Effects of PS1 deficiency on membrane protein trafficking and cleavage. PS1–deficient neurons fail to secrete Aβ, the peptide derived from proteolytic processing of APP, owing to the lack of a so-called γ-secretase activity. Mutations in PS1 or PS2 enhance γ42 cleavage. Despite the lack of sequence similarity near the γ-secretase cleavage site (see Transmembrane Domains box), APLP1 and Notch 1 are also cleaved inefficiently in PS1-deficient cells. Interestingly, in neurons lacking PS1, the maturation and the ligand-dependent autophosphorylation activity of the receptor tyrosine kinase TrkB are also severely compromised. Thus, it is likely that PS1, which is predominantly localized in the endoplasmic reticulum, may influence trafficking and metabolism of selected membrane proteins, including APP, APLP1, Notch 1, and TrkB.