Hedgehog Pathway Activation Requires Coreceptor-Catalyzed, Lipid-Dependent Relay of the Sonic Hedgehog Ligand.

Hedgehog Pathway Activation Requires Coreceptor-Catalyzed, Lipid-Dependent Relay of the Sonic Hedgehog Ligand. Dev Cell. 2020 Oct 06;: Authors: Wierbowski BM, Petrov K, Aravena L, Gu G, Xu Y, Salic A Abstract Hedgehog signaling governs critical processes in embryogenesis, adult stem cell maintenance, and tumorigenesis. The activating ligand, Sonic hedgehog (SHH), is highly hydrophobic because of dual palmitate and cholesterol modification, and thus, its release from cells requires the secreted SCUBE proteins. We demonstrate that the soluble SCUBE-SHH complex, although highly potent in cellular assays, cannot directly signal through the SHH receptor, Patched1 (PTCH1). Rather, signaling by SCUBE-SHH requires a molecular relay mediated by the coreceptors CDON/BOC and GAS1, which relieves SHH inhibition by SCUBE. CDON/BOC bind both SCUBE and SHH, recruiting the complex to the cell surface. SHH is then handed off, in a dual lipid-dependent manner, to GAS1, and from GAS1 to PTCH1, initiating signaling. These results define an essential step in Hedgehog signaling, whereby coreceptors activate SHH by chaperoning it from a latent extracellular complex to its cell-surface receptor, and point to a broader paradigm of coreceptor function. PMID: 33038332 [PubMed - as supplied by publisher]
Source: Developmental Cell - Category: Cytology Authors: Tags: Dev Cell Source Type: research