更新于：2024-11-01

GRK6

更新于：2024-11-01

基本信息

别名

G protein-coupled receptor kinase 6、G protein-coupled receptor kinase GRK6、GPRK6

+ [1]

简介

Specifically phosphorylates the activated forms of G protein-coupled receptors. Such receptor phosphorylation initiates beta-arrestin-mediated receptor desensitization, internalization, and signaling events leading to their desensitization. Seems to be involved in the desensitization of D2-like dopamine receptors in striatum and chemokine receptor CXCR4 which is critical for CXCL12-induced cell chemotaxis (By similarity). Phosphorylates rhodopsin (RHO) (in vitro) and a non G-protein-coupled receptor: LRP6 during Wnt signaling (in vitro).

关联

靶点

GRK5 x GRK6

作用机制

GRK5 inhibitors [+1]

在研机构

Purdue University

原研机构

Purdue University

在研适应症

肿瘤

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

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 相关的临床结果

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100 项与 GRK6 相关的转化医学

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0 项与 GRK6 相关的专利（医药）

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262

项与 GRK6 相关的文献（医药）

2024-10-31·The FASEB Journal

The role of polo‐like kinases 2 in the proteasomal and lysosomal degradation of alpha‐synuclein in neurons

Article

作者: Sung, Chun Chau ; Lam, Wai Yun ; Chung, Kenny K. K.

AbstractParkinson's disease (PD) is a neurodegenerative disorder caused by the degeneration of dopaminergic neurons in the brain stem. PD is mostly sporadic, but familial PD (FPD) cases are recorded in different studies. The first gene mutation that is linked to FPD is α‐synuclein (α‐syn). It was then found that α‐syn is also accumulated in Lewy body (LB), a classical pathological hallmark in PD patients. Different studies have shown that α‐syn accumulation and aggregation can be a crucial factor contributing to the degeneration of dopaminergic neurons in PD. α‐syn has been found to be degraded by the ubiquitin proteasomal system (UPS) and autophagy–lysosomal pathway (ALP). In this study, we initially explored how α‐syn phosphorylation by GRK6, PLK2 and CK2α would facilitate its degradation in relation to the UPS or ALP. Unexpectedly, we found that the degradation of α‐syn through PLK2 phosphorylation could be modulated by UPS and ALP in a novel mechanism. Specially, attenuation of UPS could increase the amount of PLK2 and then could facilitate the phosphorylation and degradation of α‐syn through ALP. To test this further in vivo, we attenuate the proteasomal activity in a well‐established A53T α‐syn transgenic PD mouse model. We found that attenuation of proteasomal activity in the A53T α‐syn transgenic mice could reduce the accumulation of α‐syn in the striatum and midbrain. Based on our results, this study provides a new insight into how α‐syn is degraded through the UPS and ALP.

2024-07-07·Zhonghua er bi yan hou tou jing wai ke za zhi = Chinese journal of otorhinolaryngology head and neck surgery

[Screening and validation of therapeutic targets for chronic sinusitis with nasal polyps based on proteomics].

Article

作者: Li, T ; Song, Z Y ; Sun, C Y ; Zhang, Y ; Yang, Y J ; Song, X C

目的： 通过蛋白质组学方法筛选慢性鼻窦炎伴鼻息肉（CRSwNP）的潜在治疗靶点，并通过实验验证其有效性。 方法： 收集自2020年6月至2021年12月于烟台毓璜顶医院耳鼻咽喉头颈外科行手术治疗的患者的鼻黏膜组织样本，其中CRSwNP患者69例，对照组（行上颌窦囊肿切除或视神经减压术）患者39例。通过液相色谱-串联质谱法（liquid chromatography-tandem mass spectrometry，LC-MS/MS）以数据独立采集（data-independent acquisition，DIA）模式分析组织样本，寻找差异表达蛋白，结合生物信息学工具对差异蛋白功能进行分析。并通过实时荧光定量聚合酶链反应（qPCR）及蛋白免疫印迹（WB）技术明确CRSwNP患者鼻组织造血细胞激酶（hematopoietic cell kinase，HCK）表达情况。同时构建CRSwNP小鼠模型并给予HCK抑制剂干预治疗，酶联免疫吸附实验（ELISA）检测不同实验组小鼠血清中炎性因子免疫球蛋白E（IgE）、白细胞介素（IL）-4及IL-5的分泌情况。 结果： 与对照组相比，CRSwNP组鼻黏膜组织筛选出差异蛋白1 850个，其中上调蛋白760个，下调蛋白1 090个。将细胞计数、CT评分等表型数据与组学结果进行加权基因共表达网络分析（weighted correlation network analysis，WGCNA）关联分析，选取MEBrown模块的575个蛋白，与通过蛋白质组学得到的1 850个差异蛋白中进一步筛选出的35个激酶取交集，获得8个蛋白激酶，分别是HCK、SYK、PDK2、FGR、PRKCB、ROR1、CAMK1及GRK6。对差异表达倍数最高的HCK进行实验验证，qPCR及WB结果表明，CRSwNP鼻组织中HCK的表达明显高于对照组（P<0.05）。在动物实验中发现，CRSwNP组小鼠血清中IgE、IL-4及IL-5分泌量较对照组显著升高（P<0.05），而经HCK抑制剂干预后，小鼠血清中IgE、IL-4及IL-5分泌量显著降低（P<0.05）。 结论： HCK抑制剂能够降低CRSwNP小鼠的炎性指标，HCK有望成为CRSwNP的潜在治疗靶点。.

2024-06-01·iScience

Robust GRK2/3/6-dependent desensitization of oxytocin receptor in neurons

Article

作者: Ahmad, Mohiuddin ; Nagaraja, Raghavendra Y ; Hoang, Hanh T M ; George, Kiran ; Tibbs, Taryn ; Li, Guangpu ; Troyano-Rodriguez, Eva

Oxytocin plays critical roles in the brain as a neuromodulator, regulating social and other affective behavior. However, the regulatory mechanisms controlling oxytocin receptor (OXTR) signaling in neurons remain unexplored. In this study, we have identified robust and rapid-onset desensitization of OXTR response in multiple regions of the mouse brain. Both cell autonomous spiking response and presynaptic activation undergo similar agonist-induced desensitization. G-protein-coupled receptor kinases (GRK) GRK2, GRK3, and GRK6 are recruited to the activated OXTR in neurons, followed by recruitment of β-arrestin-1 and -2. Neuronal OXTR desensitization was impaired by suppression of GRK2/3/6 kinase activity but remained unaltered with double knockout of β-arrestin-1 and -2. Additionally, we observed robust agonist-induced internalization of neuronal OXTR and its Rab5-dependent recruitment to early endosomes, which was impaired by GRK2/3/6 inhibition. This work defines distinctive aspects of the mechanisms governing OXTR desensitization and internalization in neurons compared to prior studies in heterologous cells.