Requirement of Smurf-mediated endocytosis of Patched1 in Sonic Hedgehog signal reception
- Nanjing Medical University, China
- Center for Cancer Research, National Cancer Institute, United States
Abstract
Cell surface reception of Sonic hedgehog (Shh) must ensure that the graded morphogenic signal is interpreted accordingly in neighboring cells to specify tissue patterns during development. Here, we report endocytic sorting signals for the receptor Patched1 (Ptch1), comprising two 'PPXY' motifs, that direct it to degradation in lysosomes. These signals are recognized by two HECT-domain ubiquitin E3 ligases, Smurf1 and Smurf2, which are induced by Shh and become enriched in Caveolin-1 lipid rafts in association with Ptch1. Smurf-mediated endocytic turnover of Ptch1 is essential for its clearance from the primary cilium and pathway activation. Removal of both Smurfs completely abolishes the ability of Shh to sustain the proliferation of postnatal granule cell precursors in the cerebellum. These findings reveal a novel step in the Shh pathway activation as part of the Ptch1 negative feedback loop that precisely controls the signaling output in response to Shh gradient signal.
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Animal experimentation: All mice were maintained and handled according to protocols (ASP 13-214) approved by the Animal Care and Use Committee of the National Cancer Institute, NIH.
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This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
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Requirement of Smurf-mediated endocytosis of Patched1 in Sonic Hedgehog signal reception
eLife 3:e02555.
https://doi.org/10.7554/eLife.02555
