A Broadly Conserved G-Protein-Coupled Receptor Kinase Phosphorylation Mechanism Controls Smoothened Activity

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Hedgehog proteins are critical regulators of embryonic tissue growth and organization in species ranging from flies to humans. Binding of the secreted Hh protein to its receptor at the surface of cells triggers an intracellular signal that is initiated by Smoothened (Smo). Upon exposure of cells to Hh, Smo becomes active and signals through a series of downstream proteins to regulate gene expression. Although Smo proteins in flies and mammals are similar, the critical regions involved in activation and signal initiation differ between the two, implying that different mechanisms have evolved in different organisms. Using the fruit fly as a model organism, we identified regions in Smo that are phosphorylated by a protein kinase called Gprk2 to enhance Smo activity. These phosphorylation sites overlap with previously identified sites in mouse Smo and are conserved in Smo proteins in many animals. Phosphorylation at these sites regulates the recruitment of Costal2 to Smo, a critical step in signal initiation, through a region of the protein that is also highly conserved. Our results indicate that Gprk2 phosphorylation represents an evolutionarily ancient and conserved mechanism for regulating Smo activity, and suggest that Smo regulation and signaling are more similar between different species than previously thought.

Vyšlo v časopise: A Broadly Conserved G-Protein-Coupled Receptor Kinase Phosphorylation Mechanism Controls Smoothened Activity. PLoS Genet 10(7): e32767. doi:10.1371/journal.pgen.1004399
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004399

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