Affinage

Showing GRK2 — ADRBK1 is a alias.

GRK2

Beta-adrenergic receptor kinase 1 · UniProt P25098

Length
689 aa
Mass
79.6 kDa
Annotated
2026-06-10
100 papers in source corpus 40 papers cited in narrative 40 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GRK2 is a multifunctional serine/threonine kinase that initiates agonist-dependent GPCR desensitization and, beyond this canonical role, acts as a phosphorylation- and scaffold-based regulator of cell migration, division, metabolism, developmental signaling, and circadian and pain physiology (PMID:33060647, PMID:26120872, PMID:22193721). In its receptor-directed mode, GRK2 is the primary kinase driving µ-opioid receptor internalization and β-arrestin2 recruitment (PMID:33060647), selectively phosphorylates C-terminal serines of agonist-activated receptors such as NTSR1 in a lipid-influenced manner (PMID:26120872), and can be recruited directly by receptors (e.g. the D2 dopamine receptor) in a G-protein-independent fashion to bias signaling toward β-arrestin (PMID:29487132); a cryo-EM structure of the NTSR1–GRK2–Gαq complex shows the GRK2 N-terminal helix docking into the receptor cytoplasmic pocket analogously to G protein, with the biased ligand SBI-553 binding the GRK2–NTSR1 interface to favor GRK2 over Gαq (PMID:37532940). GRK2 catalytic competence depends on a C-tail conformational switch (Val477) that acquires the closed active state upon receptor engagement (PMID:19338266) and on acidic phospholipid cofactors that activate the kinase while PIP2 inhibits it (PMID:7673171). GRK2 also acts through its RGS domain to sequester activated Gαq/11, negatively regulating insulin-stimulated GLUT4 translocation, and to bind APC and inhibit canonical WNT/β-catenin signaling (PMID:15241473, PMID:19556343). A broad set of non-receptor substrates extends its reach: GRK2 phosphorylates and activates HDAC6 to promote tubulin deacetylation, lamellipodial motility, and (via HDAC6/Pin1 deacetylation) tumor proliferation (PMID:22193721, PMID:27720394); phosphorylates p38 MAPK at Thr123 to dampen p38 signaling (PMID:18437630); activates Mst2 to drive centrosome separation (PMID:23904266); and phosphorylates ENaC and its regulator Nedd4/Nedd4-2, the mRNA-binding protein HuR, SAV1 in the Hippo–YAP pathway, and PERIOD2 to set circadian period (PMID:15284439, PMID:17544362, PMID:32413989, PMID:38486990, PMID:26279567). In the primary cilium GRK2 relocates to the ciliary shaft upon Smoothened activation, phosphorylates SMO, and enables active SMO to bind and inactivate the PKA catalytic subunit, transducing Hedgehog signaling (PMID:39138140, PMID:27113758). GRK2 activity, levels, and localization are tightly controlled: PKC at Ser29 relieves calmodulin inhibition (PMID:11042191), ERK and CDK2 at Ser670 impair kinase activity, trigger Pin1-dependent degradation during G2/M, and direct mitochondrial translocation after cardiac ischemia-reperfusion (PMID:10574913, PMID:11042191, PMID:20080565, PMID:30538174); c-Src tyrosine phosphorylation enhances Gαq binding (PMID:16725308); and RKIP serves as a physiological inhibitor that sequesters GRK2 from receptors following PKC-dependent activation (PMID:14654844, PMID:27568556). Loss-of-function mutations in GRK2 cause Jeune syndrome (asphyxiating thoracic dystrophy) through failed cilia-based Hedgehog signaling and failed phosphorylation of the WNT co-receptor LRP6 (PMID:33200460).

Mechanistic history

Synthesis pass · year-by-year structured walk · 40 steps
  1. 1995 Medium

    Established that GRK2 catalytic activity toward GPCRs is not intrinsic but conditioned by membrane lipids, defining a biochemical activation requirement.

    Evidence Mixed-micelle phosphorylation, photoaffinity crosslinking and kinetics on β2AR

    PMID:7673171

    Open questions at the time
    • Structural basis of the lipid-induced conformational change not resolved
    • PIP2 inhibition mechanism not defined at residue level
  2. 1996 Medium

    Demonstrated that GRK2 cooperates with β-arrestin1 to desensitize a GPCR, anchoring its canonical receptor-uncoupling role functionally.

    Evidence Co-transfection of TSH receptor with GRK2/β-arrestin1, cAMP and proliferation assays

    PMID:8885248

    Open questions at the time
    • Direct receptor phosphorylation sites not mapped
    • Overexpression system may not reflect endogenous stoichiometry
  3. 1998 Medium

    Identified the first non-receptor GRK2 substrate (tubulin), opening the concept that GRK2 acts beyond GPCR desensitization.

    Evidence GST pulldown, in vitro kinase assay, co-purification with tubulin

    PMID:9716377

    Open questions at the time
    • Functional consequence of tubulin phosphorylation in cells not established
    • Single-lab in vitro reconstitution
  4. 1999 High

    Showed that ERK1/2 phosphorylation at Ser670 is a feedback brake that impairs GRK2 receptor phosphorylation and Gβγ activation, establishing kinase regulation of the kinase.

    Evidence Mass spectrometry site ID, mutagenesis, in vitro ERK1 assay, HEK293 activity assays

    PMID:10574913

    Open questions at the time
    • Did not address downstream localization or degradation consequences of S670 phosphorylation
  5. 2000 High

    Defined PKC phosphorylation of Ser29 as the switch that relieves tonic calmodulin inhibition, linking PKC activity to GRK2 activation.

    Evidence In vitro PKC assay, peptide mapping, S29A mutagenesis, calmodulin binding assay

    PMID:11042191

    Open questions at the time
    • Cellular contexts where calmodulin inhibition dominates not delineated
  6. 2003 High

    Identified RKIP as a physiological inhibitor that, upon PKC phosphorylation, switches from Raf-1 to GRK2 to block receptor internalization, providing endogenous GRK2 regulation.

    Evidence Reciprocal Co-IP, PKC phosphorylation, RKIP knockdown, cardiomyocyte function

    PMID:14654844

    Open questions at the time
    • Quantitative contribution of RKIP across receptor types not defined
  7. 2004 High

    Established the RGS domain of GRK2 as a Gαq/11 sequestration module that negatively regulates insulin/GLUT4 metabolism independent of kinase activity.

    Evidence Antibody microinjection, siRNA, RGS-deletion mutant, glucose uptake in 3T3-L1 adipocytes

    PMID:15241473

    Open questions at the time
    • Direct structural basis of Gαq sequestration in this context not shown
  8. 2004 High

    Showed GRK2 phosphorylates the ENaC β-subunit to render the channel Nedd4-2-insensitive, extending GRK2 to ion transport regulation.

    Evidence Xenopus oocyte electrophysiology, in vitro kinase assay, co-expression

    PMID:15284439

    Open questions at the time
    • Phosphosite on ENaC β not precisely mapped in original finding
    • In vivo relevance to sodium handling not established here
  9. 2006 Medium

    Defined c-Src tyrosine phosphorylation (Y13/86/92) of the RGS region as a positive modulator of Gαq binding, adding tyrosine-kinase control of GRK2.

    Evidence Co-IP, tyrosine site mutagenesis, phosphomimetic, M1 receptor/PLC-β signaling

    PMID:16725308

    Open questions at the time
    • Single lab; physiological c-Src context not defined
  10. 2007 Medium

    Identified Nedd4/Nedd4-2 as direct GRK2 substrates, providing a mechanistic link between GRK2 and ubiquitin-ligase control of sodium transport.

    Evidence Co-IP, in vitro kinase assay, phosphosite identification (Thr466)

    PMID:17544362

    Open questions at the time
    • Functional impact on Nedd4 ligase activity not quantified
    • Limited follow-up
  11. 2009 High

    Connected ERK/CDK2-driven Ser670 phosphorylation to Pin1-dependent proteasomal degradation during G2/M, showing GRK2 turnover gates cell cycle progression.

    Evidence Cell synchronization, CDK2 in vitro phosphorylation, S670A mutagenesis, Pin1 Co-IP, flow cytometry

    PMID:20080565

    Open questions at the time
    • E3 ligase mediating Ser670/Pin1-dependent degradation not identified here
  12. 2009 High

    Revealed a kinase-independent scaffolding role: GRK2 binds PTCH1 to release cyclin B1 nuclear translocation, required for embryonic development.

    Evidence Zebrafish morpholino, kinase-dead rescue, Co-IP, domain mapping

    PMID:19502428

    Open questions at the time
    • Mammalian relevance of PTCH1–cyclin B1 control not demonstrated
  13. 2009 Medium

    Established GRK2 as a centrosomal kinase that activates Mst2 to drive EGFR-mediated centrosome separation, linking GRK2 to mitotic architecture.

    Evidence Immunofluorescence localization, knockdown, in vitro Mst2 phosphorylation, dominant-negative

    PMID:23904266

    Open questions at the time
    • Single lab; centrosomal recruitment mechanism unknown
  14. 2009 Medium

    Showed GRK2 phosphorylates p38 MAPK at Thr123 to impair MKK6 binding and p38 activation, defining a kinase-substrate node dampening inflammatory signaling.

    Evidence In vitro kinase assay, T123E mutagenesis, MKK6 Co-IP, GRK2+/- macrophage cytokine assays

    PMID:18437630

    Open questions at the time
    • Endogenous stoichiometry of p38 phosphorylation by GRK2 unclear
  15. 2009 Medium

    Defined a kinase-activity-dependent RGS-domain interaction with APC that inhibits canonical WNT/β-catenin signaling, broadening GRK2 into developmental signaling.

    Evidence Wnt luciferase reporter, Co-IP, siRNA, RGS-deletion, β-catenin imaging in osteoblasts

    PMID:19556343

    Open questions at the time
    • How kinase activity enables a scaffolding interaction not resolved
  16. 2009 Medium

    Defined the C-tail residue Val477 as required for acquiring the closed active kinase conformation upon receptor engagement, providing a conformational activation mechanism.

    Evidence Structure-guided mutagenesis, kinetic analysis, rhodopsin/β2AR phosphorylation

    PMID:19338266

    Open questions at the time
    • Direct structural snapshot of the closed state not provided in this study
  17. 2010 High

    Demonstrated cell-type-specific GRK2 dosage controls chronic pain: reduced microglial GRK2 converts acute to chronic hyperalgesia via p38/TNF-α.

    Evidence Cell-specific conditional knockdown, hyperalgesia models, intrathecal pathway inhibition

    PMID:20147541

    Open questions at the time
    • Molecular substrate of GRK2 in microglia not identified
  18. 2011 High

    Identified HDAC6 as a GRK2 substrate whose activation promotes tubulin deacetylation and cell motility, with Ser670 phosphorylation potentiating the interaction.

    Evidence Reciprocal Co-IP, in vitro kinase assay, K220R/S670A mutagenesis, live-cell imaging, migration assay

    PMID:22193721

    Open questions at the time
    • HDAC6 phosphosite(s) targeted by GRK2 not pinpointed here
  19. 2013 High

    Showed the GRK2/EPAC1 balance in nociceptors determines transition to chronic pain, establishing GRK2 as a rheostat in pain priming.

    Evidence Viral GRK2 gene transfer, Epac1 heterozygous/antisense mice, two priming models

    PMID:24231349

    Open questions at the time
    • Direct molecular link between GRK2 levels and cAMP/EPAC1 not biochemically defined
  20. 2014 Medium

    Connected insulin signaling to GRK2-mediated β2AR desensitization via IRS2-dependent recruitment, linking metabolic and adrenergic signaling in heart.

    Evidence Co-IP, β2AR phosphorylation/internalization, cAMP, IRS2 KO cardiomyocytes, contractility

    PMID:25460042

    Open questions at the time
    • Single lab; molecular detail of IRS2–GRK2 coupling incomplete
  21. 2015 High

    Refined GRK2 substrate selectivity, showing agonist- and lipid-dependent C-terminal serine phosphorylation of NTSR1 differing from β2AR/µOR consensus rules.

    Evidence Nanodisc phosphorylation, MS phosphosite mapping, NTSR1 mutagenesis

    PMID:26120872

    Open questions at the time
    • Generality of lipid-tuned phosphosite selection across receptors unknown
  22. 2015 Medium

    Placed GRK2 in the circadian machinery by phosphorylating PERIOD2 at Ser545 and suppressing mPeriod1 transcription to modulate clock period and amplitude.

    Evidence Grk2-deficient mouse rhythms, SCN electrophysiology, PER1/2 Co-IP, in vitro phosphorylation, reporter assay

    PMID:26279567

    Open questions at the time
    • Mechanism of transcriptional suppression of Period1 not defined
  23. 2016 Medium

    Established a GRK2/HDAC6/Pin1 axis promoting breast cancer proliferation, linking GRK2's HDAC6 activation to oncogenic Pin1 stabilization.

    Evidence Co-IP, knockdown/overexpression, in vitro HDAC6 phosphorylation, Pin1 acetylation, xenograft

    PMID:27720394

    Open questions at the time
    • Single lab; relative contribution of this axis among GRK2 oncogenic functions unclear
  24. 2016 Medium

    Demonstrated GRK2 kinase activity is essential for Hedgehog signaling downstream of Smoothened in vivo, placing GRK2 in the Hh pathway.

    Evidence Zebrafish grk2-null, kinase-dead rescue, Smo phosphomimetic/phospho-null analysis

    PMID:27113758

    Open questions at the time
    • Molecular mechanism downstream of Smo phosphorylation not resolved in this study
  25. 2017 Medium

    Identified the ciliary/serotonergic role via the GRK2 ortholog phosphorylating monoamine oxidase AMX-2 in C. elegans, controlling serotonin metabolism and egg-laying.

    Evidence C. elegans grk-2 genetics, metabolite measurement, Co-IP, kinase-dead rescue

    PMID:28213524

    Open questions at the time
    • Mammalian MAO regulation by GRK2 not tested
  26. 2017 Medium

    Showed EIF3d stabilizes GRK2 by blocking ubiquitin-mediated degradation, activating PI3K/Akt to drive gallbladder cancer, adding a translation-factor controller of GRK2 levels.

    Evidence Co-IP, ubiquitination/stability assays, PI3K/Akt western, in vitro/in vivo cancer assays

    PMID:28594409

    Open questions at the time
    • E3 ligase blocked by EIF3d not identified
  27. 2018 Medium

    Demonstrated D2R can directly recruit GRK2 G-protein-independently to drive β-arrestin signaling, refining the concept of GRK2-driven biased agonism.

    Evidence BRET recruitment, biased D2R mutants, biased ligand UNC9994, G-protein blockade

    PMID:29487132

    Open questions at the time
    • Structural basis of direct GRK2 recruitment not defined here
  28. 2018 High

    Defined Ser670 phosphorylation as the determinant of GRK2 mitochondrial translocation after ischemia-reperfusion, linking GRK2 to cardiomyocyte metabolic injury.

    Evidence S670A knock-in mice, cardiac IR model, mitochondrial respiration, PDH activity

    PMID:30538174

    Open questions at the time
    • Mitochondrial substrate(s) of GRK2 not identified
  29. 2019 Medium

    Mapped phosphorylation-triggered proteasomal (ischemia) and calpain (reperfusion) degradation of GRK2, showing GRK2 turnover modulates AKT-dependent cardioprotection.

    Evidence Rat/porcine heart IR, proteasome/calpain inhibitors, Pin1/AKT analysis

    PMID:31594751

    Open questions at the time
    • Specific phosphosites driving each degradation route not fully resolved
  30. 2019 Medium

    Showed calpain raises GRK2 levels by degrading its ligase MDM2 and via NF-κB transcription, mechanistically tying GRK2 abundance to cardiac hypertrophy.

    Evidence Calpain inhibitor in rats, GRK2 hemizygous mice, MDM2/NF-κB/IκB assays, mRNA quantification

    PMID:30915659

    Open questions at the time
    • Direct MDM2-mediated GRK2 ubiquitination not shown in this study
  31. 2020 High

    Established with CRISPR knockouts that GRK2 is the dominant kinase for µ-OR internalization and β-arrestin2 recruitment, quantifying its primacy among GRKs.

    Evidence GRK2/GRK3/double KO HEK293, internalization and βarr2 recruitment, rescue, CMPD101

    PMID:33060647

    Open questions at the time
    • Identity of the GRK2/3-independent sustained recruitment component unknown
  32. 2020 Medium

    Demonstrated GRK2 binds the MALT1 death domain to inhibit its scaffolding and protease activities, suppressing NF-κB and acting as a tumor suppressor in ABC-DLBCL.

    Evidence Co-IP/domain mapping, MALT1 protease assay, NF-κB reporter, knockdown, tumor models

    PMID:31961340

    Open questions at the time
    • Whether GRK2 kinase activity contributes to MALT1 inhibition not resolved
  33. 2020 Medium

    Showed GRK2 phosphorylates HuR to enhance its cytoplasmic shuttling and HIF-1α mRNA binding under hypoxia, linking GRK2 to post-transcriptional control.

    Evidence In vitro phosphorylation, phosphodefective HuR mutants, RIP for HIF-1α mRNA, fractionation

    PMID:32413989

    Open questions at the time
    • HuR phosphosite(s) targeted by GRK2 not precisely defined
  34. 2020 Medium

    Established a peripheral neuronal switch in which GRK2 tonically inhibits delta opioid receptor until PKC-phosphorylated RKIP sequesters it, restoring receptor function.

    Evidence Sensory neuron Co-IP, DOR functional assay, PKC inhibition, GRK2-RKIP pulldown

    PMID:27568556

    Open questions at the time
    • Single lab; generalizability to other receptors not tested
  35. 2020 Medium

    Distinguished GRK isoform specificity in cardiomyocytes, with GRK2 phosphorylating and desensitizing GPER, refining receptor-selective GRK roles.

    Evidence CRISPR GRK5 deletion, Co-IP, MR reporter, GRK2 pharmacological inhibition, ventricular myocytes

    PMID:32326036

    Open questions at the time
    • GRK2–GPER phosphosites and functional output not detailed
  36. 2020 Medium

    Linked GRK2 loss-of-function mutations to Jeune syndrome through failed cilia-based Hedgehog and LRP6-dependent canonical Wnt signaling, providing a human disease mechanism.

    Evidence Patient-derived GRK2-null cells, chondrocyte differentiation, Hh/Wnt reporters, LRP6 phosphorylation

    PMID:33200460

    Open questions at the time
    • Direct evidence that GRK2 phosphorylates LRP6 in vivo limited
    • Genotype–phenotype range not defined
  37. 2022 High

    Showed GRK2 desensitizes platelet ADP receptors P2Y1/P2Y12 and binds endogenous Gβγ, establishing its role in thrombosis and Ca2+/Rap1/Akt signaling.

    Evidence Platelet-specific GRK2 KO, laser thrombosis model, Ca2+/Rap1/Akt assays, Gβγ Co-IP

    PMID:35793439

    Open questions at the time
    • Direct ADP-receptor phosphosites by GRK2 not mapped
  38. 2023 High

    Provided a high-resolution structural basis for GRK2 receptor engagement and biased agonism, showing the GRK2 N-helix docks into the receptor pocket and SBI-553 clashes with Gαq.

    Evidence Cryo-EM of NTSR1–GRK2–Gαq with SBI-553

    PMID:37532940

    Open questions at the time
    • Conformational transitions during catalysis not captured
    • Generalizability across receptor classes untested structurally
  39. 2023 Medium

    Identified SAV1 as a GRK2 substrate whose phosphorylation drives its degradation, impairing Hippo-YAP and promoting synovial fibroblast proliferation in arthritis.

    Evidence Co-IP, SAV1 ubiquitination, YAP phosphorylation/translocation, CIA rat model

    PMID:38486990

    Open questions at the time
    • SAV1 phosphosite(s) and responsible E3 ligase not defined
  40. 2024 High

    Resolved the ciliary Hedgehog mechanism: GRK2 relocates to the ciliary shaft, phosphorylates SMO, and enables active SMO to bind and inactivate PKA-C, completing the Hh transduction step.

    Evidence Live-cell ciliary imaging, reconstitution, SMO phosphorylation, PKA-C binding, zebrafish/mouse models

    PMID:39138140

    Open questions at the time
    • Trigger for GRK2 ciliary relocalization not fully defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How GRK2's many context-specific functions are coordinated—which substrates, scaffolds, and localization cues dominate in a given cell type and how the phosphorylation code on GRK2 itself selects among them—remains unresolved.
  • No unifying model linking GRK2 regulatory phosphosites to substrate/localization choice
  • Stoichiometry and competition among partners in vivo unknown
  • Structural states beyond the receptor-bound complex uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 10 GO:0016740 transferase activity 7 GO:0060089 molecular transducer activity 4 GO:0098772 molecular function regulator activity 4
Localization
GO:0005886 plasma membrane 3 GO:0005856 cytoskeleton 2 GO:0005929 cilium 2 GO:0005739 mitochondrion 1 GO:0005815 microtubule organizing center 1
Pathway
R-HSA-1266738 Developmental Biology 5 R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 3 R-HSA-1430728 Metabolism 2 R-HSA-1640170 Cell Cycle 2 R-HSA-9909396 Circadian clock 1
Partners
APCGBGGNAQHDAC6MALT1PIN1PTCH1RKIP

Evidence

Reading pass · 40 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 RKIP (Raf kinase inhibitor protein) is a physiological inhibitor of GRK2. After GPCR stimulation, PKC phosphorylates RKIP at Ser153, causing RKIP to dissociate from Raf-1 and associate with GRK2, blocking GRK2 activity and inhibiting receptor internalization. Co-immunoprecipitation, PKC phosphorylation assay, cardiomyocyte functional studies, RKIP knockdown Nature High 14654844
1999 ERK1/2 phosphorylates GRK2 at Ser670, a C-terminal residue in an ERK consensus sequence, impairing GRK2 ability to phosphorylate both soluble and membrane-incorporated receptor substrates and dramatically attenuating Gβγ-mediated activation of GRK2. Mass spectrometry, mutational analysis, in vitro ERK1 phosphorylation assay, HEK293 cell kinase activity assays The Journal of biological chemistry High 10574913
2000 PKC phosphorylates GRK2 at Ser29, located in the calmodulin-binding region. Calmodulin tonically inhibits GRK2, and PKC-mediated phosphorylation at Ser29 abolishes calmodulin inhibition of GRK2 kinase activity. In vitro PKC phosphorylation assay, 2D peptide mapping, HPLC-MS site identification, S29A mutagenesis, HEK293 cell transfection, calmodulin binding/inhibition assay The Journal of biological chemistry High 11042191
2023 Cryo-EM structure of the NTSR1–GRK2–Gαq complex with arrestin-biased ligand SBI-553 reveals that the N-terminal helix of GRK2 docks into the open cytoplasmic pocket of the receptor (analogous to G protein binding). SBI-553 binds at the GRK2–NTSR1 interface to enhance GRK2 binding while clashing with Gαq binding, providing a structural basis for arrestin-biased signaling. Cryo-EM structure determination Nature High 37532940
2011 GRK2 directly associates with and phosphorylates HDAC6, stimulating its α-tubulin deacetylase activity. Phosphorylation of GRK2 at S670 specifically potentiates this interaction. GRK2 and HDAC6 co-localize in lamellipodia of migrating cells, promoting local tubulin deacetylation and enhanced cell motility. Co-immunoprecipitation, in vitro kinase assay, phosphorylation site mutagenesis (K220R, S670A), live-cell imaging, migration assay The EMBO journal High 22193721
2004 GRK2 functions as a negative regulator of insulin-stimulated GLUT4 translocation via its RGS domain, which sequesters activated Gαq/11. A GRK2 mutant lacking the RGS domain has no effect on insulin-stimulated glucose transport. Microinjection of anti-GRK2 antibody, siRNA knockdown, adenovirus-mediated overexpression of wild-type and kinase-deficient GRK2, RGS domain deletion mutant, 2-deoxyglucose uptake assay, GLUT4 translocation assay in 3T3-L1 adipocytes The EMBO journal High 15241473
2004 GRK2 phosphorylates the C-terminus of the ENaC β-subunit, rendering ENaC channels insensitive to inhibition by the ubiquitin ligase Nedd4-2, thereby maintaining channels in the active state. Electrophysiology (Xenopus oocyte expression), in vitro kinase assay, co-expression studies Proceedings of the National Academy of Sciences of the United States of America High 15284439
2009 GRK2 protein levels are transiently down-regulated during G2/M transition via CDK2-mediated phosphorylation of GRK2 at Ser670, which triggers binding to the prolyl-isomerase Pin1 and subsequent proteasomal degradation. Prevention of this phosphorylation markedly delays cell cycle progression. Cell synchronization assays, CDK2 in vitro phosphorylation, S670A mutagenesis, Pin1 co-immunoprecipitation, flow cytometry Proceedings of the National Academy of Sciences of the United States of America High 20080565
2009 GRK2 interacts with PTCH1 (patched homolog 1) at residues 262-379, reducing PTCH1 association with cyclin B1 and disrupting PTCH1-mediated inhibition of cyclin B1 nuclear translocation. This function is kinase activity-independent and is required for normal zebrafish early embryonic development. Zebrafish GRK2 morpholino knockdown, rescue with kinase-dead K220R mutant, co-immunoprecipitation, deletion mutagenesis, cell cycle and proliferation assays Proceedings of the National Academy of Sciences of the United States of America High 19502428
2006 c-Src phosphorylates GRK2 on tyrosine residues (Y13, Y86, Y92) in the RGS-homology region, which increases GRK2 interaction with Gαq and enhances inhibition of the Gαq/phospholipase Cβ signaling pathway. Co-immunoprecipitation, tyrosine phosphorylation site mutagenesis (Y13,86,92F), phosphomimetic mutant, M1 muscarinic receptor stimulation assay, PLC-β signaling assay in cells Cellular signalling Medium 16725308
1998 GRK2 directly binds tubulin via its C-terminal domain (residues 467-689) and phosphorylates tubulin (Km ~3 µM, 1.3 mol phosphate/dimer). Tubulin and Gβγ bind GRK2 independently. GRK2-mediated tubulin phosphorylation is stimulated by Gβγ and agonist-activated muscarinic receptors. GST pulldown, co-purification via tubulin polymerization-depolymerization, in vitro kinase assay, Western blot European journal of biochemistry Medium 9716377
1995 GRK2 requires acidic phospholipids for phosphorylation of the β2-adrenergic receptor; phospholipids increase catalytic activity via a conformational change in the kinase without altering Km for peptide substrate. PIP2 inhibits GRK2 activity and reduces crosslinker incorporation. Mixed micelle phosphorylation assay, photoaffinity crosslinking with [125I]ACTP, Km determination, proteolytic mapping The Journal of biological chemistry Medium 7673171
2009 GRK2 directly phosphorylates p38 MAPK at Thr123, a residue at the entrance of a docking groove. The phosphomimetic T123E mutant of p38 shows reduced binding to MKK6 and impaired p38 activation, and elevated GRK2 levels downregulate p38-dependent cellular responses. In vitro kinase assay, phosphomimetic mutagenesis (T123E), MKK6 co-immunoprecipitation, substrate phosphorylation assays (MEF2, MK2, ATF2), macrophage cytokine assay in GRK2+/- mice Journal of receptor and signal transduction research Medium 18437630
2009 GRK2 localizes to centrosomes and, upon EGF stimulation, directly phosphorylates and activates the kinase Mst2, which drives EGFR-mediated centrosome separation in a Nek2A-dependent manner. Immunofluorescence localization, GRK2 knockdown, in vitro kinase assay (GRK2 phosphorylation of Mst2), dominant-negative Mst2, centrosome separation assay Molecular biology of the cell Medium 23904266
2009 GRK2 negatively regulates WNT/β-catenin (canonical Wnt) signaling by binding APC via its RGS domain. GRK2 enzymatic activity is required for the GRK2-APC interaction and for inhibition of β-catenin stabilization and nuclear translocation. RGS domain deletion abolishes both the APC interaction and inhibition of Wnt signaling. Reporter assay (Wnt-responsive luciferase), co-immunoprecipitation, siRNA knockdown of endogenous GRK2, RGS domain deletion mutant, β-catenin immunofluorescence in calvarial osteoblasts Molecular endocrinology Medium 19556343
2015 GRK2 selectively phosphorylates only C-terminal Ser residues of agonist-activated neurotensin receptor 1 (NTSR1) in nanodiscs, in an agonist-dependent manner. Negatively charged lipids in the vicinity of NTSR1 directly affect the extent of GRK2-mediated phosphorylation. GRK2 does not require acidic residues upstream of phospho-acceptors for NTSR1 (unlike β2AR and μOR). In vitro phosphorylation in nanodiscs, mass spectrometry phosphosite mapping, NTSR1 mutational analysis Biochemistry High 26120872
2016 GRK2 promotes breast cancer progression via phosphorylation and activation of HDAC6, which deacetylates Pin1, enhancing Pin1 stability and its interactions with mitotic regulators. This GRK2/HDAC6/Pin1 axis promotes proliferation and anchorage-independent growth. Co-immunoprecipitation, GRK2 knockdown/overexpression, in vitro HDAC6 phosphorylation, Pin1 acetylation assay, tumor xenograft in mice EBioMedicine Medium 27720394
2014 Insulin stimulates GRK2 recruitment to β2AR via an IRS2-dependent mechanism. GRK2 phosphorylates β2AR at GRK sites Ser355/356, promoting β2AR internalization and suppressing βAR-induced cAMP-PKA signaling and contractile response in cardiomyocytes. Co-immunoprecipitation, β2AR phosphorylation assay, β2AR internalization assay, cAMP assay, IRS2 knockout mouse cardiomyocytes, contractility measurement Cellular signalling Medium 25460042
2007 GRK2 directly interacts with and phosphorylates both Nedd4 and Nedd4-2 at multiple sites, including Thr466 in Nedd4 located in the ww3 domain region that binds ENaC, providing a mechanism for GRK2 regulation of sodium transport. Co-immunoprecipitation, in vitro kinase assay, phosphorylation site identification Biochemical and biophysical research communications Medium 17544362
2009 GRK2 activation by receptor requires residues in the C-tail region of the kinase, particularly Val477. The V477D mutant shows a 12-fold lower kcat with no change in Km, indicating a defect in acquiring the closed (active) kinase conformation, and is resistant to activation by agonist-bound β2AR. Site-directed mutagenesis, in vitro kinase assay with Michaelis-Menten kinetics, rhodopsin and β2AR phosphorylation assay Biochemistry Medium 19338266
2018 GRK2 phosphorylation at Ser670 is required for GRK2 translocation to mitochondria post-ischemia-reperfusion injury. Mice with S670A knock-in show reduced cardiomyocyte death and better cardiac function post-IR, and cultured S670A cardiomyocytes maintain pyruvate dehydrogenase activity and glucose oxidation after IR. S670A knock-in mice, cardiac IR model, cardiomyocyte death assay, mitochondrial respiration assay, pyruvate dehydrogenase activity measurement Science signaling High 30538174
2016 An essential role for GRK2 kinase activity in Hedgehog signaling downstream of Smoothened (Smo) is established in zebrafish; grk2-null embryos are unresponsive to Shh and oncogenic Smo but remain responsive to PKA inhibition. Zebrafish grk2 loss-of-function mutants, kinase-dead rescue experiments, Smo phosphomimetic and phospho-null mutant analysis EMBO reports Medium 27113758
2024 GRK2 relocates from the ciliary base to the ciliary shaft upon Smoothened activation, phosphorylates SMO, and enables active SMO to directly bind and inactivate the PKA catalytic subunit, initiating downstream Hedgehog signal transduction. Live-cell imaging of GRK2 relocalization in primary cilia, reconstitution studies, SMO phosphorylation assay, PKA-C binding assay, in vivo zebrafish and mouse models PLoS biology High 39138140
2020 Loss-of-function mutations in GRK2 (ADRBK1) cause Jeune syndrome (asphyxiating thoracic dystrophy) by impairing cilia-based Hedgehog signaling and canonical Wnt signaling, specifically through failure to phosphorylate the Wnt co-receptor LRP6. Patient-derived GRK2 null cells, chondrocyte differentiation assay, Hedgehog pathway reporter, canonical Wnt reporter, LRP6 phosphorylation assay EMBO molecular medicine Medium 33200460
2017 GRK2 interacts with and phosphorylates monoamine oxidase AMX-2 in C. elegans, promoting its function. Loss of grk-2 leads to elevated AMX-2 and increased serotonin metabolism (5-HT→5-HIAA), causing egg-laying defects that are rescued by wild-type but not catalytically inactive GRK-2. C. elegans grk-2 loss-of-function genetics, serotonin/5-HIAA metabolite measurements, co-immunoprecipitation, GRK-2 phosphorylation of AMX-2, cell-specific rescue experiments The Journal of biological chemistry Medium 28213524
2015 GRK2 suppresses transcription of the mPeriod1 gene and physically interacts with PERIOD1 and PERIOD2 proteins to promote PERIOD2 phosphorylation at Ser545, impeding PERIOD1/2 nuclear trafficking and modulating circadian clock period and amplitude. Grk2-deficient mouse behavioral rhythms, SCN electrophysiology, GRK2 Co-IP with PER1/2, in vitro phosphorylation (Ser545), transcriptional reporter assay, nuclear trafficking assay Cell reports Medium 26279567
2020 GRK2 is found to naively associate with plasma membrane delta opioid receptor (DOR) in peripheral sensory neurons, inhibiting Gβ subunit association and reducing DOR activity. Bradykinin-activated PKC phosphorylates RKIP, sequestering GRK2 away from DOR onto RKIP, restoring DOR functionality. Co-immunoprecipitation in sensory neurons, DOR functional assay, PKC inhibition, RKIP phosphorylation assay, GRK2-RKIP pulldown Cell reports Medium 27568556
2018 The dopamine D2 receptor (D2R) can directly recruit GRK2 in a G protein-independent manner. Using βarr-preferring D2R mutants and the biased ligand UNC9994, direct GRK2 recruitment was shown to drive β-arrestin pathway activation without G protein activation. BRET-based recruitment assay, biased D2R mutants (G protein-preferring and βarr-preferring), pharmacological G protein blockade, βarr2 recruitment assay The Journal of biological chemistry Medium 29487132
2020 GRK2 and GRK3 are the primary kinases required for μ-opioid receptor (μ-OR) internalization and β-arrestin2 recruitment in HEK293 cells; GRK2 is more important than GRK3 for these processes. A GRK2/3-independent component of sustained β-arrestin2 plasma membrane recruitment also exists. CRISPR/Cas9 GRK2, GRK3, and GRK2/3 double knockout HEK293 cells, μ-OR internalization assay, β-arrestin2 recruitment assay, rescue expression, CMPD101 pharmacological inhibition Scientific reports High 33060647
2019 GRK2 is degraded at early ischemia-reperfusion via proteasome (during ischemia) and calpain (during reperfusion) following successive phosphorylation at specific sites. Preventing this degradation with calpain and proteasome inhibitors preserves AKT pathway activity and reduces I/R injury. Isolated rat and porcine heart I/R models, immunoblotting for GRK2 protein, proteasome and calpain inhibitor treatment, Pin1/AKT pathway analysis EBioMedicine Medium 31594751
2019 Calpain activation by isoproterenol increases GRK2 protein levels by degrading GRK2's ubiquitin ligase MDM2 (stabilizing GRK2) and by enhancing NF-κB-dependent GRK2 transcription via IκB proteolysis. Genetic downregulation of GRK2 prevents isoproterenol-mediated hypertrophy independently of calpain inhibition. Calpain inhibitor (SNJ-1945) in rats and GRK2 hemizygous mice, MDM2 protein assay, NF-κB/IκB western blot, GRK2 mRNA quantification, cardiac hypertrophy morphological/biochemical markers Basic research in cardiology Medium 30915659
2020 GRK5 phosphorylates and inhibits the mineralocorticoid receptor (MR) in cardiomyocytes following β2AR activation, suppressing aldosterone-induced MR transcriptional activity, whereas GRK2 phosphorylates and desensitizes GPER (G protein-coupled estrogen receptor). CRISPR/Cas9 GRK5 deletion in H9c2 cells, Co-IP of GRK5-MR, MR transcriptional reporter assay, GRK2 pharmacological inhibition, adult rat ventricular myocyte studies International journal of molecular sciences Medium 32326036
2020 GRK2 phosphorylates the mRNA-binding protein HuR, increasing HuR cytoplasmic shuttling and HuR binding to HIF-1α mRNA under hypoxia. GRK2-phosphodefective HuR mutants show defective cytosolic accumulation and lower HIF-1α mRNA binding. GRK2 in vitro phosphorylation of HuR, phosphodefective HuR mutagenesis, RIP assay (RNA immunoprecipitation) for HIF-1α mRNA, subcellular fractionation, VEGF-C assay Cancers Medium 32413989
2020 GRK2 binds the death domain of MALT1 and inhibits both MALT1 scaffolding and proteolytic activities, suppressing NF-κB activation downstream of antigen receptor signaling. Lower GRK2 levels in ABC-DLBCL are associated with enhanced tumor growth in vitro and in vivo. Co-immunoprecipitation of GRK2-MALT1, MALT1 protease activity assay, NF-κB reporter assay, GRK2 knockdown, in vitro and in vivo tumor growth assays The Journal of clinical investigation Medium 31961340
2022 GRK2 regulates ADP signaling in platelets via P2Y1 and P2Y12 receptors; platelet-specific GRK2 deletion increases ADP-stimulated Ca2+ mobilization, Rap1 activation, Akt phosphorylation, integrin activation, and impairs ADP receptor desensitization. GRK2 also binds endogenous Gβγ subunits during platelet activation. Platelet-specific GRK2 knockout mice, laser-induced thrombosis model, platelet aggregation assay, Ca2+ mobilization assay, Rap1 activation assay, Akt phosphorylation, cAMP assay, Co-IP of GRK2-Gβγ Blood advances High 35793439
2023 GRK2 phosphorylates SAV1 (Salvador homolog-1), leading to SAV1 ubiquitination and degradation; this impairs Hippo-YAP pathway activity by reducing YAP phosphorylation, promoting YAP nuclear translocation and FLS proliferation in rheumatoid arthritis. GRK2 knockdown/overexpression, Co-immunoprecipitation of GRK2-SAV1, SAV1 ubiquitination assay, YAP phosphorylation and nuclear translocation assay, CIA rat model with paroxetine treatment Acta pharmaceutica Sinica. B Medium 38486990
2017 EIF3d stabilizes GRK2 protein by blocking ubiquitin-mediated GRK2 degradation, thereby activating PI3K/Akt signaling and promoting gallbladder cancer cell proliferation and migration. Co-immunoprecipitation of EIF3d-GRK2, ubiquitination assay, GRK2 protein stability assay, PI3K/Akt signaling western blot, EIF3d knockdown/overexpression, in vitro and in vivo cancer assays Cell death & disease Medium 28594409
1996 GRK2 together with β-arrestin1 desensitizes the TSH receptor: co-transfection of GRK2 and/or β-arrestin1 reduces TSH-induced cAMP accumulation by 35-45% and blunts TSH-stimulated mitogenic activity in thyroid cells. COS7 cell co-transfection with TSH receptor + GRK2 ± β-arrestin1, cAMP accumulation assay, FRTL5 cell line stably overexpressing β-arrestin1, proliferation assay Molecular endocrinology Medium 8885248
2010 Reduced GRK2 specifically in microglia/monocytes is required and sufficient to transform acute carrageenan- or CCL3-induced hyperalgesia into chronic hyperalgesia, associated with ongoing microglial activation and increased phospho-p38 and TNF-α in the spinal cord. Separate reduction of GRK2 in Nav1.8 nociceptors increases but does not prolong hyperalgesia, and enhances CCL3-induced TRPV1 sensitization. Cre-Lox cell-specific GRK2 knockdown (LysM-Cre for microglia, Nav1.8-Cre for nociceptors), carrageenan/CCL3 hyperalgesia models, intrathecal p38/TNF-α/minocycline inhibition, TRPV1 sensitization assay The Journal of neuroscience High 20147541
2013 Reduced nociceptor GRK2 promotes cAMP signaling to EPAC1, and the balance between GRK2 and EPAC1 levels determines whether acute hyperalgesia transitions to chronic pain. Viral gene transfer to increase GRK2 or EPAC1 heterozygosity prevents chronic PGE2-induced hyperalgesia in two priming models. Viral (HSV) GRK2 gene transfer, Epac1 heterozygous and antisense-ODN mice, two hyperalgesic priming models (carrageenan and ΨεRACK), CFA chronic pain model The Journal of clinical investigation High 24231349

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Protein kinase C switches the Raf kinase inhibitor from Raf-1 to GRK-2. Nature 319 14654844
2005 Elevated myocardial and lymphocyte GRK2 expression and activity in human heart failure. European heart journal 161 16055494
1999 Feedback inhibition of G protein-coupled receptor kinase 2 (GRK2) activity by extracellular signal-regulated kinases. The Journal of biological chemistry 152 10574913
2015 Paroxetine-mediated GRK2 inhibition reverses cardiac dysfunction and remodeling after myocardial infarction. Science translational medicine 133 25739765
2012 GRK2: multiple roles beyond G protein-coupled receptor desensitization. Trends in pharmacological sciences 129 22277298
2023 GPCR activation and GRK2 assembly by a biased intracellular agonist. Nature 105 37532940
2011 A novel GRK2/HDAC6 interaction modulates cell spreading and motility. The EMBO journal 101 22193721
2010 GRK2: a novel cell-specific regulator of severity and duration of inflammatory pain. The Journal of neuroscience : the official journal of the Society for Neuroscience 96 20147541
2010 GRK2 as a novel gene therapy target in heart failure. Journal of molecular and cellular cardiology 95 20800067
2013 Targeting cardiac β-adrenergic signaling via GRK2 inhibition for heart failure therapy. Frontiers in physiology 92 24133451
2016 Cardiac Fibroblast GRK2 Deletion Enhances Contractility and Remodeling Following Ischemia/Reperfusion Injury. Circulation research 86 27601479
2013 Balancing GRK2 and EPAC1 levels prevents and relieves chronic pain. The Journal of clinical investigation 83 24231349
2000 Phosphorylation of GRK2 by protein kinase C abolishes its inhibition by calmodulin. The Journal of biological chemistry 80 11042191
2019 G Protein-Coupled Receptor Kinase 2 (GRK2) as a Potential Therapeutic Target in Cardiovascular and Metabolic Diseases. Frontiers in pharmacology 79 30837878
2019 G protein-coupled receptor kinase 2 (GRK2) as a multifunctional signaling hub. Cellular and molecular life sciences : CMLS 76 31432234
2004 GRK2 is an endogenous protein inhibitor of the insulin signaling pathway for glucose transport stimulation. The EMBO journal 76 15241473
2004 The kinase Grk2 regulates Nedd4/Nedd4-2-dependent control of epithelial Na+ channels. Proceedings of the National Academy of Sciences of the United States of America 69 15284439
2009 G protein-coupled receptor kinase 2 (GRK2) modulation and cell cycle progression. Proceedings of the National Academy of Sciences of the United States of America 66 20080565
1998 G protein-coupled receptor kinase 2 (GRK2): mechanisms of regulation and physiological functions. FEBS letters 66 9678590
2021 Paroxetine-mediated GRK2 inhibition is a disease-modifying treatment for osteoarthritis. Science translational medicine 58 33568523
2012 GRK2 inhibition in heart failure: something old, something new. Current pharmaceutical design 57 22229578
2008 Enhanced GRK2 expression and desensitization of betaAR vasodilatation in hypertensive patients. Clinical and translational science 57 20443852
2016 G Protein-coupled Receptor Kinase 2 (GRK2) Promotes Breast Tumorigenesis Through a HDAC6-Pin1 Axis. EBioMedicine 56 27720394
2017 EIF3D promotes gallbladder cancer development by stabilizing GRK2 kinase and activating PI3K-AKT signaling pathway. Cell death & disease 55 28594409
1995 The beta-adrenergic receptor kinase (GRK2) is regulated by phospholipids. The Journal of biological chemistry 54 7673171
2017 Pharmacological and Activated Fibroblast Targeting of Gβγ-GRK2 After Myocardial Ischemia Attenuates Heart Failure Progression. Journal of the American College of Cardiology 53 28818206
2011 Polymorphisms in genes coding for GRK2 and GRK5 and response differences in antihypertensive-treated patients. Pharmacogenetics and genomics 50 21127457
2015 Integrating GRK2 and NFkappaB in the Pathophysiology of Cardiac Hypertrophy. Journal of cardiovascular translational research 49 26224342
2009 Kinase activity-independent regulation of cyclin pathway by GRK2 is essential for zebrafish early development. Proceedings of the National Academy of Sciences of the United States of America 48 19502428
1998 GTP-binding-protein-coupled receptor kinase 2 (GRK2) binds and phosphorylates tubulin. European journal of biochemistry 46 9716377
2020 Dissecting the roles of GRK2 and GRK3 in μ-opioid receptor internalization and β-arrestin2 recruitment using CRISPR/Cas9-edited HEK293 cells. Scientific reports 45 33060647
2018 The dopamine D2 receptor can directly recruit and activate GRK2 without G protein activation. The Journal of biological chemistry 45 29487132
2022 The ROS/GRK2/HIF-1α/NLRP3 Pathway Mediates Pyroptosis of Fibroblast-Like Synoviocytes and the Regulation of Monomer Derivatives of Paeoniflorin. Oxidative medicine and cellular longevity 44 35132350
2020 Agonist-selective recruitment of engineered protein probes and of GRK2 by opioid receptors in living cells. eLife 44 32096468
2020 Paroxetine Attenuates Cardiac Hypertrophy Via Blocking GRK2 and ADRB1 Interaction in Hypertension. Journal of the American Heart Association 44 33372534
2012 Transient decrease in nociceptor GRK2 expression produces long-term enhancement in inflammatory pain. Neuroscience 43 22796071
2018 Restricting mitochondrial GRK2 post-ischemia confers cardioprotection by reducing myocyte death and maintaining glucose oxidation. Science signaling 42 30538174
2017 GRK2 as a therapeutic target for heart failure. Expert opinion on therapeutic targets 42 29166798
2015 G Protein-Coupled Receptor Kinase 2 (GRK2) and 5 (GRK5) Exhibit Selective Phosphorylation of the Neurotensin Receptor in Vitro. Biochemistry 42 26120872
2016 An essential role for Grk2 in Hedgehog signalling downstream of Smoothened. EMBO reports 41 27113758
2023 Reversing T Cell Dysfunction to Boost Glioblastoma Immunotherapy by Paroxetine-Mediated GRK2 Inhibition and Blockade of Multiple Checkpoints through Biomimetic Nanoparticles. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 38 36698265
2019 Calpains mediate isoproterenol-induced hypertrophy through modulation of GRK2. Basic research in cardiology 38 30915659
2017 G protein-coupled receptor kinase 2 (GRK2) as an integrative signalling node in the regulation of cardiovascular function and metabolic homeostasis. Cellular signalling 38 28389415
2016 GRK2 overexpression inhibits IGF1-induced proliferation and migration of human hepatocellular carcinoma cells by downregulating EGR1. Oncology reports 38 26936374
1996 GRK2 and beta-arrestin 1 as negative regulators of thyrotropin receptor-stimulated response. Molecular endocrinology (Baltimore, Md.) 37 8885248
2020 CP-25 inhibits PGE2-induced angiogenesis by down-regulating EP4/AC/cAMP/PKA-mediated GRK2 translocation. Clinical science (London, England : 1979) 34 31967309
2009 GRK2 activation by receptors: role of the kinase large lobe and carboxyl-terminal tail. Biochemistry 33 19338266
2009 New roles of G protein-coupled receptor kinase 2 (GRK2) in cell migration. Cell adhesion & migration 31 19372742
2014 Insulin induces IRS2-dependent and GRK2-mediated β2AR internalization to attenuate βAR signaling in cardiomyocytes. Cellular signalling 30 25460042
2009 Cell-specific roles of GRK2 in onset and severity of hypoxic-ischemic brain damage in neonatal mice. Brain, behavior, and immunity 30 19932746
2020 Antagonistic Roles of GRK2 and GRK5 in Cardiac Aldosterone Signaling Reveal GRK5-Mediated Cardioprotection via Mineralocorticoid Receptor Inhibition. International journal of molecular sciences 29 32326036
2016 GRK2 Constitutively Governs Peripheral Delta Opioid Receptor Activity. Cell reports 29 27568556
2019 Degradation of GRK2 and AKT is an early and detrimental event in myocardial ischemia/reperfusion. EBioMedicine 28 31594751
2022 Spinal Neuronal GRK2 Contributes to Preventive Effect by Electroacupuncture on Cisplatin-Induced Peripheral Neuropathy in Mice. Anesthesia and analgesia 27 34652301
2014 GRK2 in the heart: a GPCR kinase and beyond. Antioxidants & redox signaling 27 24702056
2014 Trafficking GRK2: Cellular and Metabolic consequences of GRK2 subcellular localization. Translational medicine @ UniSa 27 25147759
2023 GRK2 inhibits Flt-1+ macrophage infiltration and its proangiogenic properties in rheumatoid arthritis. Acta pharmaceutica Sinica. B 26 38261818
2022 Neuronal GRK2 regulates microglial activation and contributes to electroacupuncture analgesia on inflammatory pain in mice. Biological research 26 35115050
2011 G Protein-coupled receptor kinase 2 (GRK2): A novel modulator of insulin resistance. Archives of physiology and biochemistry 26 21615207
2006 Tyrosine phosphorylation of G-protein-coupled-receptor kinase 2 (GRK2) by c-Src modulates its interaction with Galphaq. Cellular signalling 26 16725308
2022 GRK2 in cardiovascular disease and its potential as a therapeutic target. Journal of molecular and cellular cardiology 25 35878706
2020 Mutations in GRK2 cause Jeune syndrome by impairing Hedgehog and canonical Wnt signaling. EMBO molecular medicine 25 33200460
2019 Antidiabetic and Cardioprotective Effects of Pharmacological Inhibition of GRK2 in db/db Mice. International journal of molecular sciences 25 30934608
2012 Targeting GRK2 by gene therapy for heart failure: benefits above β-blockade. Gene therapy 25 22336718
2009 Inhibition of WNT signaling by G protein-coupled receptor (GPCR) kinase 2 (GRK2). Molecular endocrinology (Baltimore, Md.) 25 19556343
2007 GRK2 interacts with and phosphorylates Nedd4 and Nedd4-2. Biochemical and biophysical research communications 25 17544362
2006 Hydrogen peroxide impairs GRK2 translation via a calpain-dependent and cdk1-mediated pathway. Cellular signalling 24 16963227
2015 GRK2 targeted knock-down results in spontaneous hypertension, and altered vascular GPCR signaling. The Journal of biological chemistry 23 25561731
2021 The Metabolic Role of GRK2 in Insulin Resistance and Associated Conditions. Cells 22 33467677
2020 A New Paroxetine-Based GRK2 Inhibitor Reduces Internalization of the μ-Opioid Receptor. Molecular pharmacology 22 32234810
2019 GRK2 and GRK5 as therapeutic targets and their role in maladaptive and pathological cardiac hypertrophy. Expert opinion on therapeutic targets 22 30701991
2017 GRK2 as negative modulator of NO bioavailability: Implications for cardiovascular disease. Cellular signalling 22 28077324
2017 Targeting GPCR-Gβγ-GRK2 signaling as a novel strategy for treating cardiorenal pathologies. Biochimica et biophysica acta. Molecular basis of disease 22 28130200
2017 Suppression of GRK2 expression reduces endothelial dysfunction by restoring glucose homeostasis. Scientific reports 22 28814745
2008 GRK2-dependent desensitization downstream of G proteins. Journal of receptor and signal transduction research 22 18437630
2022 Lycium barbarum polysaccharide antagonizes cardiomyocyte apoptosis by inhibiting the upregulation of GRK2 induced by I/R injury, and salvage mitochondrial fission/fusion imbalance and AKT/eNOS signaling. Cellular signalling 21 35065240
2019 High-glucose induces cardiac myocytes apoptosis through Foxo1 /GRK2 signaling pathway. Biochemical and biophysical research communications 21 30952428
2014 Regulatory SNPs and transcriptional factor binding sites in ADRBK1, AKT3, ATF3, DIO2, TBXA2R and VEGFA. Transcription 21 25483406
2013 GRK2 negatively regulates IGF-1R signaling pathway and cyclins' expression in HepG2 cells. Journal of cellular physiology 21 23460259
2017 GRK2/β-arrestin mediates arginine vasopressin-induced cardiac fibroblast proliferation. Clinical and experimental pharmacology & physiology 20 27862165
2016 G-Protein-Coupled Receptor Kinase 2 (GRK2) Inhibitors: Current Trends and Future Perspectives. Journal of medicinal chemistry 20 27362616
2016 Regulatory effects of GRK2 on GPCRs and non-GPCRs and possible use as a drug target (Review). International journal of molecular medicine 20 27573285
2019 Alteration of myocardial GRK2 produces a global metabolic phenotype. JCI insight 19 30946029
2024 GRK2 kinases in the primary cilium initiate SMOOTHENED-PKA signaling in the Hedgehog cascade. PLoS biology 18 39138140
2013 G protein-coupled receptor kinase 2 (GRK2) is localized to centrosomes and mediates epidermal growth factor-promoted centrosomal separation. Molecular biology of the cell 18 23904266
2008 G protein-coupled receptor kinase 2 (GRK2) in migration and inflammation. Archives of physiology and biochemistry 18 18618354
2014 Selective deletion of GRK2 alters psychostimulant-induced behaviors and dopamine neurotransmission. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 17 24776686
2011 GRK2 and β-arrestins in cardiovascular disease: Something old, something new. American journal of cardiovascular disease 17 22254193
2022 Double life: How GRK2 and β-arrestin signaling participate in diseases. Cellular signalling 16 35430346
2019 GRK2 promotes growth of medulloblastoma cells and protects them from chemotherapy-induced apoptosis. Scientific reports 16 31554835
2017 G protein-coupled receptor kinase-2 (GRK-2) regulates serotonin metabolism through the monoamine oxidase AMX-2 in Caenorhabditis elegans. The Journal of biological chemistry 16 28213524
2023 GRK2 mediated degradation of SAV1 initiates hyperplasia of fibroblast-like synoviocytes in rheumatoid arthritis. Acta pharmaceutica Sinica. B 15 38486990
2018 Low GRK2 Underlies Hyperalgesic Priming by Glial Cell-Derived Neurotrophic Factor. Frontiers in pharmacology 15 29922165
2018 GRK2 knockdown in mice exacerbates kidney injury and alters renal mechanisms of blood pressure regulation. Scientific reports 15 30061705
2022 GRK2 regulates ADP signaling in platelets via P2Y1 and P2Y12. Blood advances 14 35793439
2022 Targeted inhibition of the GRK2/HIF-1α pathway is an effective strategy to alleviate synovial hypoxia and inflammation. International immunopharmacology 14 36461590
2020 GRK2 suppresses lymphomagenesis by inhibiting the MALT1 proto-oncoprotein. The Journal of clinical investigation 14 31961340
2020 GRK2-Dependent HuR Phosphorylation Regulates HIF1α Activation under Hypoxia or Adrenergic Stress. Cancers 14 32413989
2015 GRK2 Fine-Tunes Circadian Clock Speed and Entrainment via Transcriptional and Post-translational Control of PERIOD Proteins. Cell reports 14 26279567
2013 Co-expression of GRK2 reveals a novel conformational state of the µ-opioid receptor. PloS one 14 24376730

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