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.
Highlights
Proteolysis is a non-reversible post-translational protein modification and can regulate the function of a protein by contributing to either its maturation and activation, or its degradation
Signal peptide peptidase (SPP)/signal peptide peptidase-like proteases (SPPLs) do affect trafficking indirectly, like in case of CD74, and directly by cleaving proteins that are central mediators of trafficking. This has been shown for SPP and for SPPL2c, both of which localize to the endoplasmic reticulum (ER) but with SPPL2c being expressed only in a very specific cell type in testis
It has been shown in cell culture and in vivo that lack of SPPL3 activity leads to an accumulation and/or decreased secretion of glycan modifying enzymes and, to hyperglycosylation of a variety of cellular glycoproteins (Figure 8B)
Summary
Proteolysis is a non-reversible post-translational protein modification and can regulate the function of a protein by contributing to either its maturation and activation, or its degradation. The enzymes responsible for proteolysis, the proteases, play a crucial role in regulating key cellular processes, including molecular signaling both within the cell and from cell-to-cell
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