Which protein is critical for the activation of Gli transcription factors in the Hedgehog pathway?
Hedgehog-dependent activation of Gli transcription factors requires regulated processing and ciliary trafficking mechanisms. In absence of Hedgehog, Gli2 and Gli3 phosphorylated by PKA, GSK3, CK1 create phosphodegron recognized by beta-TrCP SCF E3 ligase and Sufu sequestration, cleaved to repressor forms Gli3R blocking targets like Patched1, Hhip1. Hedgehog binding to Patched derepresses Smoothened, which accumulates in primary cilium, binds EVC2, inhibits Suppressor of Fused, stabilizing full-length Gli as activator GliA. This Smoothened-dependent conversion in cilium tip, requiring kinesin Kif7 and intraflagellar transport, critical for interpreting Hedgehog gradient during neural tube and limb patterning and digit specification.
Ref: Huangfu & Anderson, Development 2006: Smoothened ciliary localization required for Gli activator formation in Hedgehog pathway.