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      The Role of G Protein-coupled Receptor Kinases in Cancer

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          Abstract

          G protein-coupled receptors (GPCRs) are the largest family of plasma membrane receptors. Emerging evidence demonstrates that signaling through GPCRs affects numerous aspects of cancer biology such as vascular remolding, invasion, and migration. Therefore, development of GPCR-targeted drugs could provide a new therapeutic strategy to treating a variety of cancers. G protein-coupled receptor kinases (GRKs) modulate GPCR signaling by interacting with the ligand-activated GPCR and phosphorylating its intracellular domain. This phosphorylation initiates receptor desensitization and internalization, which inhibits downstream signaling pathways related to cancer progression. GRKs can also regulate non-GPCR substrates, resulting in the modulation of a different set of pathophysiological pathways. In this review, we will discuss the role of GRKs in modulating cell signaling and cancer progression, as well as the therapeutic potential of targeting GRKs.

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          Most cited references142

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          G-protein-coupled receptors and cancer.

          G-protein-coupled receptors (GPCRs), the largest family of cell-surface molecules involved in signal transmission, have recently emerged as crucial players in tumour growth and metastasis. Malignant cells often hijack the normal physiological functions of GPCRs to survive, proliferate autonomously, evade the immune system, increase their blood supply, invade their surrounding tissues and disseminate to other organs. This Review will address our current understanding of the many roles of GPCRs and their signalling circuitry in tumour progression and metastasis. We will also discuss how interfering with GPCRs might provide unique opportunities for cancer prevention and treatment.
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            Endocytosis and signalling: intertwining molecular networks.

            Cell signalling and endocytic membrane trafficking have traditionally been viewed as distinct processes. Although our present understanding is incomplete and there are still great controversies, it is now recognized that these processes are intimately and bidirectionally linked in animal cells. Indeed, many recent examples illustrate how endocytosis regulates receptor signalling (including signalling from receptor tyrosine kinases and G protein-coupled receptors) and, conversely, how signalling regulates the endocytic pathway. The mechanistic and functional principles that underlie the relationship between signalling and endocytosis in cell biology are becoming increasingly evident across many systems.
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              Structure-function of the G protein-coupled receptor superfamily.

              During the past few years, crystallography of G protein-coupled receptors (GPCRs) has experienced exponential growth, resulting in the determination of the structures of 16 distinct receptors-9 of them in 2012 alone. Including closely related subtype homology models, this coverage amounts to approximately 12% of the human GPCR superfamily. The adrenergic, rhodopsin, and adenosine receptor systems are also described by agonist-bound active-state structures, including a structure of the receptor-G protein complex for the β(2)-adrenergic receptor. Biochemical and biophysical techniques, such as nuclear magnetic resonance and hydrogen-deuterium exchange coupled with mass spectrometry, are providing complementary insights into ligand-dependent dynamic equilibrium between different functional states. Additional details revealed by high-resolution structures illustrate the receptors as allosteric machines that are controlled not only by ligands but also by ions, lipids, cholesterol, and water. This wealth of data is helping redefine our knowledge of how GPCRs recognize such a diverse array of ligands and how they transmit signals 30 angstroms across the cell membrane; it also is shedding light on a structural basis of GPCR allosteric modulation and biased signaling.
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                Author and article information

                Journal
                Int J Biol Sci
                Int. J. Biol. Sci
                ijbs
                International Journal of Biological Sciences
                Ivyspring International Publisher (Sydney )
                1449-2288
                2018
                5 February 2018
                : 14
                : 2
                : 189-203
                Affiliations
                [1 ]Centre of Reproduction Development and Aging, Faculty of Health Sciences, University of Macau, Taipa, Macau
                [2 ]Department of Ultrasound, The Secondary Affiliated Hospital of Harbin Medical University, Harbin, China
                [3 ]Department of Pathology, The Secondary Affiliated Hospital of Harbin Medical University, Harbin, China
                Author notes
                ✉ Corresponding author: Leo T.O. Lee, Centre of Reproduction, Development and Aging, Faculty of Health Sciences, University of Macau, Taipa, Macau, China; E-mail: LTOLee@ 123456umac.mo

                Competing Interests: The authors have declared that no competing interest exists.

                Article
                ijbsv14p0189
                10.7150/ijbs.22896
                5821040
                29483837
                4f70f6f0-6e14-4bb9-9e15-7913301b66ce
                © Ivyspring International Publisher

                This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license ( https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions.

                History
                : 19 September 2017
                : 17 November 2017
                Categories
                Review

                Life sciences
                g protein-coupled receptor (gpcr),g protein-coupled receptor kinase (grk),cancer,cell signaling

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