title: A novel signaling pathway mediated by the nuclear targeting of C-terminal fragments of mammalian Patched 1.
abstract: BACKGROUND
  Patched 1 (Ptc1) is a polytopic receptor protein that is essential for growth and differentiation. Its extracellular domains accept its ligand, Sonic Hedgehog, while the function of its C-terminal intracellular domain is largely obscure.
  
  
  RESULTS
  In this study, we stably expressed human Ptc1 protein in HeLa cells and found that it is subjected to proteolytic cleavage at the C-terminus, resulting in the generation of soluble C-terminal fragments. These fragments accumulated in the nucleus, while the N-terminal region of Ptc1 remained in the cytoplasmic membrane fractions. Using an anti-Ptc1 C-terminal domain antibody, we provide conclusive evidence that C-terminal fragments of endogenous Ptc1 accumulate in the nucleus of C3H10T1/2 cells. Similar nuclear accumulation of endogenous C-terminal fragments was observed not only in C3H10T1/2 cells but also in mouse embryonic primary cells. Importantly, the C-terminal fragments of Ptc1 modulate transcriptional activity of Gli1.
  
  
  CONCLUSIONS
  Although Ptc1 protein was originally thought to be restricted to cell membrane fractions, our findings suggest that its C-terminal fragments can function as an alternative signal transducer that is directly transported to the cell nucleus.
authors.affiliation: Department of Molecular Biology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kagawa
authors.forename: Yuka
authors.initials: Y
authors.lastname: Shino
authors.forename: Daigo
authors.initials: D
authors.lastname: Kobayashi
authors.forename: Syunsuke
authors.initials: S
authors.lastname: Demizu
authors.forename: Masumi
authors.initials: M
authors.lastname: Shimada
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Ariga
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kawahara
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000502:physiology; D051379:Mice; D008809:Mice, Inbred C3H; D008969:Molecular Sequence Data; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D013347:Subcellular Fractions / Q000378:metabolism; D014158:Transcription, Genetic; D000071676:Zinc Finger Protein GLI1
chemical_list: C498520:Gli1 protein, mouse; D051741:Kruppel-Like Transcription Factors; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; D000071676:Zinc Finger Protein GLI1