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Elife. 2014 Jun 12;3. doi: 10.7554/eLife.02555.

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

Author information

1
Department of Developmental Genetics, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China.
2
Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, 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.

KEYWORDS:

Patched; Smurfs; developmental biology; endocytosis; mouse; sonic Hedgehog; stem cells; ubiquitination

PMID:
24925320
PMCID:
PMC4080449
DOI:
10.7554/eLife.02555
[Indexed for MEDLINE]
Free PMC Article

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