Mechanisms of Smoothened Regulation in Hedgehog Signaling.

Jie Zhang,Zulong Liu,Jianhang Jia

doi:10.3390/cells10082138

Abstract

The seven-transmembrane protein, Smoothened (SMO), has shown to be critical for the hedgehog (HH) signal transduction on the cell membrane (and the cilium in vertebrates). SMO is subjected to multiple types of post-translational regulations, including phosphorylation, ubiquitination, and sumoylation, which alter SMO intracellular trafficking and cell surface accumulation. Recently, SMO is also shown to be regulated by small molecules, such as oxysterol, cholesterol, and phospholipid. The activity of SMO must be very well balanced by these different mechanisms in vivo because the malfunction of SMO will not only cause developmental defects in early stages, but also induce cancers in late stages. Here, we discuss the activation and inactivation of SMO by different mechanisms to better understand how SMO is regulated by the graded HH signaling activity that eventually governs distinct development outcomes.

Highlights

Hedgehog (HH) was initially discovered in Drosophila as a segment polarity gene involved in embryo patterning, and HH signaling pathways were shown to be very important in both embryonic development and post-developmental tissue homeostasis [1,2,3].Aberrant HH signaling is implicated in many human disorders, including several types of cancers [4,5,6,7]
The HH signal is transduced by a signaling cascade that is highly conserved among different species
Binding of HH to PTC-IHOG relieves PTC inhibition on SMO, allowing SMO to block the partial degradation of the cubitus interruptus (Ci)/GLI

Summary

Introduction

Hedgehog (HH) was initially discovered in Drosophila as a segment polarity gene involved in embryo patterning, and HH signaling pathways were shown to be very important in both embryonic development and post-developmental tissue homeostasis [1,2,3]. In Drosophila, at the plasma membrane, the HH receptor system includes the receptor complex patched (PTC)-interference HH (IHOG) and the signal transducer Smoothened (SMO) [8,9,10]. Binding of HH to PTC-IHOG relieves PTC inhibition on SMO, allowing SMO to block the partial degradation of the cubitus interruptus (Ci)/GLI family of zinc finger transcription factors and thereby induce the expression of HH target genes, such as decapentaplegic (dpp), ptc, and engrailed (en) [2,11] (Figure 1). SMO activation/inactivation will provide insights into fundamental developmental processes, and lead to new diagnostic tools and therapeutic approaches. This re of 11 view will mainly focus on the regulation of Drosophila SMO; we briefly discuss the differences between Drosophila and vertebrates.

SMO and Conformational

SMO Regulation by Lipid-Based Modulators

Perspectives