Abstract
The Hedgehog (Hh) family of secreted proteins governs embryonic development and adult tissue homeostasis in species ranging from insects to mammals. Deregulation of Hh pathway activity has been implicated in a wide range of human disorders, including congenital diseases and cancer. Hh exerts its biological influence through a conserved signaling pathway. Binding of Hh to its receptor Patched (Ptc), a twelve-span transmembrane protein, leads to activation of an atypical GPCR family protein and Hh signal transducer Smoothened (Smo), which then signals downstream to activate the latent Cubitus interruptus (Ci)/Gli family of transcription factors. Hh signal transduction is regulated by ubiquitination and deubiquitination at multiple steps along the pathway including regulation of Ptc, Smo and Ci/Gli proteins. Here we review the effect of ubiquitination and deubiquitination on the function of individual Hh pathway components, the E3 ubiquitin ligases and deubiquitinases involved, how ubiquitination and deubiquitination are regulated, and whether the underlying mechanisms are conserved from Drosophila to mammals.
Highlights
Hh exerts its biological influence through a conserved signaling pathway
We focus on how ubiquitination and deubiquitination regulate Hh signal transduction
Morpholino (MO)-based knockdown of Smurf1 and Smurf2 affected Sonic hedgehog (Shh) signaling in zebrafish embryos. These results suggest that the Nedd46 family of 21 of E3s plays a conserved role in mediating Ptc internalization and degradation, which is stimulated by Hh
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Given the critical roles that Hh signaling plays, it is not surprising that the pathway activity is tightly regulated through multiple mechanisms at different layers including the expression of Hh ligands and other pathway components as well as the perdurance, localization and activity of individual signaling components to ensure appropriate pathway activities essential for cell growth, differentiation, and pattern formation Among these regulatory mechanisms, post-translational modifications (PTMs) including phosphorylation, ubiquitination and sumoylation are prevalent in the regulation of Hh signaling outputs [3,5,6,7,8,9,10,11]. We focus on how ubiquitination and deubiquitination regulate Hh signal transduction
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