Fig. 1

Overview of hedgehog signaling. The N- and C-termini of hedgehog proteins are covalently modified with palmitate and cholesterol, respectively. Lipid-modified hedgehog is transported by exocytic vesicles from the endoplasmic reticulum to the plasma membrane and secreted into the extracellular space. In the receiving cell, in the absence of bound hedgehog, the sterol-sensing domain (SSD)-containing receptor patched (PTCH) inhibits transport of smoothened (SMO) to the primary cilium by limiting the binding of cholesterol to the cysteine-rich domain (CRD) of SMO. In the absence of cilia-localized active SMO, GLI proteins are partially proteolyzed in the cytoplasm and translocate to the nucleus, where they act as transcriptional repressors (GLIR). Binding of hedgehog to PTCH1 leads to trafficking of PTCH1 away from the primary cilium, relieving repression of SMO ciliary accumulation and activation by cholesterol binding to the CRD. Active SMO inhibits the partial proteolysis of full-length GLI (GLIFL), which translocates to the nucleus and activates transcription. The transcriptional activity of GLI proteins drive progenitor cells along distinct differentiation trajectories. Hedgehog signaling also drives biological processes, including stem cell maintenance and progenitor proliferation. Aberrant hedgehog signaling induces aberrant proliferation and cellular differentiation associated with cancer