更新于：2024-11-01

GRK6 x PKC

更新于：2024-11-01

基本信息

关联

项与 GRK6 x PKC 相关的药物

GF-109203X

靶点

GRK6 x PKC

作用机制

GRK6 antagonists [+1]

在研机构-

原研机构

Pfizer Inc.

在研适应症-

非在研适应症

炎症 [+2]

最高研发阶段无进展

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 GRK6 x PKC 相关的临床结果

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100 项与 GRK6 x PKC 相关的转化医学

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0 项与 GRK6 x PKC 相关的专利（医药）

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项与 GRK6 x PKC 相关的文献（医药）

2023-11-01·Journal of Oral Pathology & Medicine

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

Article

作者: Xia, Xinyu ; Wang, Liang ; Shi, Yuyuan ; Chen, Jijun ; Ma, Danhua ; Gao, Hongyan ; Wu, Wei ; Zhang, He ; Fan, Jiayan

AbstractBackgroundIn this study, we aimed to investigate the potential of miR‐19a as a biomarker of OSCC and its underlying molecular mechanisms.MethodsWe collected serum and saliva samples from 66 OSCC patients and 66 healthy control subjects. Real‐time PCR analysis, bioinformatic analysis and luciferase assays were performed to establish a potential signaling pathway of miR‐19a/GRK6/GPCRs/PKC. Flowcytometry and Transwell assays were performed to observe the changes in cell apoptosis, metastasis and invasion.ResultsWe found that miR‐19a, GPR39 mRNA and PKC mRNA were upregulated while GRK6 mRNA was downregulated in the serum and saliva samples collected from OSCC patients. Moreover, in silico analysis confirmed a potential binding site of miR‐19a on the 3′UTR of GRK6 mRNA, and the subsequent luciferase assays confirmed the molecular binding between GRK6 and miR‐19a. We further identified that the over‐expression of miR‐19a could regulate the signaling between GRK6, GPR39 and PKC via the signaling pathway of miR‐19a/GRK6/GPR39/PKC, which accordingly resulted in suppressed cell apoptosis and promoted cell migration and invasion.ConclusionCollectively, the findings of our study propose that miR‐19a is a crucial mediator in the advancement of OSCC, offering a potential avenue for the development of innovative therapeutic interventions aimed at regulating GRK6 and its downstream signaling pathways.

2020-05-01·Molecular Pharmacology3区 · 医学

Carboxy-Terminal Phosphoregulation of the Long Splice Isoform of Free-Fatty Acid Receptor-4 Mediates β-Arrestin Recruitment and Signaling to ERK1/2

3区 · 医学

Article

作者: Burns, Rebecca N ; Moniri, Nader H ; Singh, Kirti ; Senatorov, Ilya S ; Cheshmehkani, Ameneh

Free-fatty acid receptor-4 (FFA4), previously termed GPR120, is a G protein-coupled receptor (GPCR) for medium and long-chained fatty acids, agonism of which can regulate a myriad of metabolic, sensory, inflammatory, and proliferatory signals. Two alternative splice isoforms of FFA4 exist that differ by the presence of an additional 16 amino acids in the longer (FFA4-L) transcript, which has been suggested to be an intrinsically β-arrestin-biased GPCR. Although the shorter isoform (FFA4-S) has been studied more extensively, very little is known about mechanisms of regulation or signaling of the longer isoform. Because β-arrestin recruitment is dependent on receptor phosphorylation, in the current study, we used the endogenous agonist docosahexaenoic acid (DHA) to examine the mechanisms of FFA4-L phosphorylation, as well as DHA-dependent β-arrestin recruitment and DHA-dependent extracellular-signal regulated kinase-1/2 (ERK1/2) signaling in human embryonic kidney 293 cells. Our results reveal differences in basal phosphorylation of the two FFA4 isoforms, and we show that DHA-mediated phosphorylation of FFA4-L is primarily regulated by G protein-coupled receptor kinase 6, whereas protein kinase-C can also contribute to agonist-induced and heterologous phosphorylation. Moreover, our data demonstrate that FFA4-L phosphorylation occurs on the distal C terminus and is directly responsible for recruitment and interactions with β-arrestin-2. Finally, using CRISPR/Cas9 genome-edited cells, our data reveal that unlike FFA4-S, the longer isoform is unable to facilitate phosphorylation of ERK1/2 in cells that are devoid of β-arrestin-1/2. Together, these results are the first to demonstrate phosphoregulation of FFA4-L as well as the effects of loss of phosphorylation sites on β-arrestin recruitment and ERK1/2 activation. SIGNIFICANCE STATEMENT: Free-fatty acid receptor-4 (FFA4) is a cell-surface G protein-coupled receptor for medium and long-chained fatty acids that can be expressed as distinct short (FFA4-S) or long (FFA4-L) isoforms. Although much is known about FFA4-S, the longer isoform remains virtually unstudied. Here, we reveal the mechanisms of docosahexaenoic acid-induced phosphorylation of FFA4-L and subsequent β-arrestin-2 recruitment and extracellular-signal regulated kinase-1/2 activity.

2019-05-01·Journal of Biological Chemistry2区 · 生物学

Heterologous regulation of CXCR4 lysosomal trafficking

2区 · 生物学

Article

作者: Adriana Caballero ; Sarah A. Mahn ; Mudassir S. Ali ; M. Rose Rogers ; Adriano Marchese

G protein-coupled receptor (GPCR) signaling is regulated by members of the protein kinase C (PKC) and GPCR kinase (GRK) families, although the relative contribution of each to GPCR function varies among specific GPCRs. The CXC motif receptor 4 (CXCR4) is a member of the GPCR superfamily that binds the CXC motif chemokine ligand 12 (CXCL12), initiating signaling that is subsequently terminated in part by internalization and lysosomal degradation of CXCR4. The purpose of this study is to define the relative contribution of PKC and GRK to CXCR4 signaling attenuation by studying their effects on CXCR4 lysosomal trafficking and degradation. Our results demonstrate that direct activation of PKC via the phorbol ester phorbol 12-myristate 13-acetate (PMA) mimics CXCL12-mediated desensitization, internalization, ubiquitination, and lysosomal trafficking of CXCR4. In agreement, heterologous activation of PKC by stimulating the chemokine receptor CXCR5 with its ligand, CXCL13, also mimics CXCL12-mediated desensitization, internalization, ubiquitination, and lysosomal degradation of CXCR4. Similar to CXCL12, PMA promotes PKC-dependent phosphorylation of serine residues within CXCR4 C-tail that are required for binding and ubiquitination by the E3 ubiquitin ligase AIP4 (atrophin-interacting protein 4). However, inhibition of PKC activity does not alter CXCL12-mediated ubiquitination and degradation of CXCR4, suggesting that other kinases are also required. Accordingly, siRNA-mediated depletion of GRK6 results in decreased degradation and ubiquitination of CXCR4. Overall, these results suggest that PKC and GRK6 contribute to unique aspects of CXCR4 phosphorylation and lysosomal degradation to ensure proper signal propagation and termination.