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Genes Dev. 2014 Nov 15;28(22):2547-63. doi: 10.1101/gad.249425.114.

Regulation of Sufu activity by p66β and Mycbp provides new insight into vertebrate Hedgehog signaling.

Author information

1
Cardiovascular Research Institute, University of California at San Francisco, San Francisco, California 94158, USA;
2
Department of Molecular, Cell, and Developmental Biology, University of California at Los Angeles, Los Angeles, California 90095, USA;
3
Department of Cellular and Molecular Pharmacology, University of California at San Francisco, San Francisco, California 94158.
4
Cardiovascular Research Institute, University of California at San Francisco, San Francisco, California 94158, USA; pao-tien.chuang@ucsf.edu.

Abstract

Control of Gli function by Suppressor of Fused (Sufu), a major negative regulator, is a key step in mammalian Hedgehog (Hh) signaling, but how this is achieved in the nucleus is unknown. We found that Hh signaling results in reduced Sufu protein levels and Sufu dissociation from Gli proteins in the nucleus, highlighting critical functions of Sufu in the nucleus. Through a proteomic approach, we identified several Sufu-interacting proteins, including p66β (a member of the NuRD [nucleosome remodeling and histone deacetylase] repressor complex) and Mycbp (a Myc-binding protein). p66β negatively and Mycbp positively regulate Hh signaling in cell-based assays and zebrafish. They function downstream from the membrane receptors, Patched and Smoothened, and the primary cilium. Sufu, p66β, Mycbp, and Gli are also detected on the promoters of Hh targets in a dynamic manner. Our results support a new model of Hh signaling in the nucleus. Sufu recruits p66β to block Gli-mediated Hh target gene expression. Meanwhile, Mycbp forms a complex with Gli and Sufu without Hh stimulation but remains inactive. Hh pathway activation leads to dissociation of Sufu/p66β from Gli, enabling Mycbp to promote Gli protein activity and Hh target gene expression. These studies provide novel insight into how Sufu controls Hh signaling in the nucleus.

KEYWORDS:

Gli; Hh signaling; Mycbp; Sufu; p66β

PMID:
25403183
PMCID:
PMC4233246
DOI:
10.1101/gad.249425.114
[Indexed for MEDLINE]
Free PMC Article

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