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Filename: controllers/Detail.php
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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 Hh pathway activation in the vertebrate 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 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.
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http://dx.doi.org/10.1101/2023.05.10.540226 | DOI Listing |
Cereb Cortex
December 2024
Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom.
The cerebral cortex is critical for advanced cognitive functions and relies on a vast network of neurons to carry out its highly intricate neural tasks. Generating cortical neurons in accurate numbers hinges on cell signaling orchestrated by primary cilia to coordinate the proliferation and differentiation of cortical stem cells. While recent research has shed light on multiple ciliary roles in corticogenesis, specific mechanisms downstream of cilia signaling remain largely unexplored.
View Article and Find Full Text PDFSignal Transduct Target Ther
December 2024
Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Cardiac development is a complex and intricate process involving numerous molecular signals and pathways. Researchers have explored cardiac development through a long journey, starting with early studies observing morphological changes and progressing to the exploration of molecular mechanisms using various molecular biology methods. Currently, advancements in stem cell technology and sequencing technology, such as the generation of human pluripotent stem cells and cardiac organoids, multi-omics sequencing, and artificial intelligence (AI) technology, have enabled researchers to understand the molecular mechanisms of cardiac development better.
View Article and Find Full Text PDFBiol Open
November 2024
Western Washington University, 516 High Street, Bellingham WA, USA.
C. elegans gut and cuticle produce a disruptive amount of autofluorescence during imaging. Although C.
View Article and Find Full Text PDFAm J Physiol Cell Physiol
December 2024
Institute of Physiology, University Duisburg-Essen, Essen, Germany.
Over the last few decades, the primary cilium, an inconspicuous cell organelle, has increasingly become the focus of current research. The primary cilium is a microtubule-based, non-motile, antenna-like structure that is present on almost all mammalian cells. The ciliary membrane incorporates a large number of receptor molecules, which further characterize this cellular organelle.
View Article and Find Full Text PDFAirway multiciliated cells (MCs) maintain respiratory health by clearing mucus and trapped particles through the beating of motile cilia. While it is known that ciliary lengths decrease along the proximal-distal (P-D) axis of the tracheobronchial tree, how this is regulated is unclear. Here, we demonstrate that canonical Notch signaling in MCs plays a critical role in stabilizing ciliary length.
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