Review
Biochemistry & Molecular Biology
Preethi C. Karnam, Sergey A. Vishnivetskiy, Vsevolod V. Gurevich
Summary: Arrestins are a small family of proteins that bind G protein-coupled receptors (GPCRs) with high affinity to active phosphorylated GPCRs. They must have two sensors, which detect receptor-attached phosphates and the active receptor conformation independently, enabling transition into a high-affinity receptor-binding state. This transition involves a global conformational rearrangement that stabilizes the complex by bringing additional elements of the arrestin molecule in contact with a GPCR.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Medicine, Research & Experimental
Chen Li, Xu Li
Summary: The research demonstrates that circPTEN can upregulate PTEN expression by binding with miR-4470 in CRC cells, and inhibit the phosphorylation of AKT by competitively binding with TRAF6, thus suppressing the proliferation, migration, and invasion of CRC cells while promoting apoptosis.
MOLECULAR THERAPY-NUCLEIC ACIDS
(2021)
Article
Biochemistry & Molecular Biology
Ya Zhuo, Valeria L. Robleto, Adriano Marchese
Summary: beta-arrestins are versatile adaptor proteins that regulate various aspects of G protein-coupled receptor signaling. By using APEX-based proximity labeling, potential novel beta-arrestin interacting partners were discovered. Our study demonstrates that beta arr1-APEX can interact with known interacting proteins and label known beta arr1-interacting partners upon agonist stimulation. This study highlights the value of beta arr1-APEX-based proximity labeling in identifying novel players involved in GPCR signaling.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Cell Biology
Haoran Jiang, Daniella Galtes, Jialu Wang, Howard A. Rockman
Summary: This review explores the signaling pathways, dynamic structures, and physiological relevance of the three most important GPCR signaling effectors in the cardiovascular system: heterotrimeric G proteins, GPCR kinases (GRKs), and 8-arrestins. It summarizes their prominent roles in GPCR pharmacology before transitioning into less well-explored areas. The application of new technologies has contributed to an increasing understanding of GPCR structure and downstream effectors.
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
(2022)
Article
Oncology
Caitrin Crudden, Takashi Shibano, Dawei Song, Mihnea P. Dragomir, Sonia Cismas, Julianna Serly, Daniela Nedelcu, Enrique Fuentes-Mattei, Andrei Tica, George A. Calin, Ada Girnita, Leonard Girnita
Summary: This study elucidates the molecular and biological roles of biased signaling downstream RTK, providing a novel approach to enhance the efficacy of anti-IGF1R-targeted therapy in cancer by targeting system bias. The findings suggest a promising strategy for the rational design or repurposing of therapeutics to selectively cross-target the IGF1R or other RTK.
Article
Biochemistry & Molecular Biology
Pierre-Yves Jean-Charles, Vishwaesh Rajiv, Subhodeep Sarker, Sangoh Han, Yushi Bai, Ali Masoudi, Sudha K. Shenoy
Summary: Arrestins and ARTs share a conserved ART motif, and within this motif, a crucial phenylalanine residue Phe116 is identified for the formation of β-arr2-GPCR complexes. Mutations of Phe116 prevent complex formation and lead to aberrant ubiquitination and localization of β-arr2.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Review
Chemistry, Medicinal
Ningning Sun, Kyeong-Man Kim
Summary: The desensitization of G protein-coupled receptors can occur through various mechanisms including phosphorylation-dependent desensitization at the receptor level and downstream mechanisms involving the sequestration of G proteins. These mechanisms involve GRKs, arrestins, and deubiquitinated arrestins to regulate GPCR signaling and prevent G-protein activation. Further studies are needed on the interesting mechanism of arrestin deubiquitination in GPCR desensitization.
ARCHIVES OF PHARMACAL RESEARCH
(2021)
Article
Biochemistry & Molecular Biology
Hyun Kyung Lim, Hee Jung Kwon, Ga Seul Lee, Jeong Hee Moon, Joohee Jung
Summary: The activation of GPER and the reduction in ROCK1, TAGLN2, and FCHO2 expressions by Chrysin suppress pancreatic cancer progression. This finding provides a new potential strategy for the treatment of pancreatic cancer.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Qing Tang, Mingming Liu, Yang Liu, Ran-Der Hwang, Tao Zhang, Jiou Wang
Summary: The study identified NDST3 as a potent regulator of lysosomal functions, with implications in neurodegenerative diseases associated with C9orf72. Lack of NDST3 increases organelle acidification, while its downregulation exacerbates protein toxicity linked to C9orf72.
Article
Biochemistry & Molecular Biology
Richard Agren, Kristoffer Sahlholm
Summary: The study revealed that there is a difference in Ca2+ sensitivity between the two isoforms of dopamine D-2 receptor (D2LR and D2SR), with the desensitization rate of D2SR being influenced by co-expression of GRK2 and beta-arrestin2. The Ca2+ sensitive desensitization of D2SR appears to be mediated via a GRK2 phosphorylation-dependent mechanism.
Article
Biochemistry & Molecular Biology
Marta Sanchez-Soto, Noelia M. Boldizsar, Kayla A. Schardien, Nora S. Madaras, Blair K. A. Willette, Laura R. Inbody, Christopher Dasaro, Amy E. Moritz, Julia Drube, Raphael S. Haider, R. Benjamin Free, Carsten Hoffman, David R. Sibley
Summary: The recruitment and activation of beta-arrestins to the D2 dopamine receptor (D2R) are not completely dependent on GPCR kinase (GRK)-mediated receptor phosphorylation, highlighting the importance of the GRK subfamily in D2R-beta-arrestin interactions.
Article
Biochemistry & Molecular Biology
Amy E. Moritz, Nora S. Madaras, Michele L. Rankin, Laura R. Inbody, David R. Sibley
Summary: The D1 dopamine receptor can be phosphorylated by GRKs at multiple sites, including the C-terminus and the third intracellular loop. This phosphorylation regulates the sensitivity and internalization of the D1 dopamine receptor through the activation of β-arrestin.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Multidisciplinary Sciences
Eunna Huh, Jonathan Gallion, Melina A. Agosto, Sara J. Wright, Theodore G. Wensel, Olivier Lichtarge
Summary: The study suggests that somatic mutations across class A GPCRs are nonrandomly distributed, with impactful, recurrent mutations at selected positions of functional motifs. These mutations induce perturbation of G protein activation and/or beta-arrestin recruitment in multiple receptors, promoting tumor growth or survival. The findings open a window into cancer mechanisms and potential therapeutic approaches by revealing that multiple GPCRs can drive or enable cancer through mutations at cognate positions across GPCR paralogs.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Neurosciences
Sam R. J. Hoare, Paul H. Tewson, Shivani Sachdev, Mark Connor, Thomas E. Hughes, Anne Marie Quinn
Summary: Neurons integrate inputs over different time and space scales, combining fast and slow signals to produce behavior. Measuring signaling kinetics in live cells using fluorescent biosensors and dyes provides a deeper understanding of G-protein-coupled receptor signaling and therapeutic mechanisms in the nervous system.
FRONTIERS IN CELLULAR NEUROSCIENCE
(2022)
Article
Multidisciplinary Sciences
Angus Li, Samuel Liu, Rennica Huang, Seungkirl Ahn, Robert J. Lefkowitz
Summary: G protein-coupled receptors (GPCRs) regulate cellular signaling pathways by coupling to G proteins and beta-arrestins. SII, an analog of AngII, activates cellular signaling through beta-arrestin-2-dependent mechanisms but fails to activate G protein. However, overexpression of the receptor can distort the bias of ligands and may not accurately reflect their signaling profile in physiologically relevant contexts.