TY  - JOUR
AU  - Papadopoulou, Alkmini
AU  - Fluhrer, Regina
TI  - Signaling Functions of Intramembrane Aspartyl-Proteases.
JO  - Frontiers in Cardiovascular Medicine
VL  - 7
SN  - 2297-055X
CY  - Lausanne
PB  - Frontiers Media
M1  - DZNE-2021-00093
SP  - 591787
PY  - 2020
AB  - Intramembrane proteolysis is more than a mechanism to 'clean' the membranes from proteins no longer needed. By non-reversibly modifying transmembrane proteins, intramembrane cleaving proteases hold key roles in multiple signaling pathways and often distinguish physiological from pathological conditions. Signal peptide peptidase (SPP) and signal peptide peptidase-like proteases (SPPLs) recently have been associated with multiple functions in the field of signal transduction. SPP/SPPLs together with presenilins (PSs) are the only two families of intramembrane cleaving aspartyl proteases known in mammals. PS1 or PS2 comprise the catalytic center of the γ-secretase complex, which is well-studied in the context of Alzheimer's disease. The mammalian SPP/SPPL family of intramembrane cleaving proteases consists of five members: SPP and its homologous proteins SPPL2a, SPPL2b, SPPL2c, and SPPL3. Although these proteases were discovered due to their homology to PSs, it became evident in the past two decades that no physiological functions are shared between these two families. Based on studies in cell culture models various substrates of SPP/SPPL proteases have been identified in the past years and recently-developed mouse lines lacking individual members of this protease family, will help to further clarify the physiological functions of these proteases. In this review we concentrate on signaling roles of mammalian intramembrane cleaving aspartyl proteases. In particular, we will highlight the signaling roles of PS via its substrates NOTCH, VEGF, and others, mainly focusing on its involvement in vasculature. Delineating also signaling pathways that are affected and/or controlled by SPP/SPPL proteases. From SPP's participation in tumor progression and survival, to SPPL3's regulation of protein glycosylation and SPPL2c's control over cellular calcium stores, various crossovers between proteolytic activity of intramembrane proteases and cell signaling will be described.
KW  - GxGD aspartyl proteases (Other)
KW  - cellular signaling (Other)
KW  - intramembrane proteolysis (Other)
KW  - presenilin (Other)
KW  - signal peptide peptidase (Other)
KW  - signal peptide peptidase-like (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:33381526
C2  - pmc:PMC7768045
DO  - DOI:10.3389/fcvm.2020.591787
UR  - https://pub.dzne.de/record/154232
ER  -