Two transmembrane proteins are crucial for intracellular transmission of the Hh signal: the tumor suppressor membrane protein Patched (Ptch1) and the seven-transmembrane domain G-protein coupled receptor-like protein Smoothened (Smo). The activity of Smo affects the bifunctional glioma-associated oncogene transcription factors (Gli), which are transcriptional effectors of the Hh pathway. Gli proteins are members of the family of Kruppel-like factors with highly conserved Zn finger DNA-binding domains. In mammals, they are represented by three proteins: Gli1, Gli2 and Gli3. Gli1 acts principally as a transcriptional activator, whereas Gli2 and Gli3 display both activator and repressor functions. Gli proteins are extensively modified posttranslationally, and these modifications largely determine their trafficking in the cell and ultimate transcriptional output of the Hh pathway.
Among the posttranslational modifications of Gli1/2/3 are: phosphorylation, ubiquitination/proteasomal truncation, acetylation, sumoylation, methylation, and O-GlcNAcylation. In the absence of genetic or epigenetic alterations at the level of the canonical Hh pathway components,  overactivation of Gli proteins may occur non-canonically via cross-talk with other signaling pathways. Among pro-tumorigenic pathways that regulate Gli proteins independently of the canonical Ptch1-Smo axis are: the mitogen-activated kinases (MAPK) cascade, the transforming growth factor beta (TGFβ) pathway, the epidermal growth factor receptor (EGFR) pathway, and the fibroblast growth factor receptor (FGFR) pathway.


1.Niewiadomski P, et al. Cells. 2019;8(2):147. Published 2019 Feb 11.