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<p>G protein-coupled receptor kinases GRK5 and GRK6 are pivotal regulators of cellular signaling, extending beyond GPCR desensitization to modulate non-receptor pathways critical for neuronal development, immune responses, and oncogenic processes. Leveraging a comprehensive analysis of 3825 human phosphoproteomic datasets, this study identifies predominant phosphorylation sites (pS484 and pT485 in GRK5, pS484 in GRK6) and elucidates their co-phosphoregulated proteins, substrates, and interaction networks. Shared co-phosphoregulated proteins, including BRD9 and RBBP6, underscore conserved roles in mRNA processing and cellular proliferation, essential for maintaining tissue homeostasis and implicated in cancer progression. Divergent functions potentially emerge from sequence distinctions like nuclear localization signal in GRK5 driving neuronal-specific regulation via substrates like MAP1B (cytoskeletal remodeling) and ATRX (chromatin dynamics), while GRK6 palmitoylation anchors immune modulation through targets such as GIT1 (cell migration) and HSP90AA1 (inflammation). Proteogenomic profiling reveals upregulation of both kinases, particularly at pS484, in breast cancer, positioning them as oncogenic drivers in tumor growth and metastasis. These findings illuminate how GRK5 and GRK6 orchestrate balanced yet specialized signaling networks, offering biologically grounded insights for targeted therapies in neurological disorders, autoimmune conditions, and aggressive cancers like triple-negative breast cancer.</p>

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Comparative Phosphoproteomic Profiling and Network-based Interactome Analysis of GRK5 and GRK6

  • 期刊论文

  • 发表日期：

    2025年10月29日

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  • Jaytha Thomas,
  • Fathimathul Lubaba,
  • Suhail Subair,
  • Althaf Mahin,
  • Athira Perunelly Gopalakrishnan,
  • Prathik Basthikoppa Shivamurthy,
  • Athira C. Rajeev,
  • Rajesh Raju

摘要

G protein-coupled receptor kinases GRK5 and GRK6 are pivotal regulators of cellular signaling, extending beyond GPCR desensitization to modulate non-receptor pathways critical for neuronal development, immune responses, and oncogenic processes. Leveraging a comprehensive analysis of 3825 human phosphoproteomic datasets, this study identifies predominant phosphorylation sites (pS484 and pT485 in GRK5, pS484 in GRK6) and elucidates their co-phosphoregulated proteins, substrates, and interaction networks. Shared co-phosphoregulated proteins, including BRD9 and RBBP6, underscore conserved roles in mRNA processing and cellular proliferation, essential for maintaining tissue homeostasis and implicated in cancer progression. Divergent functions potentially emerge from sequence distinctions like nuclear localization signal in GRK5 driving neuronal-specific regulation via substrates like MAP1B (cytoskeletal remodeling) and ATRX (chromatin dynamics), while GRK6 palmitoylation anchors immune modulation through targets such as GIT1 (cell migration) and HSP90AA1 (inflammation). Proteogenomic profiling reveals upregulation of both kinases, particularly at pS484, in breast cancer, positioning them as oncogenic drivers in tumor growth and metastasis. These findings illuminate how GRK5 and GRK6 orchestrate balanced yet specialized signaling networks, offering biologically grounded insights for targeted therapies in neurological disorders, autoimmune conditions, and aggressive cancers like triple-negative breast cancer.