Abstract
The Hedgehog signalling pathway is evolutionarily highly conserved and essential for embryonic development of invertebrates and vertebrates. Consequently, impaired Hedgehog signalling results in very severe human diseases, ranging from holoprosencephaly to Pallister-Hall syndrome. Due to this great importance for human health, the focus of numerous research groups is placed on the investigation of the detailed mechanisms underlying Hedgehog signalling. Today, it is known that tiny cell protrusions, known as primary cilia, are necessary to mediate Hedgehog signalling in vertebrates. Although the Hedgehog pathway is one of the best studied signalling pathways, many questions remain. One of these questions is: How do primary cilia control Hedgehog signalling in vertebrates? Recently, it was shown that primary cilia regulate a special kind of proteasome which is essential for proper Hedgehog signalling. This review article will cover this novel cilia-proteasome association in embryonic Hedgehog signalling and discuss the possibilities provided by future investigations on this topic.
Highlights
In the year 1980, Christiane Nüsslein-Volhard and Eric Frank Wieschaus reported the identification of 15 loci whose mutations affect the development of the fruit fly Drosophila melanogaster larvae [1].In the course of these investigations, the hedgehog gene was discovered
The precise coordination between positive and negative regulation of HH signalling is of eminent importance
Since it is yet unknown whether the cilia-regulated proteasome is involved in the regulation of PTC and SMO, this review focuses on the negative regulation mechanisms via proteolytic processing of the GLI2 and GLI3 transcription factors by the cilia-regulated proteasome
Summary
In the year 1980, Christiane Nüsslein-Volhard and Eric Frank Wieschaus reported the identification of 15 loci whose mutations affect the development of the fruit fly Drosophila melanogaster larvae [1]. The conversion of the full-length GLI2 and GLI3 proteins into their truncated repressor forms is called proteolytic processing This processing event is realised by the ubiquitin-proteasome system (UPS). As the UPS is important for protein processing, and for protein degradation, it can influence proteins in different manners Schrader et al examined the difference between GLI1 and GLI3 They found a three-part signal mechanism which is dependent on a zinc-finger domain, the linker sequence, and the degron, which is essential for GLI3 processing [22] (Figure 1). The first processing signal is the zinc-finger domain of GLI3 This domain is not the crucial difference to distinguish proteins from being either processed or degraded, because GLI1 includes a similar zinc-finger domain.
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