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Publication : G protein-coupled receptors control the sensitivity of cells to the morphogen Sonic Hedgehog.

First Author  Pusapati GV Year  2018
Journal  Sci Signal Volume  11
Issue  516 PubMed ID  29438014
Mgi Jnum  J:330076 Mgi Id  MGI:6871480
Doi  10.1126/scisignal.aao5749 Citation  Pusapati GV, et al. (2018) G protein-coupled receptors control the sensitivity of cells to the morphogen Sonic Hedgehog. Sci Signal 11(516):eaao5749
abstractText  The morphogen Sonic Hedgehog (SHH) patterns tissues during development by directing cell fates in a concentration-dependent manner. The SHH signal is transmitted across the membrane of target cells by the heptahelical transmembrane protein Smoothened (SMO), which activates the GLI family of transcription factors through a mechanism that is undefined in vertebrates. Using CRISPR-edited null alleles and small-molecule inhibitors, we systematically analyzed the epistatic interactions between SMO and three proteins implicated in SMO signaling: the heterotrimeric G protein subunit GalphaS, the G protein-coupled receptor kinase 2 (GRK2), and the GalphaS-coupled receptor GPR161. Our experiments uncovered a signaling mechanism that modifies the sensitivity of target cells to SHH and consequently changes the shape of the SHH dose-response curve. In both fibroblasts and spinal neural progenitors, the loss of GPR161, previously implicated as an inhibitor of basal SHH signaling, increased the sensitivity of target cells across the entire spectrum of SHH concentrations. Even in cells lacking GPR161, GRK2 was required for SHH signaling, and Galphas, which promotes the activation of protein Kinase A (PKA), antagonized SHH signaling. We propose that the sensitivity of target cells to Hedgehog morphogens, and the consequent effects on gene expression and differentiation outcomes, can be controlled by signals from G protein-coupled receptors that converge on Galphas and PKA.
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