دورية أكاديمية
أعرض في EDS

GRK2 kinases in the primary cilium initiate SMOOTHENED-PKA signaling in the Hedgehog cascade.

التفاصيل البيبلوغرافية
العنوان: GRK2 kinases in the primary cilium initiate SMOOTHENED-PKA signaling in the Hedgehog cascade.
المؤلفون: Walker MF; Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.; Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.; Department of Bioengineering, University of Utah School of Medicine, Salt Lake City, Utah, United States of America., Zhang J; Department of Molecular and Cell Biology, School of Natural Sciences, University of California, Merced, California, United States of America., Steiner W; Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.; Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.; Department of Bioengineering, University of Utah School of Medicine, Salt Lake City, Utah, United States of America., Ku PI; Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, USA; Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America., Zhu JF; Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.; Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.; Department of Bioengineering, University of Utah School of Medicine, Salt Lake City, Utah, United States of America., Michaelson Z; Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.; Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.; Department of Bioengineering, University of Utah School of Medicine, Salt Lake City, Utah, United States of America., Yen YC; Department of Biological Sciences, Purdue University, West Lafayette, Indiana, United States of America., Lee A; Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.; Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.; Department of Bioengineering, University of Utah School of Medicine, Salt Lake City, Utah, United States of America., Long AB; Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, United States of America., Casey MJ; Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah, United States of America., Poddar A; Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, USA; Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America., Nelson IB; Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.; Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.; Department of Bioengineering, University of Utah School of Medicine, Salt Lake City, Utah, United States of America., Arveseth CD; Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.; Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.; Department of Bioengineering, University of Utah School of Medicine, Salt Lake City, Utah, United States of America., Nagel F; 7TM Antibodies GmbH, Jena, Germany., Clough R; Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah, United States of America., LaPotin S; Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah, United States of America., Kwan KM; Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah, United States of America., Schulz S; 7TM Antibodies GmbH, Jena, Germany.; Institute of Pharmacology and Toxicology, University Hospital Jena, Jena, Germany., Stewart RA; Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah, United States of America., Tesmer JJG; Department of Biological Sciences, Purdue University, West Lafayette, Indiana, United States of America.; Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana, United States of America., Caspary T; Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, United States of America., Subramanian R; Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, USA; Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America., Ge X; Department of Molecular and Cell Biology, School of Natural Sciences, University of California, Merced, California, United States of America., Myers BR; Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.; Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.; Department of Bioengineering, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.
المصدر: PLoS biology [PLoS Biol] 2024 Aug 13; Vol. 22 (8), pp. e3002685. Date of Electronic Publication: 2024 Aug 13 (Print Publication: 2024).
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Public Library of Science Country of Publication: United States NLM ID: 101183755 Publication Model: eCollection Cited Medium: Internet ISSN: 1545-7885 (Electronic) Linking ISSN: 15449173 NLM ISO Abbreviation: PLoS Biol Subsets: MEDLINE
أسماء مطبوعة: Original Publication: San Francisco, CA : Public Library of Science, [2003]-
مواضيع طبية MeSH: Cilia*/metabolism , Smoothened Receptor*/metabolism , Smoothened Receptor*/genetics , Hedgehog Proteins*/metabolism , G-Protein-Coupled Receptor Kinase 2*/metabolism , Signal Transduction* , Cyclic AMP-Dependent Protein Kinases*/metabolism , Zebrafish*/metabolism, Animals ; Mice ; Phosphorylation ; Zebrafish Proteins/metabolism ; Zebrafish Proteins/genetics ; NIH 3T3 Cells
مستخلص: During Hedgehog (Hh) signal transduction in development and disease, the atypical G protein-coupled receptor (GPCR) SMOOTHENED (SMO) communicates with GLI transcription factors by binding the protein kinase A catalytic subunit (PKA-C) and physically blocking its enzymatic activity. Here, we show that GPCR kinase 2 (GRK2) orchestrates this process during endogenous mouse and zebrafish Hh pathway activation in the primary cilium. Upon SMO activation, GRK2 rapidly relocalizes from the ciliary base to the shaft, triggering SMO phosphorylation and PKA-C interaction. Reconstitution studies reveal that GRK2 phosphorylation enables active SMO to bind PKA-C directly. Lastly, the SMO-GRK2-PKA pathway underlies Hh signal transduction in a range of cellular and in vivo models. Thus, GRK2 phosphorylation of ciliary SMO and the ensuing PKA-C binding and inactivation are critical initiating events for the intracellular steps in Hh signaling. More broadly, our study suggests an expanded role for GRKs in enabling direct GPCR interactions with diverse intracellular effectors.
Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: S.S. is the founder and scientific advisor of 7TM Antibodies GmbH, Jena, Germany. F.N. is an employee of 7TM Antibodies. All other authors declare no competing interests.
(Copyright: © 2024 Walker et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
التعليقات: Update of: bioRxiv. 2024 Apr 18:2023.05.10.540226. doi: 10.1101/2023.05.10.540226. (PMID: 37214942)
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معلومات مُعتمدة: R01 NS106527 United States NS NINDS NIH HHS; R35 GM148416 United States GM NIGMS NIH HHS; R15 CA235749 United States CA NCI NIH HHS; R01 CA254402 United States CA NCI NIH HHS; R35 GM133672 United States GM NIGMS NIH HHS; R01 GM143276 United States GM NIGMS NIH HHS; R01 HL071818 United States HL NHLBI NIH HHS; R01 GM145651 United States GM NIGMS NIH HHS
المشرفين على المادة: 0 (Smoothened Receptor)
0 (Hedgehog Proteins)
EC 2.7.11.16 (G-Protein-Coupled Receptor Kinase 2)
EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases)
0 (Smo protein, mouse)
EC 2.7.11.15 (GRK2 protein, mouse)
0 (Zebrafish Proteins)
تواريخ الأحداث: Date Created: 20240813 Date Completed: 20240813 Latest Revision: 20240920
رمز التحديث: 20240920
مُعرف محوري في PubMed: PMC11322411
DOI: 10.1371/journal.pbio.3002685
PMID: 39138140
قاعدة البيانات: MEDLINE
الوصف
تدمد:1545-7885
DOI:10.1371/journal.pbio.3002685