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@ARTICLE{Papadopoulou:154232,
      author       = {Papadopoulou, Alkmini and Fluhrer, Regina},
      title        = {{S}ignaling {F}unctions of {I}ntramembrane
                      {A}spartyl-{P}roteases.},
      journal      = {Frontiers in Cardiovascular Medicine},
      volume       = {7},
      issn         = {2297-055X},
      address      = {Lausanne},
      publisher    = {Frontiers Media},
      reportid     = {DZNE-2021-00093},
      pages        = {591787},
      year         = {2020},
      abstract     = {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.},
      keywords     = {GxGD aspartyl proteases (Other) / cellular signaling
                      (Other) / intramembrane proteolysis (Other) / presenilin
                      (Other) / signal peptide peptidase (Other) / signal peptide
                      peptidase-like (Other)},
      cin          = {AG Fluhrer},
      ddc          = {610},
      cid          = {I:(DE-2719)1110000-2},
      pnm          = {342 - Disease Mechanisms and Model Systems (POF3-342)},
      pid          = {G:(DE-HGF)POF3-342},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:33381526},
      pmc          = {pmc:PMC7768045},
      doi          = {10.3389/fcvm.2020.591787},
      url          = {https://pub.dzne.de/record/154232},
}