000154232 001__ 154232 000154232 005__ 20240223115102.0 000154232 0247_ $$2doi$$a10.3389/fcvm.2020.591787 000154232 0247_ $$2pmid$$apmid:33381526 000154232 0247_ $$2pmc$$apmc:PMC7768045 000154232 0247_ $$2altmetric$$aaltmetric:95981207 000154232 037__ $$aDZNE-2021-00093 000154232 041__ $$aEnglish 000154232 082__ $$a610 000154232 1001_ $$0P:(DE-2719)9000246$$aPapadopoulou, Alkmini$$b0$$udzne 000154232 245__ $$aSignaling Functions of Intramembrane Aspartyl-Proteases. 000154232 260__ $$aLausanne$$bFrontiers Media$$c2020 000154232 3367_ $$2DRIVER$$aarticle 000154232 3367_ $$2DataCite$$aOutput Types/Journal article 000154232 3367_ $$0PUB:(DE-HGF)16$$2PUB:(DE-HGF)$$aJournal Article$$bjournal$$mjournal$$s1708603392_31173 000154232 3367_ $$2BibTeX$$aARTICLE 000154232 3367_ $$2ORCID$$aJOURNAL_ARTICLE 000154232 3367_ $$00$$2EndNote$$aJournal Article 000154232 520__ $$aIntramembrane 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. 000154232 536__ $$0G:(DE-HGF)POF3-342$$a342 - Disease Mechanisms and Model Systems (POF3-342)$$cPOF3-342$$fPOF III$$x0 000154232 588__ $$aDataset connected to CrossRef, PubMed, 000154232 650_7 $$2Other$$aGxGD aspartyl proteases 000154232 650_7 $$2Other$$acellular signaling 000154232 650_7 $$2Other$$aintramembrane proteolysis 000154232 650_7 $$2Other$$apresenilin 000154232 650_7 $$2Other$$asignal peptide peptidase 000154232 650_7 $$2Other$$asignal peptide peptidase-like 000154232 7001_ $$0P:(DE-2719)2000007$$aFluhrer, Regina$$b1$$eLast author 000154232 773__ $$0PERI:(DE-600)2781496-8$$a10.3389/fcvm.2020.591787$$gVol. 7, p. 591787$$p591787$$tFrontiers in Cardiovascular Medicine$$v7$$x2297-055X$$y2020 000154232 8564_ $$uhttps://pub.dzne.de/record/154232/files/DZNE-2021-00093.pdf$$yOpenAccess 000154232 8564_ $$uhttps://pub.dzne.de/record/154232/files/DZNE-2021-00093.pdf?subformat=pdfa$$xpdfa$$yOpenAccess 000154232 909CO $$ooai:pub.dzne.de:154232$$popenaire$$popen_access$$pVDB$$pdriver$$pdnbdelivery 000154232 9101_ $$0I:(DE-HGF)0$$6P:(DE-2719)9000246$$aExternal Institute$$b0$$kExtern 000154232 9101_ $$0I:(DE-588)1065079516$$6P:(DE-2719)2000007$$aDeutsches Zentrum für Neurodegenerative Erkrankungen$$b1$$kDZNE 000154232 9131_ $$0G:(DE-HGF)POF3-342$$1G:(DE-HGF)POF3-340$$2G:(DE-HGF)POF3-300$$3G:(DE-HGF)POF3$$4G:(DE-HGF)POF$$aDE-HGF$$bGesundheit$$lErkrankungen des Nervensystems$$vDisease Mechanisms and Model Systems$$x0 000154232 9132_ $$0G:(DE-HGF)POF4-899$$1G:(DE-HGF)POF4-890$$2G:(DE-HGF)POF4-800$$3G:(DE-HGF)POF4$$4G:(DE-HGF)POF$$aDE-HGF$$bProgrammungebundene Forschung$$lohne Programm$$vohne Topic$$x0 000154232 9141_ $$y2020 000154232 915__ $$0StatID:(DE-HGF)0200$$2StatID$$aDBCoverage$$bSCOPUS$$d2022-11-16 000154232 915__ $$0StatID:(DE-HGF)0300$$2StatID$$aDBCoverage$$bMedline$$d2022-11-16 000154232 915__ $$0LIC:(DE-HGF)CCBY4$$2HGFVOC$$aCreative Commons Attribution CC BY 4.0 000154232 915__ $$0StatID:(DE-HGF)0100$$2StatID$$aJCR$$bFRONT CARDIOVASC MED : 2021$$d2022-11-16 000154232 915__ $$0StatID:(DE-HGF)0501$$2StatID$$aDBCoverage$$bDOAJ Seal$$d2021-05-13T10:28:25Z 000154232 915__ $$0StatID:(DE-HGF)0113$$2StatID$$aWoS$$bScience Citation Index Expanded$$d2021-01-27 000154232 915__ $$0StatID:(DE-HGF)0500$$2StatID$$aDBCoverage$$bDOAJ$$d2021-05-13T10:28:25Z 000154232 915__ $$0StatID:(DE-HGF)0199$$2StatID$$aDBCoverage$$bClarivate Analytics Master Journal List$$d2022-11-16 000154232 915__ $$0StatID:(DE-HGF)0150$$2StatID$$aDBCoverage$$bWeb of Science Core Collection$$d2022-11-16 000154232 915__ $$0StatID:(DE-HGF)0510$$2StatID$$aOpenAccess 000154232 915__ $$0StatID:(DE-HGF)0030$$2StatID$$aPeer Review$$bDOAJ : Blind peer review$$d2021-05-13T10:28:25Z 000154232 915__ $$0StatID:(DE-HGF)0561$$2StatID$$aArticle Processing Charges$$d2021-01-27 000154232 915__ $$0StatID:(DE-HGF)9905$$2StatID$$aIF >= 5$$bFRONT CARDIOVASC MED : 2021$$d2022-11-16 000154232 915__ $$0StatID:(DE-HGF)0160$$2StatID$$aDBCoverage$$bEssential Science Indicators$$d2021-01-27 000154232 915__ $$0StatID:(DE-HGF)1110$$2StatID$$aDBCoverage$$bCurrent Contents - Clinical Medicine$$d2022-11-16 000154232 915__ $$0StatID:(DE-HGF)0700$$2StatID$$aFees$$d2021-01-27 000154232 9201_ $$0I:(DE-2719)1110000-2$$kAG Fluhrer$$lSignal Peptide Peptidases as Models for γ-Secretase$$x0 000154232 980__ $$ajournal 000154232 980__ $$aVDB 000154232 980__ $$aUNRESTRICTED 000154232 980__ $$aI:(DE-2719)1110000-2 000154232 9801_ $$aFullTexts