Hedgehog Signalling

• the 3 types of Hedgehog genes in humans are

  • Hedgehog
  • Sonic hedgehog
  • Indian hedgehog
• Hedgehog ligands are small peptide precursors that undergo modifications where they are autoproteolytically catalyzed where the C terminal fragment is cleaved away and the functional N terminal fragment gets modified -> C terminus is covalently cholesterified (cholesterol) and the N terminus is palmitoylated to a fatty acid chain (palmitate)

  • its receptor is Patched, iHog is its co-receptor
  • the target of hedgehog signalling is the Cubitis interruptis (Ci)

  
• no Hedgehog ligand -> Ci is cleaved to make inhibitory protein fragment

  • no Hedgehog -> Patched (receptor) and iHog (co-receptor) are unengaged -> impairs Smoothened (atypical GPCR) from being displayed on the membrane -> Smoothened stays sequestered in intracellular vesicles -> Ci associated with microtubules forms a complex with Costal2 and Fused -> complex recruits kinases and gets phosphorylated by PKA (mandatory), GSK3B, CK1 then cleaved (not fully destroyed) -> C terminal fragment of Ci is a transcriptional co- repressor for hedgehog pathway target genes in the nucleus

  
• Hedgehog ligand present -> Ci is kept at full length and promotes transcription

  • presesnt Hedgehog -> Patched and iHog engaged -> Smoothened displayed on membrane to be di phosphorylated by PKA and CK1 which can destruct the microtubule complex holding Ci (binds Costal2 to disrupt binding to Ci so it doesn't get cleaved -> full length Ci transits to nucleus which is a co- activator of hedgehog target genes

  
• PKA, CK1, and GSK3 are kinases needed for the NEGATIVE regulation of hedgehog targeted genes while only PKA and CK1 are needed for POSITIVE regulation

  • negative -> PKA, CK1, GSK3
  • positive -> PKA, CK1