Sonic Hedgehog Dependent Phosphorylation by CK1α and GRK2 Is Required for Ciliary Accumulation and Activation of Smoothened

• DOI: 10.1371/journal.pbio.1001083
• Publication Date: 2011-06-17T19:40:38Z
• Authors: Yongbin Chen; Noriaki Sasai; Guoqiang Ma; Tao Yue; Jianhang Jia; James Briscoe; Jin Jiang
• Keywords: Smoothened; Cyclopamine; Phosphorylation cascade

Hedgehog (Hh) signaling regulates embryonic development and adult tissue homeostasis through the GPCR-like protein Smoothened (Smo), but how vertebrate Smo is activated remains poorly understood. In Drosophila, Hh dependent phosphorylation activates Smo. Whether this also case in vertebrates unclear, owing to marked sequence divergence between Drosophila (dSmo) involvement of primary cilia signaling. Here we demonstrate that mammalian (mSmo) multi-site its carboxyl-terminal tail by CK1α GRK2. Phosphorylation mSmo induces active conformation simultaneously promotes ciliary accumulation. We graded signals induce increasing levels fine-tune localization, conformation, activity. show induced agonists oncogenic mutations blocked antagonist cyclopamine, efficient depends on kinesin-II motor. Furthermore, provide evidence recruits initiate phosphorylation, further increases binding GRK2 mSmo, forming a positive feedback loop amplifies and/or sustains phosphorylation. Hence, despite their sequences subcellular trafficking, dSmo employ analogous mechanisms for activation.