title: Requirement of Smurf-mediated endocytosis of Patched1 in sonic hedgehog signal reception.
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.
authors.affiliation: Department of Developmental Genetics, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China.
authors.forename: Shen
authors.initials: S
authors.lastname: Yue
authors.affiliation: Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, United States.
authors.forename: Liu-Ya
authors.initials: LY
authors.lastname: Tang
authors.affiliation: Department of Developmental Genetics, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, United States.
authors.forename: Yi
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Department of Developmental Genetics, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China.
authors.forename: Qiu-Hong
authors.initials: QH
authors.lastname: Shen
authors.affiliation: Department of Developmental Genetics, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Ding
authors.affiliation: Department of Developmental Genetics, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Developmental Genetics, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China.
authors.forename: Zengdi
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Developmental Genetics, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China.
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Yu
authors.affiliation: Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, United States.
authors.forename: Ying E
authors.initials: YE
authors.lastname: Zhang
authors.affiliation: Department of Developmental Genetics, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China.
authors.forename: Steven Y
authors.initials: SY
authors.lastname: Cheng
mesh_terms: D016475:3T3 Cells; D000483:Alleles; D020816:Amino Acid Motifs; D000818:Animals; D001921:Brain / Q000378:metabolism; D004705:Endocytosis; D005091:Exons; D005347:Fibroblasts / Q000378:metabolism; D031541:Fluorescence Resonance Energy Transfer; D005786:Gene Expression Regulation; D053823:Hedgehog Proteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D034741:RNA, Small Interfering / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D011995:Recombination, Genetic; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D053823:Hedgehog Proteins; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; C465570:Shh protein, mouse; C492381:Smurf1 protein, mouse; C533325:Smurf2 protein, mouse; D044767:Ubiquitin-Protein Ligases
keywords: Patched; Smurfs; developmental biology; endocytosis; mouse; sonic Hedgehog; stem cells; ubiquitination