PUBLICATION
Regulation of Gli ciliary localization and Hedgehog signaling by the PY-NLS/karyopherin-?2 nuclear import system
- Authors
- Han, Y., Xiong, Y., Shi, X., Wu, J., Zhao, Y., Jiang, J.
- ID
- ZDB-PUB-170805-1
- Date
- 2017
- Source
- PLoS Biology 15: e2002063 (Journal)
- Registered Authors
- Keywords
- Hedgehog signaling, Medulloblastoma, Cilia, Zebrafish, Embryos, Gene expression, Immunostaining, Transcription factors
- MeSH Terms
-
- Zebrafish
- Embryo, Nonmammalian/metabolism
- Mice
- Zinc Finger Protein GLI1/metabolism*
- Animals
- Nuclear Localization Signals*
- Cilia/metabolism*
- Hedgehog Proteins/metabolism*
- NIH 3T3 Cells
- beta Karyopherins/metabolism*
- Medulloblastoma/metabolism
- Animals, Genetically Modified
- Cerebellar Neoplasms/metabolism
- Feedback, Physiological
- PubMed
- 28777795 Full text @ PLoS Biol.
Citation
Han, Y., Xiong, Y., Shi, X., Wu, J., Zhao, Y., Jiang, J. (2017) Regulation of Gli ciliary localization and Hedgehog signaling by the PY-NLS/karyopherin-?2 nuclear import system. PLoS Biology. 15:e2002063.
Abstract
Hedgehog (Hh) signaling in vertebrates depends on primary cilia. Upon stimulation, Hh pathway components, including Gli transcription factors, accumulate at primary cilia to transduce the Hh signal, but the mechanisms underlying their ciliary targeting remains largely unknown. Here, we show that the PY-type nuclear localization signal (PY-NLS)/karyopherin?2 (Kap?2) nuclear import system regulates Gli ciliary localization and Hh pathway activation. Mutating the PY-NLS in Gli or knockdown of Kap?2 diminished Gli ciliary localization. Kap?2 is required for the formation of Gli activator (GliA) in wild-type but not in Sufu mutant cells. Knockdown of Kap?2 affected Hh signaling in zebrafish embryos, as well as in vitro cultured cerebellum granule neuron progenitors (CGNPs) and SmoM2-driven medulloblastoma cells. Furthermore, Kap?2 depletion impaired the growth of cultured medulloblastoma cells, which was rescued by Gli overexpression. Interestingly, Kap?2 is a transcriptional target of the Hh pathway, thus forming a positive feedback loop for Gli activation. Our study unravels the molecular mechanism and cellular machinery regulating Gli ciliary localization and identifies Kap?2 as a critical regulator of the Hh pathway and a potential drug target for Hh-driven cancers.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping