FIGURE 2

Regulation of the Gli transcription factors by polyubiquitination. Three Gli proteins transduce the hedgehog signal. In the absence of hedgehog, the pathway repressor Gli3 is produced after ubiquitination and cleavage by the proteasome. This process requires protein kinase A, GSK3, Casein kinase I, and the E3 ligase -TrCP. Gli2 is also acted upon by -TrCP and the same set of kinases, but is fully degraded rather than cleaved by the proteasome. Both the formation of the Gli3 repressor and the destruction of Gli2 are inhibited by Shh. Transcriptional activators Gli1 and Gli2 are degraded by a separate pathway that is also mediated by -TrCP. At this time, it is unclear whether this destruction process is reversed by hedgehog addition. Several studies have also identified other E3 ligases, such as Speckle type Poz Protein, and degrons have whose function is still unclear. These studies have suggested a possible independent nuclear role for the proteasome in controlling Gli activator and repressor levels.