Hedgehog Signaling Pathway

Hedgehog signaling is a conserved signaling pathway that regulates cell growth during embryonic development and tissue homeostasis, in invertebrates as well as vertebrates.

Unrestricted Hedgehog signaling can lead to several human developmental abnormalities and diseases including, cancers.

There are three key players in the Hedgehog signaling pathway.

The lipid-modified active Hedgehog ligand that acts as a local mediator, a transmembrane protein called Patched that acts as a receptor for the Hedgehog ligand and a transcription regulator called Cubitus Interruptus or Ci that acts as the primary effector molecule.

The Ci can exist in two different forms- an intact protein form, which acts as a transcriptional activator and a cleaved form called Ci75 which acts as a transcriptional repressor for various Hedgehog-responsive genes.

The intact Ci exists in association with a multiprotein complex bound to microtubules that consist of Fused kinase and Costal-2, a kinesin-like protein.

In the absence of Hedgehog ligand, the Patched protein continuously represses the activity of Smoothened protein - a transmembrane protein present on internal cell vesicles.

This elicits the processing of Ci by three kinases, PKA, GSK3, and CK1 which phosphorylate it and mark it for further processing in the proteasome, which results in the generation of Ci75.

Ci75 then translocates to the nucleus and assists in the transcriptional repression of the Hedgehog responsive genes in association with a co-repressor.

However, upon binding of the active Hedgehog ligand to the Patched protein and a co-receptor called iHog, the Smoothened protein is activated and transported to the cell membrane.

Then, smoothened recruits the components of the multiprotein complex to the membrane and interrupts the proteolysis of Cubitus Interruptus.

The intact Cubitus Interruptus then translocates to the nucleus and recruits another co-activator molecule to induce the expression of the Hedgehog responsive genes.