Regulated proteolysis

There  are  various  unusual  signaling  pathways  for  relaying  signals  from  cell surface  receptors  to the interior  of the cell which include  regulated  proteolysis. Between these pathways is which mediated through the receptor protein Notch and the pathway   activated   through  secreted   Hedgehog   proteins   which  have   been   highly conserved across evolution and play crucial roles in animal development.  In case of the transmembrane Notch receptor the binding of its ligand Delta to the extracellular face leads to a proteolytic cleavage first in the region adjacent to the membrane and then a second cleavage within the hydrophobic transmembrane region. The released  cytoplasmic  domain  then migrates  to the nucleus where  it activates  the transcription  of several  goals  genes shown in figure.

Figure:   Cell signaling through the Notch receptor. Binding of ligand results in proteolytic cleavage of the receptor (1) on the extracellular face of the membrane. The resulting membrane-bound stub is then cleaved within the transmembrane domain (2), releasing the cytosolic tail which forms a complex with other proteins and activates gene transcription in the nucleus.

The Proteolytic cleavage within hydrophobic transmembrane region is unusual but more and more proteins are being identified which are subject to this regulated intramembrane proteolysis (RIP). The receptor cannot be reused as peptide bonds in the receptor protein are cleaved in this procedure.