Signaling Functions of Intramembrane Aspartyl-Proteases
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 conditi...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-12-01
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| Series: | Frontiers in Cardiovascular Medicine |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcvm.2020.591787/full |
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| author | Alkmini A. Papadopoulou Regina Fluhrer Regina Fluhrer |
| author_facet | Alkmini A. Papadopoulou Regina Fluhrer Regina Fluhrer |
| author_sort | Alkmini A. Papadopoulou |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-16T18:42:58Z |
| format | Article |
| id | doaj.art-7822052861c74401b20b77f2a0c07064 |
| institution | Directory Open Access Journal |
| issn | 2297-055X |
| language | English |
| last_indexed | 2024-12-16T18:42:58Z |
| publishDate | 2020-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cardiovascular Medicine |
| spelling | doaj.art-7822052861c74401b20b77f2a0c070642022-12-21T22:20:58ZengFrontiers Media S.A.Frontiers in Cardiovascular Medicine2297-055X2020-12-01710.3389/fcvm.2020.591787591787Signaling Functions of Intramembrane Aspartyl-ProteasesAlkmini A. Papadopoulou0Regina Fluhrer1Regina Fluhrer2Biochemistry and Molecular Biology, Institute of Theoretical Medicine, Medical Faculty, University of Augsburg, Augsburg, GermanyBiochemistry and Molecular Biology, Institute of Theoretical Medicine, Medical Faculty, University of Augsburg, Augsburg, GermanyGerman Center for Neurodegenerative Diseases (DZNE), Munich, GermanyIntramembrane 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.https://www.frontiersin.org/articles/10.3389/fcvm.2020.591787/fullintramembrane proteolysissignal peptide peptidasesignal peptide peptidase-likepresenilincellular signalingGxGD aspartyl proteases |
| spellingShingle | Alkmini A. Papadopoulou Regina Fluhrer Regina Fluhrer Signaling Functions of Intramembrane Aspartyl-Proteases Frontiers in Cardiovascular Medicine intramembrane proteolysis signal peptide peptidase signal peptide peptidase-like presenilin cellular signaling GxGD aspartyl proteases |
| title | Signaling Functions of Intramembrane Aspartyl-Proteases |
| title_full | Signaling Functions of Intramembrane Aspartyl-Proteases |
| title_fullStr | Signaling Functions of Intramembrane Aspartyl-Proteases |
| title_full_unstemmed | Signaling Functions of Intramembrane Aspartyl-Proteases |
| title_short | Signaling Functions of Intramembrane Aspartyl-Proteases |
| title_sort | signaling functions of intramembrane aspartyl proteases |
| topic | intramembrane proteolysis signal peptide peptidase signal peptide peptidase-like presenilin cellular signaling GxGD aspartyl proteases |
| url | https://www.frontiersin.org/articles/10.3389/fcvm.2020.591787/full |
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