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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Selective recruitment of G protein-coupled receptor kinases (GRKs) controls signaling of the insulin-like growth factor 1 receptor
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Selective recruitment of G protein-coupled receptor kinases (GRKs) controls signaling of the insulin-like growth factor 1 receptor

机译：G蛋白偶联受体激酶（GRKs）的选择性募集控制胰岛素样生长因子1受体的信号传导

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摘要

β-Arrestins are multifunctional proteins that play central roles in G protein-coupled receptor (GPCR) trafficking and signaling, β-Arrestini is also recruited to the insulin-like growth f actor-1 receptor (IGF-1R), a receptor tyrosine kinase (RTK), mediating receptor degradation and signaling. Because GPCR phosphorylation by GPCR-kinases (GRKs) governs interactions of the receptors with β-arrestins, we investigated the regulatory roles of the four widely expressed GRKs on IGF-1R signaling/degradation. By suppressing GRK expression with siRNA, we demonstrated that lowering GRK5/6 abolishes IGF1-mediated ERK and AKT activation, whereas GRK2 inhibition increases ERK activation and partially inhibits AKT signaling. Conversely, β-arrestin-mediated ERK signaling is enhanced by overexpres-sion of GRK6 and diminished by GRK2. Similarly, we demonstrated opposing effects of GRK2 and -6 on IGF-1R degradation: GRK2 decreases whereas GRK6 enhances ligand-induced degradation. GRK2 and GRK6 coimmunoprecipitate with IGF-1R and increase IGF-1R serine phosphorylation, promoting β-arrestin1 association. Using immuno-precipitation, confocal microscopy, and FRET analysis, we demonstrated p-arrestin/IGF-1R association to be transient for GRK2 and stable for GRK6. Using bioinformatic studies we identified serines 1248 and 1291 as the major serine phosphorylation sites of the IGF-1R, and subsequent mutation analysis demonstrated clear effects on IGF-1 R signaling and degradation, mirroring alterations by GRKs. Targeted mutation of S1248 recapitulates GRK2 modulation, whereas S1291 mutation resembles GRK6 effects on IGF-1 R signaling/degradation, consistent with GRK isoform-specif ic serine phosphorylation. This study demonstrates distinct roles for GRK isoforms in IGF-1 R signaling through p-arrestin binding with divergent functional outcomes.
机译：β-Arrestins是多功能蛋白，在G蛋白偶联受体（GPCR）的运输和信号传导中起着核心作用，β-Arrestini也被募集到胰岛素样生长因子1受体（IGF-1R），一种受体酪氨酸激酶（RTK），介导受体降解和信号传导。由于GPCR激酶（GRKs）的GPCR磷酸化控制着受体与β-arrestin的相互作用，因此我们研究了四种广泛表达的GRK在IGF-1R信号转导/降解中的调控作用。通过用siRNA抑制GRK表达，我们证明降低GRK5 / 6可以消除IGF1介导的ERK和AKT激活，而GRK2抑制则增加ERK激活并部分抑制AKT信号传导。相反，β-arrestin介导的ERK信号转导会由于GRK6的过度表达而增强，而被GRK2减弱。同样，我们证明了GRK2和-6对IGF-1R降解的相反作用：GRK2降低，而GRK6增强配体诱导的降解。 GRK2和GRK6与IGF-1R免疫沉淀并增加IGF-1R丝氨酸磷酸化，促进β-arrestin1缔合。使用免疫沉淀，共聚焦显微镜和FRET分析，我们证明p-arrestin / IGF-1R缔合对于GRK2是瞬时的，对GRK6是稳定的。使用生物信息学研究，我们将丝氨酸1248和1291鉴定为IGF-1R的主要丝氨酸磷酸化位点，随后的突变分析证明了对IGF-1 R信号传导和降解的明显影响，反映了GRK的变化。 S1248的靶向突变概括了GRK2的调制，而S1291突变类似于GRK6对IGF-1 R信号转导/降解的影响，与GRK亚型特异性丝氨酸磷酸化一致。这项研究证明了GRK亚型在IGF-1 R信号传导中的不同作用，其通过p-arrestin结合产生不同的功能结果。

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  • 作者

    Huiyuan Zheng; Claire Worrall; Hongchang Shen; Tarik lssad; Stefan Seregard; Ada Girnita; Leonard Girnita;

  • 作者单位

    Department of Oncology and Pathology, Cancer Center Karolinska and Karolinska Institutet and Karolinska University Hospital,17176 Stockholm, Sweden;

    Department of Oncology and Pathology, Cancer Center Karolinska and Karolinska Institutet and Karolinska University Hospital,17176 Stockholm, Sweden;

    Department of Oncology and Pathology, Cancer Center Karolinska and Karolinska Institutet and Karolinska University Hospital,17176 Stockholm, Sweden Present address: Department of Oncology, Provincial Hospital Affiliated to Shandong University, Shandong University, Jinan 250021, China;

    lnstitut Cochin, Universite Paris Descartes, Centre National de la Recherche Scientifique, Unite Mixte de Recherche 8104, Paris,France lnstitut National de la Sante et de la Recherche Medicale U1016, Paris, France;

    Ophthalmic Pathology and Oncology Service, St. Erik's Eye Hospital,112 82 Stockholm, Sweden;

    Department of Oncology and Pathology, Cancer Center Karolinska and Karolinska Institutet and Karolinska University Hospital,17176 Stockholm, Sweden Dermatology Department, Karolinska Institutet and Karolinska University Hospital,17176 Stockholm, Sweden;

    Department of Oncology and Pathology, Cancer Center Karolinska and Karolinska Institutet and Karolinska University Hospital,17176 Stockholm, Sweden;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    cancer; ubiquitination; biasing;

    机译：癌症;泛素化偏见;

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