A General Model of Hedgehog Signaling
Current models for hedgehog network function in mammals remain based, to some degree, on inferences derived from genetic and biochemical studies in the fruit fly Drosophila melanogaster. Nevertheless, for those elements that have been demonstrated in mammals, there is remarkable conservation of the basic “mechanism” of hedgehog network function from flies to mammals.
The mammalian hedgehog signal transduction network involves two types of cells, a signaling cell and a responding cell, generally located in different tissue compartments. For hedgehog signaling network activation, a member of the hedgehog family of secreted ligands (either Sonic Hedgehog (SHH), Indian Hedgehog (IHH), or Desert Hedgehog (DHH)) is produced by the signaling cell. Prior to acting as signaling molecules, the hedgehog ligands must undergo posttranslational modification. First, hedgehog ligands must be cleaved from an inactive precursor. The cleavage event is autocatalytic and leads to formation of an N-terminal cleavage product that is lipid modified by attachment of cholesterol to the C-terminus. Thereafter, the hedgehog ligand is again lipid modified by the addition of palmitate near its N-terminus. Thus active hedgehog ligand is lipid modified at both ends.
There are two related hedgehog receptors in mammals, Patched-1 (PTC1) and Patched-2 (PTC2). At least in the case of PTC1, receptor function is highly context dependent. In the absence of a hedgehog ligand, PTC1 (and probably PTC2) functions catalytically to inhibit an effector molecule called Smoothened (SMO) and prevent downstream signaling. In the presence of ligand, PTC1 can function not only to transduce the hedgehog signal by releasing its inhibition of SMO, but also to sequester hedgehog ligand and restrict the range over which free ligand can signal. Both the signal transduction and sequestration functions can be performed simultaneously. In addition, recent data suggest that PTC1 can function as a “dependence receptor” in some cell types whose survival depends on the presence of ligand-bound receptor. In these cells, ligand deprivation leads to PTC1-mediated initiation of apoptotic cell death.
Once hedgehog ligand is bound to PTC1, PTC1 inhibition of SMO is relieved, allowing SMO to effect downstream signaling. SMO activation leads ultimately to activation of any one of three zinc-finger transcription factors in the Gli family. Function of the three GLI family proteins is context dependent. GLI1 and GLI2 act primarily as transcriptional activators, while GLI3 appears to act primarily as a transcriptional repressor. Whereas GLI1 does not appear to have repressor activity, both GLI2 and GLI3 can function either as activators or repressors, depending on the overall status of the network and the form(s) of the GLI proteins produced.