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Background <p>G protein-coupled receptor kinase 2(GRK2) is a pivotal regulator of G protein-coupled receptor (GPCR) signal desensitization. It is increasingly recognized for its involvement in the pathogenesis of various malignancies through non-canonical signaling pathways.</p> Main body <p>This review systematically integrates the multilevel regulatory mechanisms of GRK2, encompassing its structure and function, key post-translational modifications (e.g. ubiquitination and phosphorylation), and dynamic subcellular localization. Analysis reveals that GRK2 exerts intricate and bidirectional regulatory roles in several solid tumors, including glioma, colorectal cancer, breast cancer, and lung cancer, with its mechanisms of action showing significant variability depending on tumor type and microenvironment. Emerging therapeutic strategies, such as small-molecule inhibitors targeting GRK2 and tissue-specific gene-editing models, show promising potential as precise oncology interventions.</p> Conclusions <p>Despite the considerable promise of GRK2-targeted therapies, their clinical translation faces critical challenges, including inadequate tissue selectivity and the risk of drug resistance. Therefore, future research should focus on overcoming these scientific hurdles to realize the full clinical application value of modulating GRK2 in oncology.</p>

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Regulation of G protein-coupled receptor kinase 2 and its role in tumors

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月16日

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  • Chenmin Liu,
  • Liuli Yang,
  • Shiyu Peng,
  • Jiangbo Jing,
  • Lijuan Ma

摘要

Background

G protein-coupled receptor kinase 2(GRK2) is a pivotal regulator of G protein-coupled receptor (GPCR) signal desensitization. It is increasingly recognized for its involvement in the pathogenesis of various malignancies through non-canonical signaling pathways.

Main body

This review systematically integrates the multilevel regulatory mechanisms of GRK2, encompassing its structure and function, key post-translational modifications (e.g. ubiquitination and phosphorylation), and dynamic subcellular localization. Analysis reveals that GRK2 exerts intricate and bidirectional regulatory roles in several solid tumors, including glioma, colorectal cancer, breast cancer, and lung cancer, with its mechanisms of action showing significant variability depending on tumor type and microenvironment. Emerging therapeutic strategies, such as small-molecule inhibitors targeting GRK2 and tissue-specific gene-editing models, show promising potential as precise oncology interventions.

Conclusions

Despite the considerable promise of GRK2-targeted therapies, their clinical translation faces critical challenges, including inadequate tissue selectivity and the risk of drug resistance. Therefore, future research should focus on overcoming these scientific hurdles to realize the full clinical application value of modulating GRK2 in oncology.