Sonic Hedgehog Activates Phospholipase A2 to Enhance Smoothened Ciliary Translocation

• DOI: 10.1016/j.celrep.2017.05.033
• Publication Date: 2017-06-06T16:17:27Z
• Authors: Angela M. Arensdorf; Miriam E. Dillard; Jacob M. Menke; Matthew W. Frank; Charles O. Rock; Stacey K. Ogden
• Keywords: Smoothened; Cyclopamine

The G protein-coupled receptor Smoothened (Smo) is the signal transducer of Sonic Hedgehog (Shh) pathway. Smo signals through protein-dependent and -independent routes, with protein-independent canonical signaling to Gli effectors requiring accumulation in primary cilium. mechanisms controlling activation trafficking are not yet clear but likely entail small-molecule binding pockets its extracellular cysteine-rich domain (CRD) and/or transmembrane bundle. Here, we demonstrate that cytosolic phospholipase cPLA2α activated Gβγ downstream release arachidonic acid. Arachidonic acid binds synergizes CRD-binding agonists, promoting ciliary high-level signaling. Chemical or genetic inhibition dampens Gli, revealing an unexpected contribution pathway activity. displaces inhibitor cyclopamine rescue CRD agonist-induced signaling, suggesting may target bundle allosterically enhance by agonist-bound Smo.