| First Author | Han Y | Year | 2017 |
| Journal | PLoS Biol | Volume | 15 |
| Issue | 8 | Pages | e2002063 |
| PubMed ID | 28777795 | Mgi Jnum | J:246208 |
| Mgi Id | MGI:5916649 | Doi | 10.1371/journal.pbio.2002063 |
| Citation | Han Y, et al. (2017) Regulation of Gli ciliary localization and Hedgehog signaling by the PY-NLS/karyopherin-beta2 nuclear import system. PLoS Biol 15(8):e2002063 |
| abstractText | 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)/karyopherinbeta2 (Kapbeta2) nuclear import system regulates Gli ciliary localization and Hh pathway activation. Mutating the PY-NLS in Gli or knockdown of Kapbeta2 diminished Gli ciliary localization. Kapbeta2 is required for the formation of Gli activator (GliA) in wild-type but not in Sufu mutant cells. Knockdown of Kapbeta2 affected Hh signaling in zebrafish embryos, as well as in vitro cultured cerebellum granule neuron progenitors (CGNPs) and SmoM2-driven medulloblastoma cells. Furthermore, Kapbeta2 depletion impaired the growth of cultured medulloblastoma cells, which was rescued by Gli overexpression. Interestingly, Kapbeta2 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 Kapbeta2 as a critical regulator of the Hh pathway and a potential drug target for Hh-driven cancers. |
