Abstract 1413 GRK2 Kinases in the Primary Cilium Initiate SMOOTHENED-PKA Signaling in the Hedgehog Cascade
Year: 2024
Type: conference-abstract
Abstract: Communication between G protein-coupled receptors (GPCRs) and kinases is fundamental to human physiology. Most GPCRs are assumed to signal to kinases exclusively via second messenger cascades. In contrast, we recently found that during Hedgehog (Hh) signal transduction in development and disease, the atypical G protein-coupled receptor (GPCR) SMOOTHENED (SMO) signals intracellularly by binding the protein kinase A catalytic subunit (PKA-C) and physically blocking its enzymatic activity. How these SMO / PKA-C interactions are regulated, such that they only occur when SMO Is in an active state, remains unclear. Here we show that GPCR kinase 2 (GRK2) orchestrates SMO / PKA-C signaling during endogenous Hh pathway activation in its native subcellular location, 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 that direct GPCR-kinase communication mechanisms regulate many cellular signaling pathways. This work was supported by the National Institutes of Health grant 1R35GM133672.
Source: Journal of Biological Chemistry
Author: Benjamin Myers
Institution: University of Utah
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,800
OpenAlex ID: W4393167665