Abstract
The Hedgehog (HH) pathway governs cell proliferation and patterning during embryonic development and is involved in regeneration, homeostasis and stem cell maintenance in adult tissues. The activity of this signaling is finely modulated at multiple levels and its dysregulation contributes to the onset of several human cancers. Ubiquitylation is a coordinated post-translational modification that controls a wide range of cellular functions and signaling transduction pathways. It is mediated by a sequential enzymatic network, in which ubiquitin ligases (E3) and deubiquitylase (DUBs) proteins are the main actors. The dynamic balance of the activity of these enzymes dictates the abundance and the fate of cellular proteins, thus affecting both physiological and pathological processes. Several E3 ligases regulating the stability and activity of the key components of the HH pathway have been identified. Further, DUBs have emerged as novel players in HH signaling transduction, resulting as attractive and promising drug targets. Here, we review the HH-associated DUBs, discussing the consequences of deubiquitylation on the maintenance of the HH pathway activity and its implication in tumorigenesis. We also report the recent progress in the development of selective inhibitors for the DUBs here reviewed, with potential applications for the treatment of HH-related tumors.
Highlights
The Hedgehog (HH) pathway governs cell proliferation and patterning during embryonic development and is involved in regeneration, homeostasis and stem cell maintenance in adult tissues
In prostate cancer specimens, the expression of HH was detected in the tumor epithelium, while GLI1 expression was found in the tumor stroma cells, suggesting their paracrine crosstalk [45]
The sumoylation of Smo at K851 induced by Hh, recruits Ubiquitin-specific protease 8 (USP8) to inhibit Smo the sumoylation of Smo at K851 induced by Hh, recruits USP8 to inhibit Smo ubiquitylation and degradation, leading to its cell surface trafficking and amplifying the Hh pathway activity, both in Drosophila and mammals [86]
Summary
Francesca Bufalieri 1 , Ludovica Lospinoso Severini 1 , Miriam Caimano 1 , Paola Infante 2, *.
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