SMURF1 and SMURF2 directly target GLI1 for ubiquitination and proteasome-dependent degradation.

The transcription factor GLI1 is the main and final effector of the Hedgehog signaling pathway, which is involved in embryonic development, cell proliferation and stemness. Whether activated through canonical or non-canonical mechanisms, GLI1 aberrant activity is associated with Hedgehog-dependent cancers, including medulloblastoma, as well as other tumoral contexts. Notwithstanding a growing body of evidence, which have highlighted the potential role of post translational modifications of GLI1, the complex mechanisms modulating GLI1 stability and activity have not been fully elucidated.

KCTD1 is a new modulator of the KCASH family of Hedgehog suppressors.

The Sonic Hedgehog (Hh) signal transduction pathway plays a critical role in many developmental processes and, when deregulated, may contribute to several cancers, including basal cell carcinoma, medulloblastoma, colorectal, prostate, and pancreatic cancer. In recent years, several Hh inhibitors have been developed, mainly acting on the Smo receptor. However, drug resistance due to Smo mutations or non-canonical Hh pathway activation highlights the need to identify further mechanisms of Hh pathway modulation.