Figure 1.

γ-secretase: Multiple targets including Notch. Since blood vessels (endothelial cells and pericytes) are a rich source of Notch ligands, Notch activity likely varies across a tumor based on vascularity and distance from a vessel. Upon binding Notch ligand, Notch receptors undergo proteolytic activation. After cleavage, the intracellular domain translocates to the nucleus, turning on transcription of CSL targets by displacing co-repressors and recruiting co-activators. There are several other known γ-secretase targets, including CD44, E-Cadherin and N-Cadherin, ERBB4 and the Low Density Lipoprotein Receptor-Related Protein (LRP). For each of these, the ectodomain of the protein is first removed, often by an ADAMS family protease, which facilitates γ-secretase activity. The effects of γ-secretase can result both from a loss of function of the full length protein and from unique activities of the intracellular fragment. In sporadic desmoid tumors, mutated β-catenin encoded by CTNNB1 accumulates in the nucleus and de-represses Wnt responsive genes. This appears to be the major oncogenic driver of desmoid. How and if Notch and β-catenin signaling interact is desmoid tumor biology is not known.