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. 2024 Jan 19;16(2):432. doi: 10.3390/cancers16020432

Figure 5.

Figure 5

Activation of the Hh/GLI signaling pathway. Left panel: In the absence of ligand binding, PTCH exerts repressive effects on SMO. GLI transcription factors are sequestered by SUFU and phosphorylated by PKA, CK1, and GSK3β, marking them for proteolytic cleavage. The cleavage of the C-terminal domain creates GLIr, the repressor form of the transcription factor. GLIr then translocates into the nucleus and represses the transcription of Hh/GLI target genes. Right panel: Hh ligand binding to the extracellular domain of PTCH inhibits the receptor, relieving the repressive effects on SMO. SMO then inhibits the sequestration by SUFU and phosphorylation by PKA, CK1, and GSK3β, sparing GLI from proteolytic cleavage. The fulllength form of GLI is a transcriptional activator that translocates into the nucleus and promotes the transcription of Hh/GLI target genes such as PTCH1, GLI1, BCL2, Cyclin D1, etc. PTCH: Protein patched homolog; SMO: Smoothened; GLI1: glioma-associated oncogene 1; SUFU: Suppressor Of Fused Homolog; PKA: protein kinase A; CK1: Casein kinase 1; GSK3β: Glycogen Synthase Kinase 3 Beta; GLIr: the repressor form of the transcription factor GLI; Hh/GLI target genes: Hedgehog/glioma-associated oncogene target genes; GLIa: the transcriptional activator of GLI; PTCH1: Protein patched homolog 1; BCL2: B-cell lymphoma 2.