Requirement of Smurf-mediated endocytosis of Patched1 in sonic hedgehog signal reception

Shen Yue, Liu Ya Tang, Ying Tang, Yi Tang, Qiu Hong Shen, Jie Ding, Yan Chen, Zengdi Zhang, Ting Ting Yu, Ying E. Zhang, Steven Y. Cheng

Research output: Contribution to journalArticlepeer-review

78 Scopus citations

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.

Original languageEnglish (US)
Article numbere02555
JournaleLife
Volume2014
Issue number3
DOIs
StatePublished - Jun 12 2014
Externally publishedYes

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