Another twist to the GLI code

The canonical Hedgehog (Hh) signalling pathway is essential for vertebrate development and its uncontrolled activation is a common occurrence in human cancers. Hh signalling converges in the modification of a family of transcription factors, GLI1, GLI2 and GLI3, to orchestrate a cell type and context-specific transcriptional response. Despite binding to very similar responsive elements, the GLI family members can exert diverse and even opposing functions. A recent article by Tolosa et al. (Biochem. J. 477, 3131–3145, 2020) reveals an unexpected layer of complexity, through physical and functional interaction between GLI1 and GLI2. This commentary discusses the biological significance of the findings and incorporates them into an updated ‘GLI code'.