidylinositol 4,5-bisphosphate. (cf. EC 2.7.11.14, rhodopsin kinase and EC 2.7.11.15, beta-adrenergic-receptor kinase).
SYNONYMS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
by G protein-coupled receptor kinase 6
-
-
G protein-coupled receptor kinase
-
-
G protein-coupled receptor kinase
-
-
G protein-coupled receptor kinase
Q99MK8
-
G protein-coupled receptor kinase 2
-
-
G protein-coupled receptor kinase 4
-
-
G protein-coupled receptor kinase 4
-
-
G protein-coupled receptor kinase 4
-
-
G protein-coupled receptor kinase 4gamma
P32298
-
G protein-coupled receptor kinase 5
-
-
G protein-coupled receptor kinase 5
-
-
G protein-coupled receptor kinase 5
-
-
G protein-coupled receptor kinase 5
-
-
G protein-coupled receptor kinase 6
-
-
G protein-coupled receptor kinase 6
O70293
-
G protein-coupled receptor kinase 6
-
-
G protein-coupled receptor kinase GRK4
P32298
-
G protein-coupled receptor kinase GRK5
P43249
-
G protein-coupled receptor kinase GRK5
P34947
-
G protein-coupled receptor kinase GRK5
Q62833
-
G protein-coupled receptor kinase GRK6
P43250
-
G protein-coupled receptor kinase GRK6
P97711
-
G protein-coupled receptor kinase-6
-
-
G-protein coupled receptor kinase
-
-
G-protein coupled receptor kinase 5
Q8VEB1
-
G-protein coupled receptor kinase 5
Mus musculus C75BL/6
Q8VEB1
-
-
G-protein coupled receptor kinase 6
O70293
-
G-protein coupled receptor kinase 6
Mus musculus C75BL/6
O70293
-
-
G-protein-coupled receptor kinase 5
-
-
G-protein-coupled receptor kinase 5
P34947
-
G-protein-coupled receptor kinase 6
-
-
GPCR kinase
-
-
GPCR kinase
-
-
GPCR kinase 2
-
-
GPCR kinase 4
P32298
-
GRK-6
-
-
GRK2
Q99MK8
-
GRK3
-
-
GRK3
-
-
GRK4
-
-
GRK4gamma
P32298
-
GRK5
-
-
GRK5
P43249
-
GRK5
-
-
GRK5
Q8VEB1
-
GRK5
Mus musculus C75BL/6
Q8VEB1
-
-
GRK6
P43250
-
GRK6
-
-
GRK6
O70293
-
GRK6
Mus musculus C75BL/6
O70293
-
-
additional information
-
enzymes belong to the GRK family, GRK4, GRK5, and GRK6 form the GRK4 subfamily
additional information
-
GRK4 belongs to the GRK4 subfamily of the GRK family
additional information
-
GRK6 is a member of the GRK4 subfamily of GRKs
additional information
-
the enzyme belongs to the GRK4 subfamily
additional information
-
the enzyme belongs to the GRK4 subfamily of the GRK family
additional information
-
the enzyme belongs to the GRK4 subfamily, consisting of GRK4, GRK5 and GRK6
additional information
P34947
cf. EC 2.7.11.15 and EC 2.7.11.14
additional information
-
the enzyme belongs to the GRK4 subfamily
additional information
-
enzymes belong to the GRK family, GRK4, GRK5, and GRK6 form the GRK4 subfamily
additional information
-
GRK5 is a member of the GRK family
additional information
-
GRK6 belongs to the GRK4 subfamily of the GRK family
additional information
-
the enzyme belongs to the GRK4-6 family
CAS REGISTRY NUMBER
COMMENTARY
127407-08-3
-
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
-
SwissProt
Manually annotated by BRENDA team
2 isoforms: GRK4A and GRK4B
SwissProt
Manually annotated by BRENDA team
4 isoforms: GRK4alpha, GRK4beta, GRK4gamma, GRK4delta
SwissProt
Manually annotated by BRENDA team
4 splicing variants of GRK4
-
-
Manually annotated by BRENDA team
4 splicing variants of GRK4, i.e. GRK4alpha, GRK4beta, GRK4gamma, and GRK4delta, overview
-
-
Manually annotated by BRENDA team
Americans
-
-
Manually annotated by BRENDA team
Han Chinese, gene GRK4
-
-
Manually annotated by BRENDA team
multiple splice variants of GRK4 and GRK6
-
-
Manually annotated by BRENDA team
4 isoforms mGRK6-A, mGRK6-B, mGRK-C, and mGRK-D by alternative splicing
-
-
Manually annotated by BRENDA team
female and male C57BL/6 mice
UniProt
Manually annotated by BRENDA team
GRK5; C57BL/six mice
UniProt
Manually annotated by BRENDA team
GRK6; C57BL/six mice
UniProt
Manually annotated by BRENDA team
mixed C57Bl/6 x SVJ/129 background mice
-
-
Manually annotated by BRENDA team
Mus musculus C75BL/6
GRK5; C57BL/six mice
UniProt
Manually annotated by BRENDA team
Mus musculus C75BL/6
GRK6; C57BL/six mice
UniProt
Manually annotated by BRENDA team
isozyme GRK6 A and GRK6 B
-
-
Manually annotated by BRENDA team
male Wistar rats
-
-
Manually annotated by BRENDA team
Sprague-Dawley rats
-
-
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
-
depletion of endogenous GRK2 enhances canonical signaling
malfunction
Q99MK8
inhibition of vascular smooth muscle GRK2 enhances beta-adrenergic receptor signaling
malfunction
-
GRK5 or GRK6 knockdown has no effect on C3aR (G protein coupled receptors for C3a) desensitization, but causes a significant decrease in C3a-induced mast cell degranulation. GRK5 or GRK6 knockdown render mast cells more responsive to C3a for ERK1/2 phosphorylation
malfunction
-
GRK5-depleted cells are more sensitive to undergoing cell death from polo-like kinase 1 (PLK1) inhibition, and this increased susceptibility corresponds to decreased NPM1 phosphorylation. Conversely, cells with higher GRK5 levels exhibit reduced sensitivity to PLK1 inhibition
malfunction
-
knockdown of GRK2 or GRK3 expression using shRNA causes a more sustained Ca2+ mobilization, attenuated C3aR (G protein coupled receptors for C3a) desensitization, and enhanced degranulation as well as ERK1/2 phosphorylation when compared to shRNA control cells
malfunction
-
knockdown of GRK5 expression leads to G2/M arrest, characterized by a prolonged G2 phase, which can be rescued by expression of wild type but not catalytically inactive GRK5
malfunction
-
knockdown of GRK5 in osteosarcoma cells inhibits DNAdamage-induced apoptosis via a p53-mediated mechanism
malfunction
-
over expression of kinase-inactive K215R GRK5 or GRK5 knockdown leads to G2/M arrest in the cell cycle. Loss of GRK5 activity results in decreased cyclin D1 expression, Rb protein phosphorylation and E2F target gene expression involved in cell cycle control, silencing of GRK5 by RNA interference attenuates in vitro cell proliferation. Reduced expression of GRK5 goes ahead with reduced xenograft tumor growth in mice
malfunction
-
transient overexpression of GRK5, but not kinase dead mutant K215R, results in a significant increase in p53 phosphorylation
physiological function
-
GRK2 inhibits Wnt1-induced activation of a reporter construct and reduces Wnt3a-dependent stabilization and nuclear translocation of beta-catenin,
physiological function
-
the RH domain of GRK5 interacts with IkappaBalpha and causes inhibition of NFkappaB activity, GRK5 overexpression causes nuclear accumulation of IkappaBalpha leading to the inhibition of NFkappaB transcriptional activity, the GRK5-RH domain inhibits TNFalpha transcription, inhibits endothelial cell migration, and vascular tube formation
physiological function
-
GRK2 and GRK3 are involved in C3aR (G protein coupled receptors for C3a) desensitization, GRK5 and GRK6 promote C3a-induced mast cell degranulation but inhibit ERK1/2 phosphorylation via C3aR desensitization-independent mechanisms
physiological function
-
GRK5 has an important role in the regulation of prostate tumor growth
physiological function
-
GRK5 is localized in the centrosome and regulates microtubule nucleation and normal cell cycle progression
physiological function
-
GRK5 phosphorylates nucleophosmin and regulates the sensitivity of cells to PLK1 inhibition
physiological function
-
GRK5 phosphorylates p53 at Thr-55, which promotes the degradation of p53, leading to inhibition of p53-dependent apoptotic response to genotoxic damage
SUBSTRATE
PRODUCT                      
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
LITERATURE
(Substrate)
COMMENTARY
(Product)
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
ATP + a G protein-coupled receptor
ADP + a phosphorylated G protein-coupled receptor
show the reaction diagram
-
the GRKs are important in the cardiovascular system, the major G protein-coupled receptor regulatory pathway involves phosphorylation of activated receptors by GRKs, followed by binding of arrestin proteins, which prevent receptors from activating downstream heterotrimeric G protein pathways while allowing activation of arrestin-dependent signaling pathways, general mechanisms of GRK-arrestin regulation, overview, physiological functions and potential pathophysiological roles of GRKs and arrestins in human disorders, overview
-
-
?
ATP + a G protein-coupled receptor
ADP + a phosphorylated G protein-coupled receptor
show the reaction diagram
-
cell surface localized receptors
-
-
?
ATP + activated form of G protein-coupled receptors
ADP + phosphorylated G protein-coupled receptors
show the reaction diagram
P32298
-
-
-
-
ATP + alpha-synuclein
ADP + phosphorylated alpha-synuclein
show the reaction diagram
-
GRK5 phosphorylates Ser-129 of alpha-synuclein at the plasma membrane and induces translocation of phosphorylated alpha-synuclein to the perikaryal area, GRK5 promotes alpha-linolenic acid-induced oligomerization of alpha-synuclein, alpha-synuclein phosphorylation by GRK5 plays a crucial role in the pathogenesis of sporadic Parkinson's disease, sPD, phosphorylation at Ser129
-
-
?
ATP + alpha1-adrenergic receptor
ADP + alpha1-adrenergic receptor phosphate
show the reaction diagram
Q8VEB1
GRK5 is also active with alpha1-adrenergic receptors. GRK5 activity, but not GRK2 activity, toward alpha1-adrenergic receptors can lead to transactivation of the tyrosine kinase receptor for epidermal growth factor in myocytes, cf. EC 2.7.11.15
-
-
?
ATP + ATP + G protein-coupled receptor
ADP + phosphorylated G protein-coupled receptor
show the reaction diagram
Q99MK8
-
-
-
?
ATP + ATP + G protein-coupled receptor
ADP + phosphorylated G protein-coupled receptor
show the reaction diagram
-
-
-
-
?
ATP + beta 2-adrenergic receptor
ADP + phosphorylated beta 2-adrenergic receptor
show the reaction diagram
-
-
-
-
?
ATP + beta 2-adrenergic receptor
ADP + phosphorylated beta 2-adrenergic receptor
show the reaction diagram
P43249
phosphorylation in an agonist-dependent manner, phosphorylates the C-terminal tail regions of both receptor proteins
-
-
?
ATP + beta-adrenergic receptor
ADP + phosphorylated beta-adrenergic receptor
show the reaction diagram
-
desensitization of the receptor by GRK4, GRK5, and GRK6
-
-
?
ATP + BLT1 receptor
ADP + phosphorylated BLT1 receptor
show the reaction diagram
-
GRK6, ablation of GRK6 leads to augmented signaling by leukotriene B4 acting through the BLT1 receptor
-
-
?
ATP + BLT1 receptor
ADP + phosphorylated BLT1 receptor
show the reaction diagram
-
GRK6
-
-
?
ATP + central M2 muscarinic receptor
ADP + phosphorylated central M2 muscarinic receptor
show the reaction diagram
-
desensitization of the receptor by GRK5, GRK5 regulates pulmmonary responses by activation of the airway receptor, but does not regulate the peripheral cardiac muscarinic receptors, GRK5
-
-
?
ATP + CXCR4 receptor
ADP + phosphorylated CXCR4 receptor
show the reaction diagram
-
GRK6, the pathway is important in facilitating neutrophil retention in the bone marrow
-
-
?
ATP + CXCR4 receptor
ADP + phosphorylated CXCR4 receptor
show the reaction diagram
-
GRK6
-
-
?
ATP + dopamine D1 receptor
ADP + phosphorylated dopamine D1 receptor
show the reaction diagram
-
-
-
-
?
ATP + dopamine D1 receptor
ADP + phosphorylated dopamine D1 receptor
show the reaction diagram
-
rapid desensitization of the receptor by GRK4 and GRK6, Na+/H+ exchanger activity of the receptor, overview, GRK4 and GRK6
-
-
?
ATP + dopamine D1 receptor
ADP + phosphorylated dopamine D1 receptor
show the reaction diagram
-
dopamine D1 receptors in IEC-6 rapidly desensitize to D1-like agonist stimulation and GRK 6 isozymes A and B, but not GRK 4, appear to be involved in agonist-mediated responsiveness and desensitization
-
-
?
ATP + dopamine D1 receptor
ADP + phosphorylated dopamine D1 receptor
show the reaction diagram
-
GRK4
-
-
?
ATP + G protein-coupled receptor
ADP + phosphorylated G protein-coupled receptor
show the reaction diagram
-
-
-
-
?
ATP + G protein-coupled receptor
ADP + phosphorylated G protein-coupled receptor
show the reaction diagram
-
phosphorylation has a regulatory role
-
-
?
ATP + G protein-coupled receptor
ADP + phosphorylated G protein-coupled receptor
show the reaction diagram
-
regulation mechanism of GRK5, overview, regulation by phosphorylation at specific sites via distinct specific kinases, overview
-
-
?
ATP + G protein-coupled receptor
ADP + phosphorylated G protein-coupled receptor
show the reaction diagram
-
the GPCRs possess multiple phosphorylation sites for serine/threonine kinases
-
-
?
ATP + G-protein-coupled receptor
ADP + phosphorylated G-protein-coupled receptor
show the reaction diagram
-
leading to receptor endocytosis
-
-
?
ATP + protein
ADP + phosphoprotein
show the reaction diagram
P43249
major autophosphorylation sites are Ser484 and Thr485
-
-
?
ATP + protein p105
ADP + phosphorylated protein p105
show the reaction diagram
-
recombinant GST-tagged p105, residues 497-968, substrate, GRK5 binds and phosphorylates p105, to which arrestin-2 is already C-terminally bound
-
-
?
ATP + rhodopsin
ADP + phosphorylated rhodopsin
show the reaction diagram
-
-
-
-
?
ATP + rhodopsin
ADP + phosphorylated rhodopsin
show the reaction diagram
P43249
GRK5 phosphorylates rhodopsin in a light-dependent manner, phosphorylates the C-terminal tail region
-
-
?
ATP + rhodopsin
ADP + phosphorylated rhodopsin
show the reaction diagram
P32298
reaction only with GRK4alpha isoform, no reaction with GRK4beta, GRK4gamma, GRK4delta
-
-
?
ATP + rhodopsin
ADP + phosphorylated rhodopsin
show the reaction diagram
-
light-activated rhodopsin, recombinant isoforms mGRK6-A, mGRK6-B, and mGRK-C, the latter showing highest activity
-
-
?
ATP + rhodopsin
ADP + phosphorylated rhodopsin
show the reaction diagram
-
urea treated outer segments of rhodopsin
-
-
?
ATP + rhodopsin
ADP + rhodopsin phosphate
show the reaction diagram
-
cf. EC 2.7.11.14, rhodopsin is also a substrate of GRK5
-
-
?
ATP + [beta2-adrenergic receptor]
ADP + [beta2-adrenergic receptor]phosphate
show the reaction diagram
-
GRK4-6
-
-
?
ATP + [beta2-adrenergic receptor]
ADP + [beta2-adrenergic receptor] phosphate
show the reaction diagram
-
GRK5 plays a distinctive role in the phosphorylation of the beta2AR, cf. EC 2.7.11.15, recombinant FLAG-tagged beta2-adrenergic receptor stably expressed in HEK-293 cells
-
-
?
ATP + [dopamine D1 receptor]
ADP + [dopamine D1 receptor]phosphate
show the reaction diagram
-
GRK4 constitutively phosphorylates active and inactive receptor, in the latter case diminishing stimulation of the receptor by dopamine, phosphorylation reduces receptor desensitization and internalization, followed by reduced cAMP accumulation, GRK4 phosphorylates active and inactive receptor
-
-
?
ATP + [follicle-stimulating hormone receptor]
ADP + [follicle-stimulating hormone receptor]phosphate
show the reaction diagram
-
GRK4-6
-
-
?
ATP + [G protein-coupled receptor]
ADP + [G protein-coupled receptor]phosphate
show the reaction diagram
-
GRK4-6
-
-
?
ATP + [G-protein-coupled receptor]
ADP + [G-protein-coupled receptor]phosphate
show the reaction diagram
-
-
-
-
?
ATP + [luteinizing hormone/chorionic gonadotropin receptor]
ADP + [luteinizing hormone/chorionic gonadotropin receptor]phosphate
show the reaction diagram
-
GRK4-6
-
-
?
ATP + [M2 muscarinic receptor]
ADP + [M2 muscarinic receptor]phosphate
show the reaction diagram
-
GRK4-6
-
-
?
ATP + [M3 muscarinic acetylcholine receptor]
ADP + phospho-[M3 muscarinic acetylcholine receptor]
show the reaction diagram
-
GRK6 plays a major role in specific M3 muscarinic acetylcholine receptor regulation
-
-
?
ATP + [rhodopsin]
ADP + [rhodopsin]phosphate
show the reaction diagram
-
GRK4-6
-
-
?
nucleophosmin 1 + ATP
phosphorylated nucleophosmin 1 + ADP
show the reaction diagram
-
-
-
-
?
p53 + ATP
phosphorylated-p53 + ADP
show the reaction diagram
-
-
-
-
?
ATP + [TSH receptor]
ADP + [TSH receptor]phosphate
show the reaction diagram
-
GRK4-6, GRK4-6, receptor activation
-
-
?
additional information
?
-
-
substrate specificity
-
-
-
additional information
?
-
P43250
GRK6, but not other GRKs tested, incorporated tritium after incubation with [3H]palmitate in Sf9 and in COS-7 cells overexpressing the kinase
-
-
-
additional information
?
-
P32298
enzyme is involved in fertilization
-
-
-
additional information
?
-
Q62833
enzyme mainly involved in homologous desensitization of the TSH receptor
-
-
-
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
?
-
-
GRK5 and especially GRK6 have selective regulatory roles in cAMP accumulation response of the secretin receptor to agonists like beta-arrestin-1 or forskolin, overview
-
-
-
additional information
?
-
-
GRK5 defects can cause obstructive airway diseases such as asthma
-
-
-
additional information
?
-
-
GRK5 elevates blood pressure in vascular smooth muscle via Gi signaling involing the beta1-adrenergic receptor, mechanism overview
-
-
-
additional information
?
-
-
GRKs are involved in diverse physiological processes and pathologies, overview
-
-
-
additional information
?
-
-
the enzyme is involved in GPCR signal transduction pathways and desensitization
-
-
-
additional information
?
-
-
the GRK4 isozymes are differentially regulated, overview
-
-
-
additional information
?
-
-
the GRK4-6 family member enzymes mediate beta-adrenergic receptor desensitization, the beta-adrenergic receptor is stimulated by agonists such as isoproterenol, cholera toxin, or forskolin, and induces cAMP production
-
-
-
additional information
?
-
-
the variable C-terminal extension of GRK6 constitutes an accessorial autoregulatory domain
-
-
-
additional information
?
-
-
GRK5 performs autophosphorylation
-
-
-
additional information
?
-
-
structure-activity relationships of the enzyme C-terminus, overview
-
-
-
additional information
?
-
-
the GRKs are specific for GPCRs and arrestins, overview
-
-
-
additional information
?
-
-
arrestin-2 and GRK5, not GRK6, interact with NFkappaB1 p105 and negatively regulate lipopolysaccharide-stimulated ERK1/2 activation in macrophages, overview
-
-
-
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
-
-
-
additional information
?
-
-
GRK4 is involved in activity of dopamine receptors in renal proximal tubules and mediates sodium reabsorption and blood pressure regulation
-
-
-
additional information
?
-
-
GRK6 is a key regulator of dopaminergic signaling and lymphocyte chemotaxis, GRK6 structure-function relationship determination and analysis
-
-
-
additional information
?
-
-
no binding to RH domain of G protein Galphaq and Galpha-11 by GRK4
-
-
-
additional information
?
-
-
G protein-coupled receptor kinases and arrestins are key participants in the canonical pathways leading to phosphorylation-dependent G protein-coupled receptor, GPCR, desensitization, endocytosis, intracellular trafficking and resensitization as well as in the modulation of important intracellular signaling cascades by GPCR, structure-function relationships, overview. GRK activity is tightly modulated by mechanisms including phosphorylation by different kinases and interaction with several cellular proteins such as calmodulin, caveolin or RKIP
-
-
-
additional information
?
-
O70293, Q8VEB1
G protein-coupled receptors and Toll-like receptors play a crucial role in the regulation of macrophage biology and innate immunity, overview
-
-
-
additional information
?
-
O70293
G protein-coupled receptors are involved in regulating pain signaling in the context of inflammation. G protein-coupled receptor kinases modulate signaling through these receptors, GRK6 controls post-inflammatory visceral hyperalgesia, overview
-
-
-
additional information
?
-
Q8VEB1
GRK5 is important for myocardial regulation, and is up-regulated in the dysfunctional heart. But GRK5 also is a nuclear a class II histone deacetylase kinase that plays a key role in maladaptive cardiac hypertrophy apparently independent of any action directly on G protein coupled receptors, overview. Chronic Gq signaling results in the translocation of GRK5 to the nucleus, where GRK5 activity plays a role in MEF2 activation, which has implications for induction of hypertrophic gene expression. GRK5 interacts with histone deacetylase kinases in vivo
-
-
-
additional information
?
-
-
GRK6 plays a role in determining the course of inflammation and controls chronicity and severity of dextran sodium sulphate-induced colitis in mice, overview
-
-
-
additional information
?
-
-
GRK4 inhibits GalphaS-coupled GPCR signaling and lacks a PH domain, and GRK4gamma interacts with inactive GalphaS, inactive Gbeta, and inactive Galpha13, and to a lesser extent also with active GalphaS, subunits of heterotrimeric G proteins, overview
-
-
-
additional information
?
-
-
GRK5 also phosphorylates rhodopsin, cf. EC 2.7.11.14
-
-
-
additional information
?
-
-
no interaction of the RH domains of GRK5 and GRK6 with Galpha proteins. GRK5 contains a DNA-binding nuclear localization sequence that allows its binding to DNA and its localization in the nucleus upon GPCR activation, interaction with other oroteins, detailed overview
-
-
-
additional information
?
-
Mus musculus C75BL/6
O70293, Q8VEB1
G protein-coupled receptors and Toll-like receptors play a crucial role in the regulation of macrophage biology and innate immunity, overview
-
-
-
NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
LITERATURE
(Substrate)
COMMENTARY
(Product)
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
ATP + a G protein-coupled receptor
ADP + a phosphorylated G protein-coupled receptor
show the reaction diagram
-
the GRKs are important in the cardiovascular system, the major G protein-coupled receptor regulatory pathway involves phosphorylation of activated receptors by GRKs, followed by binding of arrestin proteins, which prevent receptors from activating downstream heterotrimeric G protein pathways while allowing activation of arrestin-dependent signaling pathways, general mechanisms of GRK-arrestin regulation, overview, physiological functions and potential pathophysiological roles of GRKs and arrestins in human disorders, overview
-
-
?
ATP + alpha-synuclein
ADP + phosphorylated alpha-synuclein
show the reaction diagram
-
GRK5 phosphorylates Ser-129 of alpha-synuclein at the plasma membrane and induces translocation of phosphorylated alpha-synuclein to the perikaryal area, GRK5 promotes alpha-linolenic acid-induced oligomerization of alpha-synuclein, alpha-synuclein phosphorylation by GRK5 plays a crucial role in the pathogenesis of sporadic Parkinson's disease, sPD
-
-
?
ATP + ATP + G protein-coupled receptor
ADP + phosphorylated G protein-coupled receptor
show the reaction diagram
Q99MK8
-
-
-
?
ATP + ATP + G protein-coupled receptor
ADP + phosphorylated G protein-coupled receptor
show the reaction diagram
-
-
-
-
?
ATP + beta-adrenergic receptor
ADP + phosphorylated beta-adrenergic receptor
show the reaction diagram
-
desensitization of the receptor by GRK4, GRK5, and GRK6
-
-
?
ATP + BLT1 receptor
ADP + phosphorylated BLT1 receptor
show the reaction diagram
-
GRK6, ablation of GRK6 leads to augmented signaling by leukotriene B4 acting through the BLT1 receptor
-
-
?
ATP + central M2 muscarinic receptor
ADP + phosphorylated central M2 muscarinic receptor
show the reaction diagram
-
desensitization of the receptor by GRK5, GRK5 regulates pulmmonary responses by activation of the airway receptor, but does not regulate the peripheral cardiac muscarinic receptors
-
-
?
ATP + CXCR4 receptor
ADP + phosphorylated CXCR4 receptor
show the reaction diagram
-
GRK6, the pathway is important in facilitating neutrophil retention in the bone marrow
-
-
?
ATP + dopamine D1 receptor
ADP + phosphorylated dopamine D1 receptor
show the reaction diagram
-
rapid desensitization of the receptor by GRK4 and GRK6, Na+/H+ exchanger activity of the receptor, overview
-
-
?
ATP + dopamine D1 receptor
ADP + phosphorylated dopamine D1 receptor
show the reaction diagram
-
dopamine D1 receptors in IEC-6 rapidly desensitize to D1-like agonist stimulation and GRK 6 isozymes A and B, but not GRK 4, appear to be involved in agonist-mediated responsiveness and desensitization
-
-
?
ATP + dopamine D1 receptor
ADP + phosphorylated dopamine D1 receptor
show the reaction diagram
-
GRK4
-
-
?
ATP + G protein-coupled receptor
ADP + phosphorylated G protein-coupled receptor
show the reaction diagram
-
phosphorylation has a regulatory role
-
-
?
ATP + G protein-coupled receptor
ADP + phosphorylated G protein-coupled receptor
show the reaction diagram
-
regulation mechanism of GRK5, overview, regulation by phosphorylation at specific sites via distinct specific kinases, overview
-
-
?
ATP + G-protein-coupled receptor
ADP + phosphorylated G-protein-coupled receptor
show the reaction diagram
-
leading to receptor endocytosis
-
-
?
ATP + protein p105
ADP + phosphorylated protein p105
show the reaction diagram
-
-
-
-
?
ATP + rhodopsin
ADP + phosphorylated rhodopsin
show the reaction diagram
-
-
-
-
?
ATP + [beta2-adrenergic receptor]
ADP + [beta2-adrenergic receptor] phosphate
show the reaction diagram
-
GRK5 plays a distinctive role in the phosphorylation of the beta2AR
-
-
?
ATP + [dopamine D1 receptor]
ADP + [dopamine D1 receptor]phosphate
show the reaction diagram
-
GRK4 constitutively phosphorylates active and inactive receptor, in the latter case diminishing stimulation of the receptor by dopamine, phosphorylation reduces receptor desensitization and internalization, followed by reduced cAMP accumulation
-
-
?
ATP + [G protein-coupled receptor]
ADP + [G protein-coupled receptor]phosphate
show the reaction diagram
-
GRK4-6
-
-
?
ATP + [G-protein-coupled receptor]
ADP + [G-protein-coupled receptor]phosphate
show the reaction diagram
-
-
-
-
?
ATP + [M3 muscarinic acetylcholine receptor]
ADP + phospho-[M3 muscarinic acetylcholine receptor]
show the reaction diagram
-
GRK6 plays a major role in specific M3 muscarinic acetylcholine receptor regulation
-
-
?
ATP + [TSH receptor]
ADP + [TSH receptor]phosphate
show the reaction diagram
-
GRK4-6, receptor activation
-
-
?
additional information
?
-
P32298
enzyme is involved in fertilization
-
-
-
additional information
?
-
Q62833
enzyme mainly involved in homologous desensitization of the TSH receptor
-
-
-
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
?
-
-
GRK5 and especially GRK6 have selective regulatory roles in cAMP accumulation response of the secretin receptor to agonists like beta-arrestin-1 or forskolin, overview
-
-
-
additional information
?
-
-
GRK5 defects can cause obstructive airway diseases such as asthma
-
-
-
additional information
?
-
-
GRK5 elevates blood pressure in vascular smooth muscle via Gi signaling involing the beta1-adrenergic receptor, mechanism overview
-
-
-
additional information
?
-
-
GRKs are involved in diverse physiological processes and pathologies, overview
-
-
-
additional information
?
-
-
the enzyme is involved in GPCR signal transduction pathways and desensitization
-
-
-
additional information
?
-
-
the GRK4 isozymes are differentially regulated, overview
-
-
-
additional information
?
-
-
the GRK4-6 family member enzymes mediate beta-adrenergic receptor desensitization, the beta-adrenergic receptor is stimulated by agonists such as isoproterenol, cholera toxin, or forskolin, and induces cAMP production
-
-
-
additional information
?
-
-
the variable C-terminal extension of GRK6 constitutes an accessorial autoregulatory domain
-
-
-
additional information
?
-
-
arrestin-2 and GRK5, not GRK6, interact with NFkappaB1 p105 and negatively regulate lipopolysaccharide-stimulated ERK1/2 activation in macrophages, overview
-
-
-
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
-
-
-
additional information
?
-
-
GRK4 is involved in activity of dopamine receptors in renal proximal tubules and mediates sodium reabsorption and blood pressure regulation
-
-
-
additional information
?
-
-
GRK6 is a key regulator of dopaminergic signaling and lymphocyte chemotaxis
-
-
-
additional information
?
-
-
G protein-coupled receptor kinases and arrestins are key participants in the canonical pathways leading to phosphorylation-dependent G protein-coupled receptor, GPCR, desensitization, endocytosis, intracellular trafficking and resensitization as well as in the modulation of important intracellular signaling cascades by GPCR, structure-function relationships, overview. GRK activity is tightly modulated by mechanisms including phosphorylation by different kinases and interaction with several cellular proteins such as calmodulin, caveolin or RKIP
-
-
-
additional information
?
-
O70293, Q8VEB1
G protein-coupled receptors and Toll-like receptors play a crucial role in the regulation of macrophage biology and innate immunity, overview
-
-
-
additional information
?
-
O70293
G protein-coupled receptors are involved in regulating pain signaling in the context of inflammation. G protein-coupled receptor kinases modulate signaling through these receptors, GRK6 controls post-inflammatory visceral hyperalgesia, overview
-
-
-
additional information
?
-
Q8VEB1
GRK5 is important for myocardial regulation, and is up-regulated in the dysfunctional heart. But GRK5 also is a nuclear a class II histone deacetylase kinase that plays a key role in maladaptive cardiac hypertrophy apparently independent of any action directly on G protein coupled receptors, overview. Chronic Gq signaling results in the translocation of GRK5 to the nucleus, where GRK5 activity plays a role in MEF2 activation, which has implications for induction of hypertrophic gene expression. GRK5 interacts with histone deacetylase kinases in vivo
-
-
-
additional information
?
-
-
GRK6 plays a role in determining the course of inflammation and controls chronicity and severity of dextran sodium sulphate-induced colitis in mice, overview
-
-
-
additional information
?
-
Mus musculus C75BL/6
O70293, Q8VEB1
G protein-coupled receptors and Toll-like receptors play a crucial role in the regulation of macrophage biology and innate immunity, overview
-
-
-
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Ca2+
-
inhibits GRK5
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
actin
-
-
actinin
-
inhibits GRK5
-
alpha-actinin
-
-
Ca2+
-
inhibits GRK5
Ca2+/calmodulin
-
inhibit GRK5 with an IC50 of 40-50 nM, inhibition mechanism via inducing inhibitory autophosphorylation and blocking of membrane association
-
Calmodulin
P32298
reaction of isoenzyme GRK4alpha with rhodopsin, IC50: 80 nM
Calmodulin
-
inhibits GRK5
Calmodulin
-
-
Calmodulin
-
inhibits the phosphorylation of rhodopsin by GRK5
caveolin
-
inhibits GRK5
-
caveolin
-
-
-
GRK2ct
Q99MK8
carboxylterminal portion of GRK2
-
heparin
-
GRK inhibitor
RKIP
-
-
-
RNA aptamer C13
-
development and synthesis of a highly specific RNA aptamer C13 that potently inhibits GRK2, EC 2.7.11.15, and GRK5, inhibitor secondary structure, overview
-
heparin
-
inhibits GRK6
additional information
-
phosphorylation by PKC inhibits GRK5
-
additional information
-
the variable C-terminal extension of GRK6 constitutes a domain with autoinhibitory function involving residues D560, S566, and L576 of 3 inhibitory elements and an intervening stimulatory element
-
additional information
-
GRK6 activity on the M3 muscarinic acetylcholine receptor is not affected by phorbol-12,13-dibutyrate and Ro 31-8220
-
additional information
O70293, Q8VEB1
activation of Toll-like receptors selectively decreases arrestin-2 and GRK5 protein level in primary macrophages, mechanism, overview; activation of Toll-like receptors selectively decreases arrestin-2 and GRK6 protein level in primary macrophages, mechanism, overview
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
arrestins
-
arrestins modulate the enzyme activity having a regulatory role, regulation of arrestins, overview
-
isoproterenol
-
stimulates the phosphorylation activity of GRK5 by10-15fold at 0.001 mM
phosphatidylinositol 4,5-bisphosphate
-
activates the receptor phosphorylation activity of GRK5, but not its autophosphorylation or peptide phosphorylation activity
Phospholipids
-
activate GRK5
methacholine
-
stimulation of M3 muscarinic acetylcholine receptor phosphorylation is reversible by atropine
additional information
-
no interaction with G protein Gbetagamma subunits by GRK4, which contains no N-terminal RGS domain
-
additional information
-
autophosphorylation of GRK5 is stimulated by phospholipids, such as phosphatidylinositol-4,5-bisphosphate
-
additional information
-
GRK6 activity on the M3 muscarinic acetylcholine receptor is not affected by phorbol-12,13-dibutyrate and Ro 31-8220
-
additional information
-
phosphorylation activates the enzyme
-
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.00004 - 0.00005
Ca2+/calmodulin
-
inhibit GRK5 with an IC50 of 40-50 nM, inhibition mechanism via inducing inhibitory autophosphorylation and blocking of membrane association
-
0.00008
Calmodulin
P32298
reaction of isoenzyme GRK4alpha with rhodopsin, IC50: 80 nM
0.000079
RNA aptamer C13
-
inhibition of GRK5
-
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
-
physiologic activity of lungs in wild-type and GRK5-deficient mice, overview
additional information
-
-
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
7
-
assay at
7.4
-
assay at
7.5
-
assay at
7.5
-
assay at
8
-
assay at
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
22
-
assay at room temperature
30
-
assay at
30
-
assay at
30
-
assay at
37
-
assay at
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
P43249
very weak activity
Manually annotated by BRENDA team
-
expression of GRK4 in the brain is limited to cerebellar Purkinje cells
Manually annotated by BRENDA team
-
GRK4 predominantly
Manually annotated by BRENDA team
-
GRK5 accumulates in Lewy bodies and colocalizes with alpha-synuclein in the pathological structures of the brains of sporadic Parkinson's disease patients
Manually annotated by BRENDA team
P32298
spermatogonia cell line GC-1 spg
Manually annotated by BRENDA team
-
enriched in GRK2 and GRK5
Manually annotated by BRENDA team
P43249
high activity
Manually annotated by BRENDA team
-
GRK5 expression is increased in heart failure
Manually annotated by BRENDA team
-
intestinal epithelial cell line
Manually annotated by BRENDA team
P43249
very weak activity
Manually annotated by BRENDA team
-
GRK4 predominantly
Manually annotated by BRENDA team
P43249
very weak activity
Manually annotated by BRENDA team
P43249
high activity
Manually annotated by BRENDA team
O70293, Q8VEB1
peritoneal macrophages, activation of Toll-like receptors selectively decreases arrestin-2 and GRK5 protein level in primary macrophages, mechanism, overview
Manually annotated by BRENDA team
O70293, Q8VEB1
peritoneal macrophages, activation of Toll-like receptors selectively decreases arrestin-2 and GRK6 protein level in primary macrophages, mechanism, overview
Manually annotated by BRENDA team
-
GRK4, GRK5, and GRK6
Manually annotated by BRENDA team
-
parvalbumin-positive interneurons express more of GRK2 and less of arrestin-2 than medium spiny
Manually annotated by BRENDA team
-
highly expressed
Manually annotated by BRENDA team
P43249
high activity
Manually annotated by BRENDA team
-
neuroblastoma cell line, contains no GRK5
Manually annotated by BRENDA team
P97711
predominantly expressed in
Manually annotated by BRENDA team
P32298
GRK4gamma is the only detectable isoform in human sperm
Manually annotated by BRENDA team
P43249
very weak activity
Manually annotated by BRENDA team
-
GRK4 predominantly
Manually annotated by BRENDA team
-
increased expression of GRK4 in hyperfunctioning thyroid nodule
Manually annotated by BRENDA team
-
prepared without lymphocytic infiltrations in the tumor, GRKs expression patterns, moderate expression level of GRK4
Manually annotated by BRENDA team
Mus musculus C75BL/6
-
peritoneal macrophages, activation of Toll-like receptors selectively decreases arrestin-2 and GRK6 protein level in primary macrophages, mechanism, overview, peritoneal macrophages, activation of Toll-like receptors selectively decreases arrestin-2 and GRK5 protein level in primary macrophages, mechanism, overview
-
Manually annotated by BRENDA team
additional information
P43249
most abundantly in lung, heart, retina, and lingual epithelium, but expressed very little in brain, liver, kidney, or testis
Manually annotated by BRENDA team
additional information
-
analysis of GRK5 expression rate and mRNA level in heart and lymphocytes by RT-PCR
Manually annotated by BRENDA team
additional information
-
GRK5 and GRK6 are expressed in a wide variety of tissues, expression patterns, overview
Manually annotated by BRENDA team
additional information
-
wide tissue distribution of GRK5 and GRK6
Manually annotated by BRENDA team
additional information
-
GRK5 and GRK6 are ubiquitously expressed in mammalian tissues
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
-
association of GRK6 with the cell membrane is mediated in part by the palmitoylation of cysteine residues that lie in a C-terminal region
-
Manually annotated by BRENDA team
-
GRK5 co-localizes with gamma-tubulin, centrin, and pericentrin in centrosomes. The centrosomal localization of GRK5 is observed predominantly at interphase and although its localization is not dependent on microtubules, it can mediate microtubule nucleation of centrosome
Manually annotated by BRENDA team
-
the GRK5 subcellular distribution in the human striatal neurons is altered by its phosphorylation: phosphorylated GRK5 is found in plasma membrane and cytosolic fractions
Manually annotated by BRENDA team
P43249
GRK5 protein does not undergo agonist-dependent translocation from cytosol to membranes as do beta-adrenergic receptor kinase and rhodopsin kinase, but rather appears to associate with membranes constitutively
Manually annotated by BRENDA team
-
anchoring of GRK4 by palmitoyl residue at the C-terminus
Manually annotated by BRENDA team
-
anchoring via palmitoylation
Manually annotated by BRENDA team
-
GRK2 is enriched more than 4fold in the nucleus compared to cytoplasm, phosphorylated GRK5 is enriched more than 4fold in the nucleus compared to cytoplasm
Manually annotated by BRENDA team
-
constitutive association, location of GRK4-6 near the activated receptors, covalent attachment by fatty acids to the C-terminus, e.g. palmitoylated GRK4 and GRK6, or by electrostatic interactions with phospholipids, e.g. for GRK5
Manually annotated by BRENDA team
-
the GRK5 subcellular distribution in the human striatal neurons is altered by its phosphorylation: phosphorylated GRK5 is found in plasma membrane and cytosolic fractions
Manually annotated by BRENDA team
-
the GRK5 subcellular distribution in the human striatal neurons is altered by its phosphorylation: unphosphorylated enzyme preferentially localizes to synaptic membranes
Manually annotated by BRENDA team
additional information
-
GRK4, GRK5, and GRK6 lack the G protein betagamma-subunit binding domain but use direct PIP2 binding and/or covalent lipid modification with palmitate to reside primarily at the plasma membrane
-
Manually annotated by BRENDA team
additional information
Q8VEB1
chronic Gq signaling results in the translocation of GRK5 to the nucleus, where GRK5 activity plays a role in MEF2 activation, which has implications for induction of hypertrophic gene expression
-
Manually annotated by BRENDA team
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
?
-
x * 69000, GRK5, SDS-PAGE
?
-
x * 69000, about, GRK5 catalytic domain, domain structure, overview
dimer
-
2 * 66050, recombinant acetylated, full-length, palmitoylation-deficient GRK6, mass spectrometry
additional information
-
GRK family domain structure
additional information
-
GRK4 subfamily multidomain structure, overview
additional information
-
the variable C-terminal extension of GRK6 constitutes an accessorial autoregulatory domain consisting of 3 autoregulatory elements involving residues D560, S566, and L576 and an intervening stimulatory element
additional information
-
domain structure of GRK4-6, overview
additional information
-
GRK4, GRK5, and GRK6 lack the G protein betagamma-subunit binding domain but use direct PIP2 binding and/or covalent lipid modification with palmitate to reside primarily at the plasma membrane
additional information
-
GRK6 structure-function relationship determination and analysis, the structure involves the RH-kinase domain core, and small and large kinase lobes, comparison to the structure of GRK2, EC 2.7.11.15, overview
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
phosphoprotein
P43249
major autophosphorylation sites are Ser484 and Thr485
lipoprotein
-
palmitoylation of GRK6 appears essential for membrane association
lipoprotein
-
GRK4 is palmitoylated at the C-terminus
phosphoprotein
-
GRK5 performs autophosphorylation and is phosphorylated by protein kinase C
phosphoprotein
-
GRKs are regulated by phopshorylation
phosphoprotein
-
phosphorylation, e.g. by PKA, PKC, ERK1/2 or c-SRC, activates the enzyme
lipoprotein
-
GRK4-6 are permanently modulated by fatty acids and/or phospholipids
phosphoprotein
-
GRK5 performs autophosphorylation and is phosphorylated by protein kinase C
phosphoprotein
-
regulation of GRK5 by phosphorylation through PKC, GRK5 is activated by autophosphorylation, autophosphorylation is stimulated by phospholipids, such as phosphatidylinositol-4,5-bisphosphate, overview
phosphoprotein
-
the GRK5 subcellular distribution in the human striatal neurons is altered by its phosphorylation
lipoprotein
-
GRK6 is palmitoylated at Cys561, Cys562, and Cys565
additional information
-
mechanisms of regulation of GRK protein stability and degradation, e.g. via ubiquitination or protease cleavage, overview
lipoprotein
-
the C-terminus of GRK6 is palmitoylated, not required for phosphorylation activity
additional information
-
mechanisms of regulation of GRK protein stability and degradation, e.g. via ubiquitination or protease cleavage, overview
Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
-
P43249
partial purification of GRK5 from HEK-293 cell membranes, separation from GRK2 and GRK6, overview
-
recombinant GST-tagged GRK5 from insect Sf9 cells by ion exchange and heparin affinity chromatography
-
GRK2 by gel filtration from Sf9 cells
-
recombinant isozymes mGRK6-A, mGRK6-B, and mGRK-C from Sf9 insect cells by sequential gel filtration and heparin affinity chromatography
-
Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
gene encoding GRK5 with SM22alpha promoter for construction of transgenic mice expressing the enzyme in vascular smooth muscle
-
co-expression of isozyme GRK4gamma and dopamine D1 receptor in HEK-293 cells leads to phosphorylation of the receptor by GRK4, this effect is not seen with isozyme GRK4beta and GRK4delta
-
co-expression of rat thyrotropin receptor with GRK4, GRK5, and GRK6 in HEK-293 cells, receptor phosphorylation occurs with GRK5 and GRK6
-
expressed in BAEC cells and HEK-293 cells
-
expression of GRK4gamma in 293T cells, which are devoid of endogenous GRK4gamma
-
expression of GRK6 in both Spodoptera frugiperda Sf9 and Trichoplusia ni High5 insect cells as a soluble, palmitoylation-deficient mutant in which three potential palmitoylation sites, located at Cys561, Cys562, and Cys565, are converted to Ser
-
expression of GST-tagged GRK5 in Spodoptera frugiperda Sf9 cells using the baculovirus transfection method
-
expression of kinase-dead GRK4 mutant in HEK-293 cells
-
gene GRK5, co-expression with human alpha-synuclein in HEK-293 cells and co-localization in the plasma membrane, functional co-expression of GRK5 and alpha-synuclein in primary cortical neurons from the cerebral cortex of fetal mice
-
GRK4, DNA and amino acid sequence determination of polymorphisms, genotyping of American twins
-
GRK4, DNA and amino acid sequence determination of polymorphisms, genotyping of Han Chinese individuals
-
stable overexpression of wild-type and K215R mutant GRK6 in SH-SY5Y neuroblastoma cells via adenovirus infection system
-
transient overexpression of wild-types and dominant negative mutants of GRK5 and GRK6 in NG108-15 mouse neuroblastoma x rat glioma hybrid cells
-
co-overexpression of GRK5 with MEF2 receptor leads to increased MEF2 activity in myocytes
Q8VEB1
expression of isoforms mGRK6-A, mGRK6-B, mGRK-C, and mGRK-D in Spodoptera frugiperda Sf9 cells via baculovirus infection system, transient expression of isoforms mGRK6-A, mGRK6-B, mGRK-C, and mGRK-D in COS-7 cells, recombinant isoforms mGRK6-A, mGRK6-B, and mGRK-C are membrane-associated, recombinant isoform mGRK6-D is inactive and located in the nucleus
-
transient overexpression of wild-types and dominant negative mutants of GRK5 and GRK6 in COS-7 cells
-
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
GRK2 is increased in expression and activity in lymphocytes and vascular smooth muscle in human hypertension
Q99MK8
parvalbumin-positive interneurons express more of GRK2 and less of arrestin-2 than medium spiny neurons
-
ENGINEERING
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
A142V
-
expression of the GRK4gamma mutant in transgenic mice leads to development of hypertension and lack of D1 agonist-induced diuresis and natriuresis in the mice
A142V
-
naturally occuring functional polymorphism, the mutation leads to increased GRK4 activity and phosphorylation of dopamine receptors, phenotype
A486V
-
naturally occuring functional polymorphism, the mutation leads to increased GRK4 activity and phosphorylation of dopamine receptors, phenotype
C561S/C562S/C565S
-
site-directed mutagenesis, mutation of palmitoylation sites, the mutant protein retains its ability to phosphorylate rhodopsin, albeit with a 5fold higher Km and 2fold lower Vmax compared with those of wild-type GRK6
F527D
-
site-directed mutagenesis, mutant structure in comparison to the wild-type enzyme
I165E
-
site-directed mutagenesis, mutant structure in comparison to the wild-type enzyme
I165E/F527D
-
site-directed mutagenesis, mutant structure in comparison to the wild-type enzyme
I39E
-
site-directed mutagenesis, mutant structure in comparison to the wild-type enzyme
I39E/I165E
-
site-directed mutagenesis, mutant structure in comparison to the wild-type enzyme
K215R
-
site-directed mutagenesis, dominant negative mutants of GRK5 or GRK6, overexpression of mutant GRK6 or mutant GRK5 in NG108-15 mouse neuroblastoma x rat glioma hybrid cells results in selective increase in secretin-stimulated cyclic AMP response, the dominant negative mutant of GRK5 has no effect on cAMP response
K215R
-
site-directed mutagenesis, inactive, dominant negative mutant of GRK6, 30fold overexpression in SH-SY5Y cells produces a 50% suppression of endogenous M3 muscarinic acetylcholine receptor phosphorylation and desensitization by the wild-type enzyme, GRK5 K215R mutant overexpression has no effect
K215R
-
the GRK5 mutant binds to alpha-synuclein but does not phosphorylate it
K215R
-
kinase-dead mutant of GRK5
K215R
-
a GRK5 kinase-dead mutant, fails to phosphorylate p53
K215R
-
catalytically inactive mutant is not able to rescue the phenotype of HeLa GRK5 knockdown cells
K215R
-
inactive kinase mutant is not able to rescue the phenotype of PC3 cells that stably express lentiviral small hairpin RNA and target GRK5. Over expression of kinase-inactive K215R, GRK5, or GRK5 knockdown leads to G2/M arrest in the cell cycle
K216M/K217M
-
site-directed mutagenesis, kinase-dead GRK4 mutant, overexpression in HEK-293 cells leads to partially desensitization of GPCR
K216M/K217M
-
a kinase-dead GRK4gamma mutant, that interacts with GalphaS and Galpha13 in the same way as the wild-type GRK4gamma
R65L
-
naturally occuring functional polymorphism, the mutation leads to increased GRK4 activity and phosphorylation of dopamine receptors, phenotype
R65L
-
naturally occuring functional polymorphism, the mutation leads to increased GRK4 activity and phosphorylation of dopamine receptors, the mutation plays a role in blood pressure regulation in adolescents and young adults, phenotype
K215R
-
inactive dominant negative mutants of GRK5 or GRK6, overexpression of the GRK5 mutant in myometrial cells does not influence beta-adrenergic receptor sensitivity, while overexpression of GRK6 mutant leads to a 70% increase in isoproterenol-stimulated beta-adrenergic signaling via the beta-adrenergic receptor
additional information
-
construction of transgenic mice overexpressing GRK5 2fold in vascular smooth muscle leading to hypertension in the mutant mice with a 25-35% increase in blood pressure, which segregates with sex, male show higher blood pressure than female mice, and is dependent on Gi-mediated signaling, inhibition of the latter by pertussis toxin or inhibition of beta1-adrenergic receptor activity restore blood pressure to normal level
K220R
-
kinase-dead mutant
additional information
-
overexpression of wild-type GRK6 increase the endogenous M3 muscarinic acetylcholine receptor phosphorylation and desensitization level
additional information
-
transient overexpression of wild-type GRK6 in NG108-15 mouse neuroblastoma x rat glioma hybrid cells results in highly selective inhibition of secretin-stimulated cyclic AMP accumulation without afffecting the A2 adenosine receptor responsiveness to cAMP, while overexpression of wild-type GRK5 leads to a partly selective inhibition of secretin-stimulated cyclic AMP response and to inhibition of A2 adenosine receptor responsiveness
additional information
-
GRK short hairpin RNA knockdown, GRK5 knockout results in altered central and lung M2 muscarinic receptor regulation, with normal heart M2 receptor regulation, while GRK4 knockout does not result in an altered phenotype, GRK6 knockout leads to altered central dopamine receptor regulation deficient lymphocyte chemotaxis, increased acute inflammation and neutrophil chemotaxis, positive correlation between certain GRK4 polymorphisms, or haplotypes, and hypertensive disease
additional information
-
haplotypic association of the GRK5 gene with susceptibility to sporadic Parkinson's disease, the haplotype contains two functional single-nucleotide polymorphisms, m22.1 and m24, in introns of the GRK5 gene, which bind to Yin Yang-1, YY1, and cAMP response element-binding protein 1, CREB-1, respectively, and increases transcriptional activity of the reporter gene, overview
R65L/A142V/A486V
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co-expression in CHO cells with the dopamine D1 receptor causes enhanced desensitization and agonist-independent phosphorylation of the receptor
additional information
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construction of GRK5 deletion mutant mice
additional information
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construction of isozymes mGRK6-A, mGRK6-B, mGRK-C, and mGRK-D by alternative splicing, recombinant isoforms mGRK6-A, mGRK6-B, and mGRK-C are membrane-associated, recombinant isoform mGRK6-D is inactive and located in the nucleus, structure-activity relationships of the enzyme C-terminus, overview
additional information
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construction of transgenic tissue specific or knockout mice
additional information
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phenotypes of several GRK and arrestin knockout mice mutants and of transgenic mice overexpressing GRK4 or GRK5, overview
additional information
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GRK short hairpin RNA knockdown, GRK5 knockout results in altered central and lung M2 muscarinic receptor regulation, with normal heart M2 receptor regulation, while GRK4 knockout does not result in an altered phenotype, GRK6 knockout leads to altered central dopamine receptor regulation deficient lymphocyte chemotaxis, increased acute inflammation and neutrophil chemotaxis, positive correlation between certain GRK4 polymorphisms, or haplotypes, and hypertensive disease, knockout mice phenotypes, detailed overview
additional information
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GRK5 knockdown results in enhanced IkappaB kinase-mediated p105 phosphorylation and degradation, and correlates well with an enhanced LPS-stimulated ERK1/2 phosphorylation
additional information
O70293
capsaicin-induced referred hyperalgesia post-colitis is increased in GRK6-deficient mice compared to wild-type mice. However, referred hyperalgesia post-colitis is not affected by ablation of GRK6. GRK6 overexpression inhibits the in vitro sensitization of the capsaicin receptor TRPVI by interleukin 1beta, overview
additional information
Q8VEB1
cardiac GRK5 overexpression augments hypertrophy in vivo, pressure overload causes GRK5 nuclear accumulation in vivo, overview
additional information
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severity of colitis is increased in GRK6-deficient and GRK6+/- mice and is accompanied by increased keratinocyte-derived chemokine levels and increased granulocyte infiltration, the chemotactic response of GRK6-/- granulocytes to supernatants of colon cultures is enhanced, phenotype, overview
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
diagnostics
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GRK5 levels in heart and peripheral lymphocytes correlate well, therefore the lymphocytic enzyme level might be a very suitable marker for determining the sympathetic drive to heart failure during clinical course and treatment of human congestive heart failure patients
medicine
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inhibition of GRK2 activity in osteoblasts as therapeutic strategy for increasing bone mass