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Laura Nogués, Clara Reglero, Verónica Rivas, Alicia Salcedo, Vanesa Lafarga, Maria Neves, Paula Ramos, Marta Mendiola, Alberto Berjón, Kostas Stamatakis, Xiao Zhen Zhou, Kun Ping Lu, David Hardisson, Federico Mayor, Petronila Penela
In addition to oncogenic drivers, signaling nodes can critically modulate cancer-related cellular networks to strength tumor hallmarks. We identify G-protein-coupled receptor kinase 2 (GRK2) as a relevant player in breast cancer. GRK2 is up-regulated in breast cancer cell lines, in spontaneous tumors in mice, and in a proportion of invasive ductal carcinoma patients. Increased GRK2 functionality promotes the phosphorylation and activation of the Histone Deacetylase 6 (HDAC6) leading to de-acetylation of the Prolyl Isomerase Pin1, a central modulator of tumor progression, thereby enhancing its stability and functional interaction with key mitotic regulators...
October 1, 2016: EBioMedicine
Daisuke Asai, Masaharu Murata, Riki Toita, Takahito Kawano, Hideki Nakashima, Jeong-Hun Kang
A series of amino acid substitutions was made in a previously identified β-tubulin-derived GRK2 substrate peptide ((404)DEMEFTEAESNMN(416)) to examine the role of amino acid residues surrounding the phosphorylation site. Anionic amino acid residues surrounding the phosphorylation site played an important role in the affinity for GRK2. Compared to the original peptide, a modified peptide (Ac-EEMEFSEAEANMN-NH2) exhibited markedly higher affinity for GRK2, but very low affinity for GRK5, suggesting that it can be a sensitive and selective peptide for GRK2...
October 6, 2016: Amino Acids
Xiuqing Tian, Qing Wang, Rui Guo, Lingling Xu, Qin M Chen, Yinglong Hou
BACKGROUND: Paroxetine is a selective serotonin reuptake inhibitor utilized in the treatment of depression and anxiety disorders. Recent studies have identified paroxetine as a G protein-coupled receptor kinase-2 (GRK2) inhibitor capable of reversing cardiac dysfunction and remodeling in experimental models of acute myocardial infarction (AMI). We determine the clinical importance of paroxetine on cardiac functions in patients having AMI with depression (AMID) in comparison with fluoxetine, an unrelated selective serotonin reuptake inhibitor that does not inhibit GRK2...
2016: Neuropsychiatric Disease and Treatment
Elena Tutunea-Fatan, Fabiana A Caetano, Robert Gros, Stephen S G Ferguson
No abstract text is available yet for this article.
September 23, 2016: Journal of Biological Chemistry
Stefanie Klenke, Kristina Renckhoff, Andrea Engler, Jürgen Peters, Ulrich H Frey
Real-time PCR is an indispensable technique for mRNA expression analysis but conclusions depend on appropriate reference gene selection. However, while reference gene selection has been a topic of publications, this issue is often disregarded when measuring target mRNA expression. Therefore, we (1) evaluated the frequency of appropriate reference gene selection, (2) suggest an easy-to-use tool for least variability reference gene selection, (3) demonstrate application of this tool, and (4) show effects on target gene expression profiles...
September 20, 2016: Naunyn-Schmiedeberg's Archives of Pharmacology
Meryl C Woodall, Benjamin P Woodall, Erhe Gao, Ancai Yuan, Walter J Koch
RATIONALE: G protein-coupled receptor kinase 2 (GRK2) is an important molecule upregulated after myocardial injury and during heart failure. Myocyte-specific GRK2 loss before and after myocardial ischemic injury improves cardiac function and remodeling. The cardiac fibroblast plays an important role in the repair and remodeling events following cardiac ischemia; the importance of GRK2 in these events has not been investigated. OBJECTIVE: The aim of this study is to elucidate the in vivo implications of deleting GRK2 in the cardiac fibroblast after ischemia/reperfusion (I/R) injury...
September 6, 2016: Circulation Research
Chen-Chen Han, Yang Ma, Yifan Li, Yang Wang, Wei Wei
G protein-coupled receptor kinase 2 (GRK2) is a key member of the G protein-coupled receptor kinase (GRK) family. GRK2 activity is regulated by the C-terminus of GRK2 which contains a plekstrin homology domain and the N-terminus of GRK2 which contains the RGS homology domain with binding sites for several proteins and lipids such as G protein-coupled receptors (GPCRs), G protein, phospholipase C, phosphatidylinositol 4,5-bisphosphate, extracellular signal‑regulated kinase, protein kinase A and Gβγ...
October 2016: International Journal of Molecular Medicine
Allison Doyle Brackley, Ruben Gomez, Armen N Akopian, Michael A Henry, Nathaniel A Jeske
Opioids remain the standard for analgesic care; however, adverse effects of systemic treatments contraindicate long-term administration. While most clinical opioids target mu opioid receptors (MOR), those that target the delta class (DOR) also demonstrate analgesic efficacy. Furthermore, peripherally restrictive opioids represent an attractive direction for analgesia. However, opioid receptors including DOR are analgesically incompetent in the absence of inflammation. Here, we report that G protein-coupled receptor kinase 2 (GRK2) naively associates with plasma membrane DOR in peripheral sensory neurons to inhibit analgesic agonist efficacy...
September 6, 2016: Cell Reports
Benjamin P Woodall, Meryl C Woodall, Timothy S Luongo, Laurel A Grisanti, Douglas G Tilley, John W Elrod, Walter J Koch
GRK2, a G protein-coupled receptor kinase, plays a critical role in cardiac physiology. Adrenergic receptors are the primary target for GRK2 activity in the heart; phosphorylation by GRK2 leads to desensitization of these receptors. As such, levels of GRK2 activity in the heart directly correlate with cardiac contractile function. Furthermore, increased expression of GRK2 after cardiac insult exacerbates injury and speeds progression to heart failure. Despite the importance of this kinase in both the physiology and pathophysiology of the heart, relatively little is known about the role of GRK2 in skeletal muscle function and disease...
October 14, 2016: Journal of Biological Chemistry
Ping Huang, Xiaoyan Lu, Baohong Yuan, Tao Liu, Liangcheng Dai, Yunjun Liu, Hui Yin
Astragaloside IV (AS-IV), an active saponin purified from Astragali Radix, has been identified with broad biological and pharmacological activities. In the present study, we continue to explore the potential effect of AS-IV on antibacterial response using an acute E. coli peritoneal infection model. Our findings implied that administration of AS-IV decreases mortality in mice challenged by lethal E. coli infection. The protection of AS-IV was related to promotion of neutrophil extravasation into the peritoneum and bacterial clearance...
October 2016: International Immunopharmacology
George R Pope, Sharada Tilve, Craig A McArdle, Stephen J Lolait, Anne-Marie O'Carroll
Apelin acts via the G protein-coupled apelin receptor (APJ) to mediate effects on cardiovascular and fluid homeostasis. G protein-coupled receptor (GPCR) trafficking has an important role in the regulation of receptor signalling pathways and cellular functions, however in the case of APJ the mechanisms and proteins involved in apelin-induced trafficking are not well understood. We generated a stable HEK-293 cell line expressing N-terminus HA-tagged mouse (m) APJ, and used a semi-automated imaging protocol to quantitate APJ trafficking and ERK1/2 activation following stimulation with [Pyr(1)]apelin-13...
December 5, 2016: Molecular and Cellular Endocrinology
Zhengyu Zha, Xiao-Ran Han, Matthew D Smith, Qun-Ying Lei, Kun-Liang Guan, Yue Xiong
Population-based and case-control studies in different ethnicities have linked a polymorphism, C825T, in exon 10 of GNB3 gene to hypertension and several additional diseases. The 825T allele is associated with alternative splicing and results in a shortened Gβ3 protein, referred to as Gβ3s, which loses 41 amino acids encompassing one WD40 repeat domain. The mechanism of how Gβ3 C825T polymorphism is associated with hypertension has remained unclear, but an impairment of its canonical function in G-protein-coupled receptor signaling has been ruled out...
2016: Cell Discovery
Wen-Li Zhao, Di Wang, Chun-Yan Liu, Xiao-Fan Zhao
G-protein-coupled receptors (GPCRs) transmit extracellular signals across the cell membrane. GPCR kinases (GRKs) desensitize GPCR signals in the cell membrane. However, the role and mechanism of GRKs in the desensitization of steroid hormone signaling are unclear. In this study, we propose that GRK2 is phosphorylated by protein kinase C (PKC) in response to induction by the steroid hormone 20-hydroxyecdysone (20E), which determines its translocation to the cell membrane of the lepidopteran Helicoverpa armigera...
2016: Scientific Reports
Karthik Rajkumar, Aare Nichita, Pawan Kumar Anoor, Swathi Raju, Surya Satyanarayana Singh, Sandeepta Burgula
UNLABELLED: Phosphatidylethanolamine-binding protein 1 (PEBP1), also known as Raf kinase inhibitor protein, belongs to PEBP family of proteins. It is known to interact with many proteins that are mainly involved in pathways that monitor cell proliferation and differentiation. PEBP1 in many cells interacts with several pathways, namely MAPK, GRK2, NF-кB, etc. that keeps the cell proliferation and differentiation in check. This protein is expressed by many cells in humans, including neurons where it is predominantly involved in production of choline acetyltransferase...
August 2016: Cell Biochemistry and Function
P Penela
G-protein-coupled receptors (GPCRs) are responsible for regulating a wide variety of physiological processes, and distinct mechanisms for GPCR inactivation exist to guarantee correct receptor functionality. One of the widely used mechanisms is receptor phosphorylation by specific G-protein-coupled receptor kinases (GRKs), leading to uncoupling from G proteins (desensitization) and receptor internalization. GRKs and β-arrestins also participate in the assembly of receptor-associated multimolecular complexes, thus initiating alternative G-protein-independent signaling events...
2016: Progress in Molecular Biology and Translational Science
(no author information available yet)
No abstract text is available yet for this article.
July 1, 2016: Journal of Biological Chemistry
Manuela Guccione, Roberta Ettari, Sabrina Taliani, Federico Da Settimo, Maria Zappalà, Silvana Grasso
G Protein-coupled Receptor Kinase 2 (GRK2) is a G protein-coupled receptor kinase that is ubiquitously expressed in many tissues and regulates various intracellular mechanisms. The up- or down-regulation of GRK2 correlates with several pathological disorders. GRK2 plays an important role in the maintenance of heart structure and function; thus, this kinase is involved in many cardiovascular diseases. GRK2 up-regulation can worsen cardiac ischemia; furthermore, increased kinase levels occur during the early stages of heart failure and in hypertensive subjects...
June 30, 2016: Journal of Medicinal Chemistry
Jingwen Yang, Zhangfei Shen, Xue Jiang, Huipeng Yang, Haishan Huang, Lili Jin, Yajie Chen, Liangen Shi, Naiming Zhou
Agonist-induced internalization plays a key role in the tight regulation of the extent and duration of G protein-coupled receptor signaling. Previously, we have shown that the Bombyx corazonin receptor (BmCrzR) activates both Gαq- and Gαs-dependent signaling cascades. However, the molecular mechanisms involved in the regulation of the internalization and desensitization of BmCrzR remain to be elucidated. Here, vectors for expressing BmCrzR fused with enhanced green fluorescent protein (EGFP) at the C-terminal end were used to further characterize BmCrzR internalization...
July 19, 2016: Biochemistry
Li Zhou, Meng-Yi Wang, Zhi-Yong Liang, Wei-Xun Zhou, Lei You, Bo-Ju Pan, Quan Liao, Yu-Pei Zhao
G-protein-coupled receptor kinase 2 (GRK2) was found to regulate biological behaviors in some cancers, including pancreatic cancer (PC). However, its clinicopathologic and prognostic implications in cancer remain unclear. This study was designed to address the issues in PC. Expression of GRK2 was measured by Western blotting and tissue microarray-based immunohistochemical staining in 3 and 171 patients with PC, respectively. The H-score was used to evaluate the staining results. In addition, GRK2 expression was correlated with clinicopathologic variables and overall survival...
October 2016: Human Pathology
A Franco, M Ciccarelli, D Sorriento, L Napolitano, A Fiordelisi, B Trimarco, M Durante, G Iaccarino
High-precision radiation therapy is a clinical approach that uses the targeted delivery of ionizing radiation, and the subsequent formation of reactive oxygen species (ROS) in high proliferative, radiation sensitive cancers. In particular, in thoracic cancer ratdiation treatments, can not avoid a certain amount of cardiac toxicity. Given the low proliferative rate of cardiac myocytes, research has looked at the effect of radiation on endothelial cells and consequent coronary heart disease as the mechanism of ratdiation induced cardiotoxicity...
May 2016: Translational Medicine @ UniSa
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