Beyond γ-secretase activity: The multifunctional nature of presenilins in cell signalling pathways.
The presenilins are the catalytic subunit of the membrane-embedded tetrameric γ-secretase protease complexes. More that 90 transmembrane proteins have been reported to be γ-secretase substrates, including the widely studied amyloid precursor protein (APP) and the Notch receptor, which are precursors for the generation of amyloid-β peptides and biologically active APP intracellular domain (AICD) and Notch intracellular domain (NICD). The diversity of γ-secretase substrates highlights the importance of presenilin-dependent γ-secretase protease activities as a regulatory mechanism in a range of biological systems. However, there is also a growing body of evidence that supports the existence of γ-secretase-independent functions for the presenilins in the regulation and progression of an array of cell signalling pathways. In this review, we will present an overview of current literature that proposes evolutionarily conserved presenilin functions outside of the γ-secretase complex, with a focus on the suggested role of the presenilins in the regulation of Wnt/β-catenin signalling, protein trafficking and degradation, calcium homeostasis and apoptosis.
Signal Transduction Laboratory, School of Biochemistry & Cell Biology, ABCRF, Western Gateway Building, University College Cork, Cork, Ireland.
Stephen P
SP
Duggan
Signal Transduction Laboratory, School of Biochemistry & Cell Biology, ABCRF, Western Gateway Building, University College Cork, Cork, Ireland. Electronic address: jv.mccarthy@ucc.ie.
Justin V
JV
McCarthy
D000544:Alzheimer Disease / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D006801:Humans; D053763:Presenilins / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000502:physiology*
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D053763:Presenilins; D053829:Amyloid Precursor Protein Secretases
Alzheimer's disease; Apoptosis; Autophagy; Calcium homeostasis; Presenilin; Protein trafficking; Wnt signalling; γ-Secretase