Division of Hematology-Oncology, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA.
Divisions of Molecular Genomic Pathology and Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA.
Cells. 2021 Feb 3;10(2):307. doi: 10.3390/cells10020307.
G protein-coupled receptor kinase 2 (GRK2) is emerging as a key integrative signaling node in a variety of biological processes ranging from cell growth and proliferation to migration and chemotaxis. As such, GRK2 is now implicated as playing a role in the molecular pathogenesis of a broad group of diseases including heart failure, cancer, depression, neurodegenerative disease, and others. In addition to its long-known canonical role in the phosphorylation and desensitization of G protein-coupled receptors (GPCRs), recent studies have shown that GRK2 also modulates a diverse array of other molecular processes via newly identified GRK2 kinase substrates and via a growing number of protein-protein interaction binding partners. GRK2 belongs to the 7-member GRK family. It is a multidomain protein containing a specific N-terminal region (referred to as αN), followed by a regulator of G protein signaling homology (RH) domain, an AGC (Protein kinase A, G, C serine/threonine kinase family) kinase domain, and a C-terminal pleckstrin homology (PH) domain. GPCRs mediate the activity of many regulators of the immune system such as chemokines and leukotrienes, and thus GRK proteins may play key roles in modulating the lymphocyte response to these factors. As one of the predominant GRK family members expressed in immune cells, GRK2's canonical and noncanonical actions play an especially significant role in normal immune cell function as well as in the development and progression of disorders of the immune system. This review summarizes our current state of knowledge of the roles of GRK2 in lymphocytes. We highlight the diverse functions of GRK2 and discuss how ongoing investigation of GRK2 in lymphocytes may inform the development of new therapies for diseases associated with lymphocyte dysregulation.
G 蛋白偶联受体激酶 2（GRK2）作为各种生物学过程中的关键整合信号节点而崭露头角，这些过程范围从细胞生长和增殖到迁移和趋化性。因此，GRK2 现在被认为在包括心力衰竭、癌症、抑郁症、神经退行性疾病等在内的广泛疾病的分子发病机制中发挥作用。除了其在 G 蛋白偶联受体（GPCR）磷酸化和脱敏中的长期已知的经典作用外，最近的研究表明，GRK2 还通过新鉴定的 GRK2 激酶底物和越来越多的蛋白质-蛋白质相互作用结合伙伴来调节多种其他分子过程。GRK2 属于 7 个成员的 GRK 家族。它是一种多结构域蛋白，包含一个特定的 N 端区域（称为αN），后面是 G 蛋白信号调节同源（RH）结构域、AGC（蛋白激酶 A、G、C 丝氨酸/苏氨酸激酶家族）激酶结构域和一个 C 端的pleckstrin 同源（PH）结构域。GPCR 介导许多免疫系统调节剂的活性，如趋化因子和白三烯，因此 GRK 蛋白可能在调节淋巴细胞对这些因子的反应中发挥关键作用。作为在免疫细胞中表达的主要 GRK 家族成员之一，GRK2 的经典和非经典作用在正常免疫细胞功能以及免疫系统疾病的发展和进展中起着特别重要的作用。这篇综述总结了我们目前对 GRK2 在淋巴细胞中的作用的了解。我们强调了 GRK2 的多种功能，并讨论了对淋巴细胞中 GRK2 的持续研究如何为与淋巴细胞失调相关的疾病的新疗法的发展提供信息。
