In general substrates that undergo regulated intramembrane
In general substrates that undergo regulated intramembrane proteolysis are initially cleaved in the extracellular domain by sheddases such as TACE (TNFα converting enzyme) or ADAM (a disintegrin and metalloproteinase domain)/α-secretase, or by aspartyl proteases, such as BACE/β-secretase, before cleavage by the I-CLiP family of proteases . Recently, cleavage of peripheral membrane proteins and proteolysis within substrate ectodomains and luminal loop has been described , , . Furthermore, it has been reported that prerequisite ectodomain shedding may not be required for subsequent cleavage by γ-secretase for some substrates . For several substrates γ-secretase cleavage plays an essential role in a signalling paradigm whereby generation of intracellular domains (ICDs) allows for the spatial segregation of divergent signalling pathways or as is the case for Notch, allows for the translocation of ICDs to the nucleus where they enable transcriptional activation activity . Indeed, Psen1 knockout animals display a predominant Notch loss-of function phenotype resulting from loss of γ-secretase cleavage of Notch, highlighting the importance of γ-secretase in Notch signalling , , . Cleavage can also be used as a signal for degradation of transmembrane protein fragments and the maintenance of so-called ‘membrane proteostasis’ . Given the molar concentration calculator of known γ-secretase substrates the presenilins are proposed to be critically involved in regulating several cell signalling pathways mediated by these molecules, a thorough presentation of which have been reviewed elsewhere , , , , , .
Beyond their role in γ-secretase protease complexes, it has been proposed and in some cases demonstrated that the presenilins have many highly conserved γ-secretase independent regulatory functions in cellular processes and cell signalling, including Wnt signalling, endoplasmic reticulum (ER) calcium homeostasis, as well as lysosomal function and autophagy , , , , , , , , , , , . Evolutionarily many ICliPs are conserved from prokaryotes through to multicellular eukaryotes. Homologues of rhomboids, S2Ps, SPP and γ-secretase have all been identified in animals, plants (Arabidopsis thaliana and Physcomitrella patens) and protozoa (Dictyostelium discoideum) , , , , . Genetic evidence from presenilin-deficient mice supports this proposal, where mice deficient in Psen1 and Psen2 have a more severe phenotype than seen in animals deficient in other γ-secretase components, Aph-1, Pen-2 or Nicastrin, , , , . Similarly, reconstitution studies in P. patens revealed that loss of presenilins was associated with distinct phenotypes that could be fully rescued by catalytically inactive presenilin and human presenilin , supporting the existence of conserved γ-secretase independent functions for presenilins from plants to humans. This review will focus on current evidence for the existence of γ-secretase independent functions for the presenilins in a diversity of cellular processes; including the regulation of Wnt/β-catenin signalling, calcium homeostasis, cell survival, protein trafficking and degradation.
Post-translational modification of the presenilins Compelling evidence for a role for the presenilins in a diversity of γ-secretase-dependent and -independent cell signalling events come from the study of presenilin post-translational modification and from the identification of distinct protein binding domains with the amino acid sequence of the presenilins (Fig. 2). The presenilins undergo endoproteolysis, caspase cleavage, phosphorylation, and ubiquitination, which regulate presenilin function and interaction with numerous proteins , , . Early studies showed that PS1 is phosphorylated by protein kinase A (PKA) , protein kinase C (PKC) , glycogen synthase kinase 3β (GSK3β) , c-Jun. N-terminal kinases (JNK)  and cyclin dependent kinase 5 (CDK5) ,  (Fig. 2B), resulting in a variety of biological responses including alterations in γ-secretase activity,  Wnt/β-catenin signalling,  caspase-3 cleavage of PS1 and PS2 , and presenilin stability .