Abstract
Hedgehog signalling (Hh) is a developmental conserved pathway strongly involved in cancers when deregulated. This important pathway is orchestrated by numerous regulators, transduces through distinct routes and is finely tuned at multiple levels. In this regard, ubiquitylation processes stand as essential for controlling Hh pathway output. Although this post-translational modification governs proteins turnover, it is also implicated in non-proteolytic events, thereby regulating the most important cellular functions. The HECT E3 ligase Itch, well known to control immune response, is emerging to have a pivotal role in tumorigenesis. By illustrating Itch specificities on Hh signalling key components, here we review the role of this HECT E3 ubiquitin ligase in suppressing Hh-dependent tumours and explore its potential as promising target for innovative therapeutic approaches.
Highlights
Hedgehog (Hh) signalling cascade is an evolutionarily conserved pathway that plays a pivotal role in developmental processes, tissues homeostasis and stem cell/progenitors maintenance [1,2].Hh signals act as long-range morphogens to control cell patterning and differentiation in several embryonic tissues, such as the central nervous system (CNS)
Dysregulation of the Hh pathway observed in MB and other tumours can be caused by ligand-independent events, such as genetic mutations of pathway components (PTCH, SMO, Suppressor of Fused (SuFu), REN, GLI1/GLI2 amplification) [7,8] or ligand-dependent mechanisms of activation [9,10]
Itch is a monomeric Homologous to the E6-associated protein Carboxyl-Terminus (HECT)-type E3 ubiquitin ligases (E3s) ubiquitin ligase belonging to the neural precursor cell-expressed developmentally downregulated protein 4 (NEDD4) subgroup sharing a characteristic modular structure: a N-terminal lipid-interacting C2 domain, four WW domains for protein-protein interaction and a C-terminal catalytic HECT domain [35]
Summary
Hedgehog (Hh) signalling cascade is an evolutionarily conserved pathway that plays a pivotal role in developmental processes, tissues homeostasis and stem cell/progenitors maintenance [1,2]. This interaction triggers the activation of the GLI zinc finger transcription factors that translocate in the nucleus and promote the transcription of several Hh target genes involved in the most important biological processes [6]. Dysregulation of the Hh pathway observed in MB and other tumours can be caused by ligand-independent events, such as genetic mutations of pathway components (PTCH, SMO, SuFu, REN, GLI1/GLI2 amplification) [7,8] or ligand-dependent mechanisms of activation [9,10]. Molecular mechanisms underlying Hh signalling arrest are crucial for controlling the fates of the pathway after its activation In this regard, ubiquitin-dependent proteolytic processes play a crucial role [13]. Other key components of Hh pathway, such as SMO, PTCH and SuFu, are emerging as tightly regulated through ubiquitylation processes, indicating that this post-translational modification serves as a general mechanism in the dynamic regulation of the Hh pathway
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