Affinage

GRK6

G protein-coupled receptor kinase 6 · UniProt P43250

Length
576 aa
Mass
66.0 kDa
Annotated
2026-06-10
59 papers in source corpus 28 papers cited in narrative 28 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GRK6 is a palmitoylated serine/threonine kinase of the GRK family that phosphorylates agonist-activated G protein-coupled receptors to drive their desensitization, β-arrestin recruitment, and internalization across diverse physiological systems (PMID:8366096, PMID:8077221, PMID:26886170). Its catalytic core comprises intimately associated kinase and RGS-homology domains that adopt an open, inactive conformation in the absence of an activated receptor, implying that GPCR engagement triggers kinase-domain closure as the activation step (PMID:16613860). Membrane targeting and intrinsic catalytic output are both governed by thioester palmitoylation of a C-terminal cysteine cluster (Cys561/562/565): palmitoylation is required for membrane partitioning and elevates kinase activity ~10-fold even toward soluble substrates, while a palmitoylation-deficient mutant has impaired receptor affinity and turnover (PMID:7961702, PMID:9341194, PMID:9819198). Through this activity GRK6 terminates signaling at a broad receptor repertoire—CXCR4, CCR7, CMKLR1, the secretin receptor, FFA4/GPR120, the oxytocin receptor, and the platelet thrombin receptors PAR1/PAR4—with physiological consequences including lymphocyte and neutrophil chemotaxis, dendritic-cell haptotaxis, uterine contractility, and hemostasis (PMID:12032308, PMID:12598420, PMID:14704365, PMID:24412271, PMID:26886170, PMID:28457871, PMID:30576947, PMID:31899801). Recruitment to activated chemoattractant receptors is selective, requiring an intact CXCR4 C-terminus and the COMMD3/8 adaptor complex (PMID:19956569, PMID:31088898). Beyond canonical GPCR signaling, GRK6 phosphorylates IκBα at Ser32/Ser36 to promote NF-κB-driven inflammatory transcription and cooperates with GIT1 to activate Rac1 for apoptotic-cell engulfment; loss of GRK6 in mice causes autoimmune disease and impaired clearance of senescent red blood cells (PMID:23443560, PMID:25881508). A T2D-associated GRK6-P384S variant is hyperactive yet mislocalized to the cytosol and fails to support β-cell proinsulin processing, linking GRK6 localization to insulin secretion (PMID:36030052).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 1993 High

    Established GRK6 as a distinct GRK-family kinase that phosphorylates agonist-activated GPCRs, defining its core biochemical identity.

    Evidence cDNA cloning and in vitro receptor phosphorylation of β2AR and rhodopsin with baculovirus-expressed enzyme

    PMID:8366096

    Open questions at the time
    • Physiological receptor substrates not yet defined
    • No structural or regulatory mechanism
  2. 1994 High

    Identified C-terminal cysteine palmitoylation as the membrane-anchoring determinant, answering how a soluble kinase reaches its membrane receptor substrates.

    Evidence Metabolic [3H]palmitate labeling, hydroxylamine sensitivity, Cys mutagenesis, and subcellular fractionation; parallel purified-enzyme substrate assays

    PMID:7961702 PMID:8077221

    Open questions at the time
    • Palmitoyltransferase responsible not identified
    • Whether palmitoylation is dynamic/regulated unknown
  3. 1997 High

    Showed palmitoylation is functionally required for receptor phosphorylation and sequestration, linking lipid modification to enzymatic competence in cells.

    Evidence Cys→Ser and CAAX-geranylgeranylated mutants tested in vesicle binding, kinase assays, and β2AR sequestration in COS-1 cells; splice variant characterization

    PMID:9316417 PMID:9341194

    Open questions at the time
    • Distinct functions of GRK6a vs GRK6b isoforms not resolved
  4. 1998 High

    Demonstrated palmitoylation enhances intrinsic catalytic activity beyond mere membrane localization, revealing a second layer of regulation.

    Evidence Separation of palmitoylated vs non-palmitoylated fractions, soluble casein substrate assays, chemical depalmitoylation, geranylgeranylation rescue

    PMID:9819198

    Open questions at the time
    • Structural basis for activity enhancement unknown
  5. 1999 Medium

    Mapped in vivo autophosphorylation sites (Ser484/Thr485), addressing how GRK6 regulates its own activity state.

    Evidence K215R catalytic-dead and phosphomimetic mutants with SDS-PAGE mobility shift and phosphatase treatment in COS-7 cells

    PMID:10334944

    Open questions at the time
    • Functional consequence of autophosphorylation not established
    • Single lab, indirect mobility-shift readout
  6. 2002 High

    Revealed an unexpected positive role for GRK6 in chemotaxis despite its desensitizing function, complicating the simple receptor-shutoff model.

    Evidence GRK6-knockout mice with membrane GTPase, transwell, and transendothelial migration assays alongside βarrestin2- and GRK5-KO controls

    PMID:12032308

    Open questions at the time
    • Mechanism reconciling impaired desensitization with impaired migration unresolved
  7. 2003 Medium

    Extended GRK6 substrate range to the secretin receptor with selectivity over other GPCRs, demonstrating receptor-specific desensitization.

    Evidence WT and dominant-negative GRK6 overexpression in NG108-15 cells with cAMP accumulation readout

    PMID:12598420

    Open questions at the time
    • Direct receptor phosphorylation not shown
    • Single lab overexpression system
  8. 2004 High

    Placed GRK6 as the desensitizer of CXCR4 in neutrophils, connecting it to in vivo neutrophil mobilization and bone marrow retention.

    Evidence GRK6-KO neutrophils in calcium flux and chemotaxis assays plus in vivo G-CSF mobilization

    PMID:14704365

    Open questions at the time
    • Direct CXCR4 phosphorylation sites not mapped here
  9. 2006 High

    Provided the structural model: an intimately associated kinase/RGS-H core in an open conformation, proposing GPCR-induced domain closure as the activation mechanism.

    Evidence 2.6 Å X-ray crystal structure with comparison to GRK2 and dimerization functional assays

    PMID:16613860

    Open questions at the time
    • Receptor-bound/activated conformation not captured
    • Direct demonstration of domain closure upon GPCR binding lacking
  10. 2009 Medium

    Explained receptor-side specificity of recruitment by showing GRK6 requires the CXCR4 C-terminus, and linked this to disease (WHIM syndrome) and chaperone-dependent stability in myeloma.

    Evidence Reciprocal co-IP of GRK6/GRK3 with WT vs WHIM-mutant CXCR4 plus β-arrestin/internalization/ERK readouts; GRK6-HSP90 co-IP and siRNA in myeloma

    PMID:19956569 PMID:19996089

    Open questions at the time
    • Structural basis of C-terminal recognition unknown
    • Single-lab co-IP for each interaction
  11. 2013 High

    Uncovered a non-GPCR-desensitization function: GRK6-GIT1-Rac1 signaling drives apoptotic-cell engulfment, with loss causing autoimmunity and defective RBC clearance.

    Evidence GRK6-KO mice, engulfment and Rac1 activation assays, GRK6-GIT1 co-IP, mass spectrometry, autoimmune phenotyping

    PMID:23443560

    Open questions at the time
    • Whether GRK6 kinase activity is required for GIT1/Rac1 effect not fully resolved
  12. 2013 Low

    Linked GRK6 to CXCR2 regulation in sensory neurons and neuropathic pain, extending its receptor partners to a pain context.

    Evidence GRK6-CXCR2 co-IP, immunofluorescence colocalization, lentiviral overexpression with behavioral pain assays in CCI rats

    PMID:27145805

    Open questions at the time
    • No direct CXCR2 phosphorylation assay
    • Single co-IP with behavioral readout only
  13. 2014 Medium

    Defined GRK6 phosphorylation sites on FFA4/GPR120 controlling the balance between β-arrestin recruitment and Gαq/11 calcium signaling.

    Evidence GRK6 over/knockdown in HEK293, phosphosite mutagenesis, β-arrestin-2 recruitment and calcium assays

    PMID:24412271

    Open questions at the time
    • In vivo relevance not tested
    • Single lab
  14. 2015 High

    Established a direct non-GPCR substrate, IκBα, placing GRK6 as a positive driver of NF-κB inflammatory transcription downstream of TNF-α.

    Evidence In vitro kinase assay on IκBα Ser32/36, kinase-dead mutant, BRET conformational sensor, GRK6-KO macrophages with inflammatory gene readouts

    PMID:25881508

    Open questions at the time
    • How TNF-α routes signal to GRK6 conformational change unknown
  15. 2016 Medium

    Expanded the in vivo physiological roster (oxytocin receptor desensitization and hematopoietic stem cell maintenance), reinforcing GRK6 as a broad GPCR/kinase regulator.

    Evidence GRK6-KO mice with uterine telemetry and β-arrestin/OXTR assays; GRK6-DNA-PKcs co-IP, KO HSC phenotyping with α-lipoic acid rescue

    PMID:26886170 PMID:27882944

    Open questions at the time
    • Whether DNA-PKcs is a direct GRK6 substrate not established
    • ROS link to HSC defect indirect
  16. 2017 High

    Distinguished GRK6's role in haptotaxis vs chemotaxis, showing it is essential for directional migration along immobilized CCL21-CCR7 gradients.

    Evidence GRK6-KO mice, controlled immobilized gradient assays, live-cell tracking, in vivo migration

    PMID:28457871

    Open questions at the time
    • Molecular basis for haptotaxis specificity unclear
  17. 2019 High

    Identified the COMMD3/8 adaptor complex as the determinant of selective GRK6 recruitment to activated chemoattractant receptors, answering how GRK6 is targeted.

    Evidence COMMD3/8-GRK6 co-IP, receptor phosphorylation assay, COMMD8/COMMD3-KO mice, B cell migration and humoral immunity readouts

    PMID:31088898

    Open questions at the time
    • Structural architecture of the COMMD3/8-GRK6-receptor assembly unknown
  18. 2020 High

    Demonstrated agonist-selective desensitization of platelet PAR1/PAR4 by GRK6, establishing a hemostatic function and direct receptor binding.

    Evidence CRISPR GRK6-KO mice/platelets, GRK6-PAR1 co-IP, PAR1 phosphorylation, signaling and in vivo thrombosis assays

    PMID:31899801

    Open questions at the time
    • Why TxA2 receptor escapes GRK6 regulation unexplained
  19. 2023 Medium

    Connected palmitoylation-driven membrane translocation to inflammatory PI3K/AKT signaling, generalizing the lipid-modification regulatory theme to innate immunity.

    Evidence Acyl-RAC palmitoylation assay, fractionation, immunofluorescence, knockdown/overexpression with PI3K/AKT readouts in Kupffer cells

    PMID:37012861

    Open questions at the time
    • Direct GRK6 substrate in PI3K/AKT pathway not identified
    • Single lab
  20. 2022 High

    Linked GRK6 localization to insulin processing and a T2D-associated variant, showing mislocalized hyperactive GRK6-P384S fails to support proinsulin conversion.

    Evidence siRNA/inhibitor/rescue in MIN6 cells, proprotein convertase activity, insulin/proinsulin ELISA, mutant localization imaging

    PMID:36030052

    Open questions at the time
    • How GRK6 regulates proprotein convertase expression mechanistically unknown
  21. 2024 Medium

    Implicated palmitoylation-dependent GRK6 in cancer signaling and metastasis through the β-arrestin2/MAPK/NF-κB axis, and in HIF1α/VHL regulation.

    Evidence Palmitoylation-deficient mutant, knockdown/overexpression, migration and in vivo lung colonization assays, pharmacological inhibition (breast cancer); RNAi with HIF1α/VHL readouts (lung adenocarcinoma)

    PMID:34136390 PMID:39741338

    Open questions at the time
    • Direct substrate driving metastatic signaling not defined
    • VHL-HIF1α link lacks direct biochemical mechanism

Open questions

Synthesis pass · forward-looking unresolved questions
  • How activated GPCRs convert the open kinase/RGS-H conformation into a closed, catalytically competent state remains structurally undefined, as does the integration of palmitoylation, COMMD3/8 recruitment, and conformational activation into a unified activation cycle.
  • No receptor-bound GRK6 structure
  • Activation-cycle ordering of lipid modification, adaptor recruitment, and domain closure unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0098772 molecular function regulator activity 4 GO:0008289 lipid binding 3 GO:0016740 transferase activity 3
Localization
GO:0005886 plasma membrane 4 GO:0005829 cytosol 2
Pathway
R-HSA-168256 Immune System 6 R-HSA-162582 Signal Transduction 5 R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-109582 Hemostasis 1
Partners
COMMD3COMMD8CXCR2CXCR4DNA-PKCSGIT1HSP90PAR1
Complex memberships
COMMD3/8 adaptor complex

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 GRK6 was cloned as a 576-amino acid serine/threonine kinase that phosphorylates activated G protein-coupled receptors (β2-adrenergic receptor and rhodopsin) in a stimulus-dependent fashion, establishing it as a member of the GRK family with substrate specificity distinct from βARK and rhodopsin kinase. cDNA cloning, baculovirus overexpression in Sf9 cells, in vitro receptor phosphorylation assay The Journal of biological chemistry High 8366096
1994 GRK6 is palmitoylated at a cluster of three C-terminal cysteines (Cys561, Cys562, Cys565) via a thioester bond, and this palmitoylation is essential for membrane association; palmitoylated GRK6 partitions exclusively to the membrane fraction. Metabolic labeling with [3H]palmitate, hydroxylamine treatment, HPLC, site-directed mutagenesis, subcellular fractionation The Journal of biological chemistry High 7961702
1994 Purified GRK6 phosphorylates rhodopsin, β2-adrenergic receptor, and m2 muscarinic receptor in a stimulus-dependent manner; GRK6 shares inhibition by heparin/dextran sulfate and preference for non-acidic peptide substrates with GRK5, but has lower stoichiometry on these receptors than GRK5 or βARK and does not undergo significant autophosphorylation. Protein purification (SP-Sepharose/heparin-Sepharose), in vitro kinase assays with receptor substrates and peptides, inhibitor titration The Journal of biological chemistry High 8077221
1997 Palmitoylation of GRK6 is required for its membrane binding and activity toward receptor substrates: a palmitoylation-deficient mutant (Cys→Ser) shows ~5-fold higher Km and ~2-fold lower Vmax for rhodopsin and minimal β2-adrenergic receptor sequestration in COS-1 cells, while a geranylgeranylated GRK6 mutant (CAAX-tagged) shows enhanced membrane binding and ~14-fold higher Vmax. Site-directed mutagenesis, phospholipid vesicle binding assay, in vitro kinase assay, β2AR sequestration assay in COS-1 cells The Journal of biological chemistry High 9341194
1997 Two GRK6 splice variants (GRK6a: 576 aa, GRK6b: 589 aa with a distinct C-terminal region due to a 2-bp intron insert) are expressed in rat tissues; GRK6a predominates in brain, GRK6b is more abundant in peripheral tissues; both isoforms phosphorylate light-activated rhodopsin and a synthetic peptide substrate. RT-PCR cloning, in vitro kinase assay with CHO cell cytosol extracts The American journal of physiology Medium 9316417
1998 Palmitoylation of GRK6 increases its kinase catalytic activity intrinsically (beyond membrane localization): palmitoylated GRK6 is 10-fold more active than non-palmitoylated GRK6 at phosphorylating β2AR, and this elevated activity is also observed with the soluble substrate casein. Chemical depalmitoylation reduces casein phosphorylation activity, indicating palmitoylation directly enhances catalytic activity. Separation of palmitoylated vs. non-palmitoylated GRK6 fractions, in vitro kinase assays (β2AR and casein substrates), chemical depalmitoylation, geranylgeranylation rescue Biochemistry High 9819198
1999 GRK6 autophosphorylates on Ser484 and Thr485 in vivo (in COS-7 cells), as revealed by electrophoretic mobility shift: catalytically inactive GRK6-K215R runs at 63 kDa (hypophosphorylated), while GRK6-K215R with S484D/T485D phosphomimetic mutations (GRK6-RDD) restores the 66 kDa mobility of wild-type GRK6. The C5a receptor (C5aR) is not a substrate for GRK6 in this system. Site-directed mutagenesis, SDS-PAGE mobility shift analysis, phosphatase treatment, overexpression in COS-7 cells Biochemical and biophysical research communications Medium 10334944
2002 GRK6 plays a positive regulatory role in CXCL12 (SDF-1)-stimulated chemotaxis of T and B lymphocytes: GRK6-knockout mice show increased CXCL12-stimulated membrane GTPase activity (indicating impaired receptor desensitization) yet paradoxically impaired chemotaxis of T cells in transwell and transendothelial migration assays. GRK6-knockout mice, membrane GTPase activity assay, transwell migration assay, transendothelial migration assay Proceedings of the National Academy of Sciences of the United States of America High 12032308
2003 GRK6 selectively desensitizes the secretin receptor in NG108-15 cells: overexpression of wild-type GRK6 reduces secretin-stimulated cAMP accumulation while dominant-negative GRK6 (K215R) enhances it, without affecting adenosine A2 or prostanoid IP receptor responses. Transient overexpression of WT and dominant-negative GRK6 in NG108-15 cells, cAMP accumulation assay British journal of pharmacology Medium 12598420
2004 GRK6 mediates desensitization of CXCR4 in neutrophils: GRK6-deficient neutrophils show enhanced SDF-1-induced chemotaxis in vitro and impaired desensitization of calcium responses to SDF-1; in vivo, GRK6-deficient mice have profoundly impaired G-CSF-induced neutrophil mobilization from bone marrow, attributed to enhanced CXCR4-mediated bone marrow retention. GRK6-knockout mice, in vitro chemotaxis assay (transwell), calcium flux assay, in vivo G-CSF treatment with blood neutrophil counting Journal of leukocyte biology High 14704365
2006 Crystal structure of human GRK6 at 2.6 Å resolution reveals: (1) the catalytic core consists of intimately associated kinase and RGS homology (RGS-H) domains; (2) despite ATP analog binding, the kinase domain is in an open/inactive conformation, suggesting GPCRs activate GRKs by inducing kinase domain closure; (3) a putative phospholipid-binding site near the N-terminus; (4) structural elements in the substrate channel that influence GPCR access and specificity; (5) the RGS-H domain forms a dimer interface in the crystal using conserved hydrophobic residues, but dimerization is not required for receptor phosphorylation. X-ray crystallography (2.6 Å), structural comparison with GRK2, functional assays for dimerization The Journal of biological chemistry High 16613860
2009 GRK6 fails to associate with WHIM-syndrome-associated mutant CXCR4 (lacking the C-terminal 19 residues) after ligand activation, while GRK3 associates normally; this impaired GRK6 recruitment correlates with delayed β-arrestin 2 recruitment, slower receptor internalization, and slower ERK1/2 activation, providing a molecular mechanism for CXCR4 dysfunction in WHIM syndrome. Co-immunoprecipitation of GRK6 and GRK3 with WT vs. WHIM-mutant CXCR4, β-arrestin recruitment assay, internalization assay, ERK activation assay PloS one Medium 19956569
2009 GRK6 expression in multiple myeloma cells is stabilized by direct association with the HSP90 chaperone; GRK6 silencing suppresses STAT3 phosphorylation and reduces MCL1 levels and phosphorylation, causing selective lethality in myeloma cells. Co-immunoprecipitation (GRK6-HSP90 interaction), siRNA knockdown, Western blot for STAT3 phosphorylation and MCL1, cell viability assays Blood Medium 19996089
2010 GRK6 is recruited to the lyso-PC-activated G2A receptor in neutrophils (PMNs) as demonstrated by co-immunoprecipitation and digital microscopy, contributing to receptor desensitization as part of a signaling complex that also includes clathrin and β-arrestin-1. Co-immunoprecipitation, Western blot, subcellular fractionation, FRET-based digital microscopy The Biochemical journal Medium 20799926
2013 GRK6 promotes apoptotic cell clearance by cooperating with GIT1 to activate Rac1, enabling cytoskeletal rearrangement of phagocytes for engulfment; this pathway acts independently of the known DOCK180/ELMO/Rac1 and GULP1/Rac1 engulfment pathways. GRK6-deficient mice develop autoimmune disease and accumulate iron stores in splenic red pulp due to impaired senescent red blood cell clearance. GRK6-knockout mice, engulfment assays, co-immunoprecipitation (GRK6-GIT1), Rac1 activation assay, mass spectrometry, autoimmune phenotyping Nature communications High 23443560
2014 GRK6 mediates agonist-induced homologous phosphorylation of FFA4/GPR120 at Thr347, Ser350, and Ser357 in the C-terminal tail; concurrent mutation of these sites impairs β-arrestin-2 recruitment to the receptor membrane and enhances Gαq/11-mediated calcium responses. GRK6 overexpression/knockdown in HEK293 cells, phosphorylation site mutagenesis, β-arrestin-2 recruitment assay, calcium flux assay Biochemical pharmacology Medium 24412271
2015 GRK6 directly phosphorylates IκBα at Ser32/Ser36 (the canonical NF-κB activation phosphorylation sites); GRK6 kinase activity is required for promoting NF-κB signaling after TNF-α stimulation; TNF-α induces a conformational change in GRK6 (monitored by BRET probe); GRK6 knockout in macrophages attenuates TNF-α-induced inflammatory gene transcription. In vitro kinase assay (GRK6 phosphorylating IκBα), kinase-dead mutant, BRET conformational sensor, GRK6-KO macrophages, inflammatory gene expression Biochemical and biophysical research communications High 25881508
2016 GRK6 interacts with and regulates phosphorylation of DNA-PKcs (DNA-dependent protein kinase, catalytic subunit); GRK6 knockout leads to impaired HSC self-renewal, lymphocytopenia, and loss of multiple hematopoietic progenitor populations, which are partially rescued by reactive oxygen species scavenger α-lipoic acid. GRK6-knockout mice, co-immunoprecipitation (GRK6-DNA-PKcs), Western blot for phosphorylation, transcriptome/proteomic analysis, α-lipoic acid rescue experiment Cell death & disease Medium 27882944
2016 GRK6 mediates desensitization of the oxytocin receptor (OXTR): GRK6-deficient mice display enhanced uterine contractility and high rates of term stillbirth; β-arrestin recruitment to OXTR (required for homologous desensitization) is dependent on GRK6 as shown in a heterologous cell model. GRK6-knockout mice, telemetry measurement of uterine contractility, β-arrestin recruitment assay in heterologous cell model, comparison with GRK5-KO Molecular endocrinology High 26886170
2017 GRK6 mediates signal termination of CCR7 and is essential for haptotactic (immobilized gradient) but not chemotactic (soluble gradient) CCL21-guided migration of dendritic cells; GRK6 deficiency impairs directionality along stable tissue-bound CCL21 gradients in vitro and in vivo. GRK6-knockout mice, controlled immobilized gradient assay, live-cell tracking, in vivo migration assay Current biology : CB High 28457871
2018 GRK6 regulates chemerin-activated CMKLR1 in inflammatory macrophages: arrestin recruitment to CMKLR1 is enhanced by GRK6 co-expression; internalization of endogenous CMKLR1 is decreased in GRK6- and β-arrestin 2-deficient macrophages; GRK6/β-arrestin 2 deficiency increases macrophage migration toward chemerin and alters AKT and ERK signaling. GRK6-knockout mice, macrophage CMKLR1 internalization assay, β-arrestin recruitment assay, migration assay, AKT/ERK signaling measurement Molecular immunology Medium 30576947
2019 The COMMD3/8 protein complex acts as an adaptor that selectively recruits GRK6 to activated chemoattractant receptors (including CXCR4), enabling GRK6-mediated receptor phosphorylation and β-arrestin-mediated signaling; COMMD8 stability depends on COMMD3; deficiency of COMMD8 or COMMD3 impairs B cell migration and humoral immunity. Co-immunoprecipitation (COMMD3/8-GRK6 complex), receptor phosphorylation assay, COMMD8/COMMD3-knockout mice, B cell migration assay, humoral immune response assay The Journal of experimental medicine High 31088898
2020 GRK6 regulates platelet hemostatic responses through agonist-selective GPCR desensitization: GRK6-knockout platelets show increased activation (Ca2+ mobilization, Akt activation, granule secretion) in response to PAR4 agonist and ADP but not TxA2; thrombin stimulation of human platelets increases GRK6 binding to PAR1 and PAR1 phosphorylation; GRK6 deletion in MEG-01 cells decreases PAR1 phosphorylation; GRK6-KO mice form larger thrombi. CRISPR-Cas9 GRK6-KO mice, platelet aggregation/secretion/Ca2+ assays, co-immunoprecipitation (GRK6-PAR1), Western blot for Akt/PAR1 phosphorylation, in vivo thrombosis model Blood advances High 31899801
2022 GRK6 regulates insulin processing and secretion in pancreatic β-cells: GRK6 knockdown in MIN6 cells reduces proprotein convertase expression and activity, impairing proinsulin-to-insulin conversion and reducing cellular insulin while enhancing proinsulin secretion; GRK6 rescue restores glucose-stimulated insulin secretion. The T2D-associated mutant GRK6-P384S is more catalytically active than WT GRK6 but displays cytosolic rather than plasma membrane localization and fails to enhance proinsulin processing. siRNA knockdown, pharmacological inhibition, GRK6 overexpression/rescue in MIN6 cells, proprotein convertase activity assay, insulin/proinsulin ELISA, subcellular localization imaging The Journal of biological chemistry High 36030052
2024 Palmitoylation of GRK6 is required for its activation of the β-Arrestin 2/MAPKs/NF-κB signaling axis and for promoting metastasis in triple-negative breast cancer cells; kinase activity inhibition suppresses β-Arrestin 2 activation and cell migration. GRK6 knockdown/overexpression, palmitoylation-deficient mutant, Western blot for MAPK/NF-κB signaling, in vitro migration assay, in vivo lung colony-forming assay, pharmacological GRK6 inhibition Breast cancer research : BCR Medium 39741338
2023 LPS-induced palmitoylation of GRK6 increases its membrane translocation in Kupffer cells; palmitoylation-dependent membrane localization is required for GRK6 to activate the PI3K/AKT inflammatory signaling pathway; inhibiting GRK6 palmitoylation reduces membrane translocation and attenuates inflammatory response. Palmitoylation assay (Acyl-RAC), membrane/cytoplasmic protein fractionation, immunofluorescence, siRNA knockdown and overexpression, PI3K/AKT signaling readouts International immunopharmacology Medium 37012861
2024 GRK6 depletion in lung adenocarcinoma cells induces HIF1α levels and activity, an effect mechanistically linked to regulation of VHL levels by GRK6. RNAi knockdown, RNA-seq, Western blot for HIF1α, VHL expression analysis, tissue microarray validation Frontiers in oncology Low 34136390
2013 GRK6 interacts with CXCR2 in dorsal root ganglion neurons as demonstrated by co-immunoprecipitation and immunofluorescence colocalization; GRK6 overexpression suppresses enhanced CXCR2 expression in DRG of CCI rats and attenuates neuropathic pain. Co-immunoprecipitation (GRK6-CXCR2), immunofluorescence, lentiviral GRK6 overexpression, behavioral pain assays Molecular pain Low 27145805

Source papers

Stage 0 corpus · 59 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Defective lymphocyte chemotaxis in beta-arrestin2- and GRK6-deficient mice. Proceedings of the National Academy of Sciences of the United States of America 255 12032308
1993 Molecular cloning and expression of GRK6. A new member of the G protein-coupled receptor kinase family. The Journal of biological chemistry 117 8366096
2010 Lentiviral overexpression of GRK6 alleviates L-dopa-induced dyskinesia in experimental Parkinson's disease. Science translational medicine 111 20410529
1994 Palmitoylation of G protein-coupled receptor kinase, GRK6. Lipid modification diversity in the GRK family. The Journal of biological chemistry 108 7961702
2009 Kinome-wide RNAi studies in human multiple myeloma identify vulnerable kinase targets, including a lymphoid-restricted kinase, GRK6. Blood 94 19996089
2005 L-DOPA reverses the MPTP-induced elevation of the arrestin2 and GRK6 expression and enhanced ERK activation in monkey brain. Neurobiology of disease 79 15686961
2006 The structure of G protein-coupled receptor kinase (GRK)-6 defines a second lineage of GRKs. The Journal of biological chemistry 78 16613860
2004 GRK6 deficiency is associated with enhanced CXCR4-mediated neutrophil chemotaxis in vitro and impaired responsiveness to G-CSF in vivo. Journal of leukocyte biology 77 14704365
1994 Expression, purification, and characterization of the G protein-coupled receptor kinase GRK6. The Journal of biological chemistry 69 8077221
1996 Differentially regulated expression of the G-protein-coupled receptor kinases, betaARK and GRK6, during myelomonocytic cell development in vitro. Blood 65 8977246
2009 Impaired recruitment of Grk6 and beta-Arrestin 2 causes delayed internalization and desensitization of a WHIM syndrome-associated CXCR4 mutant receptor. PloS one 57 19956569
2014 Mechanisms of homologous and heterologous phosphorylation of FFA receptor 4 (GPR120): GRK6 and PKC mediate phosphorylation of Thr³⁴⁷, Ser³⁵⁰, and Ser³⁵⁷ in the C-terminal tail. Biochemical pharmacology 53 24412271
2017 Dendritic Cells Interpret Haptotactic Chemokine Gradients in a Manner Governed by Signal-to-Noise Ratio and Dependent on GRK6. Current biology : CB 50 28457871
1998 Palmitoylation increases the kinase activity of the G protein-coupled receptor kinase, GRK6. Biochemistry 45 9819198
1998 Sequestration of human muscarinic acetylcholine receptor hm1-hm5 subtypes: effect of G protein-coupled receptor kinases GRK2, GRK4, GRK5 and GRK6. The Journal of pharmacology and experimental therapeutics 44 9495886
2013 GRK6 deficiency in mice causes autoimmune disease due to impaired apoptotic cell clearance. Nature communications 42 23443560
1997 Altered activity of palmitoylation-deficient and isoprenylated forms of the G protein-coupled receptor kinase GRK6. The Journal of biological chemistry 38 9341194
2019 The COMMD3/8 complex determines GRK6 specificity for chemoattractant receptors. The Journal of experimental medicine 36 31088898
2019 MiR-19b-3p attenuates IL-1β induced extracellular matrix degradation and inflammatory injury in chondrocytes by targeting GRK6. Molecular and cellular biochemistry 36 31227976
2010 Lysophosphatidylcholines activate G2A inducing G(αi)₋₁-/G(αq/)₁₁- Ca²(+) flux, G(βγ)-Hck activation and clathrin/β-arrestin-1/GRK6 recruitment in PMNs. The Biochemical journal 36 20799926
2013 Growth factor receptor-Src-mediated suppression of GRK6 dysregulates CXCR4 signaling and promotes medulloblastoma migration. Molecular cancer 33 23497290
2017 Secreted miR-27a Induced by Cyclic Stretch Modulates the Proliferation of Endothelial Cells in Hypertension via GRK6. Scientific reports 31 28106155
1997 Molecular cloning of two rat GRK6 splice variants. The American journal of physiology 27 9316417
2018 Chemerin-activated functions of CMKLR1 are regulated by G protein-coupled receptor kinase 6 (GRK6) and β-arrestin 2 in inflammatory macrophages. Molecular immunology 25 30576947
2016 Overexpression of GRK6 attenuates neuropathic pain via suppression of CXCR2 in rat dorsal root ganglion. Molecular pain 25 27145805
2020 GRK6 regulates the hemostatic response to injury through its rate-limiting effects on GPCR signaling in platelets. Blood advances 23 31899801
2016 GRK6 regulates ROS response and maintains hematopoietic stem cell self-renewal. Cell death & disease 23 27882944
2012 The role of GRK6 in animal models of Parkinson's disease and L-DOPA treatment. Scientific reports 23 22393477
2015 Overexpression of GRK6 rescues L-DOPA-induced signaling abnormalities in the dopamine-depleted striatum of hemiparkinsonian rats. Experimental neurology 22 25687550
2015 GRK6 phosphorylates IκBα at Ser(32)/Ser(36) and enhances TNF-α-induced inflammation. Biochemical and biophysical research communications 20 25881508
2021 Design, Synthesis, and Characterization of 4-Aminoquinazolines as Potent Inhibitors of the G Protein-Coupled Receptor Kinase 6 (GRK6) for the Treatment of Multiple Myeloma. Journal of medicinal chemistry 18 34291633
2013 GRK6 expression in patients with hepatocellular carcinoma. Asian Pacific journal of tropical medicine 17 23375037
2020 Role of GRK6 in the Regulation of Platelet Activation through Selective G Protein-Coupled Receptor (GPCR) Desensitization. International journal of molecular sciences 15 32486261
1995 Chromosomal mapping of the genes GPRK5 and GPRK6 encoding G protein-coupled receptor kinases GRK5 and GRK6. Cytogenetics and cell genetics 14 7789183
2017 The association of single-nucleotide polymorphisms in the oxytocin receptor and G protein-coupled receptor kinase 6 (GRK6) genes with oxytocin dosing requirements and labor outcomes. American journal of obstetrics and gynecology 12 28526450
2016 Enhanced Uterine Contractility and Stillbirth in Mice Lacking G Protein-Coupled Receptor Kinase 6 (GRK6): Implications for Oxytocin Receptor Desensitization. Molecular endocrinology (Baltimore, Md.) 12 26886170
1999 Overexpression of wild-type and catalytically inactive forms of GRK2 and GRK6 fails to alter the agonist-induced phosphorylation of the C5a receptor (CD88): evidence that GRK6 is autophosphorylated in COS-7 cells. Biochemical and biophysical research communications 12 10334944
2019 Hypermethylation of the G protein-coupled receptor kinase 6 (GRK6) promoter inhibits binding of C/EBPα, and GRK6 knockdown promotes cell migration and invasion in lung adenocarcinoma cells. FEBS open bio 10 30984536
2014 Functional consequences of perturbed CXCL12 signal processing: analyses of immature hematopoiesis in GRK6-deficient mice. Stem cells and development 10 25316534
2003 G protein-coupled receptor kinase 6 (GRK6) selectively regulates endogenous secretin receptor responsiveness in NG108-15 cells. British journal of pharmacology 10 12598420
1997 Molecular cloning of rat G-protein-coupled receptor kinase 6 (GRK6) from brain tissue, and its mRNA expression in different brain regions and peripheral tissues. Brain research. Molecular brain research 10 9387888
2022 Overexpression of GRK6 alleviates chronic visceral hypersensitivity through downregulation of P2Y6 receptors in anterior cingulate cortex of rats with prenatal maternal stress. CNS neuroscience & therapeutics 9 35349212
2022 M2 macrophages-derived exosomal miR-3917 promotes the progression of lung cancer via targeting GRK6. Biological chemistry 9 36261031
2020 Downregulation of GRK6 in arcuate nucleus promotes chronic visceral hypersensitivity via NF-κB upregulation in adult rats with neonatal maternal deprivation. Molecular pain 9 32484026
2013 Expression of G-protein-coupled receptor kinase 6 (GRK6) after acute spinal cord injury in adult rat. Journal of molecular histology 9 23359120
2023 GRK6 palmitoylation increasing its membrance translocation promotes LPS-induced inflammation by PI3K/ AKT pathway in kuppfer cells. International immunopharmacology 8 37012861
2013 Decreased expression and role of GRK6 in spinal cord of rats after chronic constriction injury. Neurochemical research 8 23979726
2023 miR-19a may function as a biomarker of oral squamous cell carcinoma (OSCC) by regulating the signaling pathway of miR-19a/GRK6/GPCRs/PKC in a Chinese population. Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology 7 37706561
2022 G protein-coupled receptor kinase 6 (GRK6) regulates insulin processing and secretion via effects on proinsulin conversion to insulin. The Journal of biological chemistry 7 36030052
2013 GRK-6 mediates FSH action synergistically enhanced by estrogen and the oocyte in rat granulosa cells. Biochemical and biophysical research communications 7 23583200
1997 Identification and chromosomal localization of a processed pseudogene of human GRK6. Gene 7 9016947
2024 GRK6 palmitoylation dictates triple-negative breast cancer metastasis via recruiting the β-Arrestin 2/MAPKs/NF-κB signaling axis. Breast cancer research : BCR 5 39741338
2023 Therapeutic potential and protective role of GRK6 overexpression in pulmonary arterial hypertension. Vascular pharmacology 4 37742818
2021 GRK6 Depletion Induces HIF Activity in Lung Adenocarcinoma. Frontiers in oncology 3 34136390
2018 Effect of the 5-HT4 receptor agonist tegaserod on the expression of GRK2 and GRK6 in the rat gastrointestinal tract. BMC research notes 3 29884229
2025 Ligand-based cheminformatics and free energy-inspired molecular simulations for prioritizing and optimizing G-protein coupled receptor kinase-6 (GRK6) inhibitors in multiple myeloma treatment. Computational biology and chemistry 2 39824142
2025 REST elevation-dependent chromatin remodeling and alternative Grk6 transcript synthesis hyperactivates Cxcr4-Sdf1 signaling in cerebellar granule cell progenitors. bioRxiv : the preprint server for biology 0 41278839
2016 [Effect of GRK6 on Proliferation of Multiple Myeloma MM1R Cells and Its Mechanism]. Zhongguo shi yan xue ye xue za zhi 0 27784368
2015 A novel monoclonal antibody against human GRK6 antigen. Monoclonal antibodies in immunodiagnosis and immunotherapy 0 25723280

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