Role of Signalpeptide Peptidase-like 3 (SPPL3) in cell growth, adhesion and migration

• Applicant: Professorin Dr. Regina Fluhrer
• Subject Area: Cell Biology ; Biochemistry
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 580021555

Deregulation in cell adhesion, migration and proliferation can affect wound healing, cancer development and metastasis as well as the development of many immunological phenotypes. However, the detailed mechanisms and signaling cascades that control these processes as well as the potentials of targeted manipulations are, so far, not fully understood. Signalpeptide Peptidase-like 3 (SPPL3), an intramembrane aspartyl protease, was shown to cleave a variety of enzymes implicated in modification of N- and O-linked glycans as well as in glycosaminoglycan biosynthesis. By adapting the expression level of SPPL3 a cell can rapidly change the glycan pattern of many proteins and lipids within the secretory pathway and the plasma membrane. Such changes in glycan patterns have been associated with inhibited immune recognition of tumor cells, cancer development and metastasis but also in context of other migration-dependent processes like wound-healing. Preliminary data suggest that cells with exogenous SPPL3 expression comprise reduced cell proliferation speed but increased migratory capacity. In addition, proteomic data from SPPL3 knock out and overexpressing cells suggest SPPL3-dependent regulation of candidate proteins involved in cell proliferation, adhesion, migration, and dynamics of the cytoskeleton. Based on that we will address the question how SPPL3 can affect the migration and proliferation behavior of cells and whether this has potential pathological impact. In particular, we will test the following hypotheses:• SPPL3 affects cell migration speed via changes in integrin glycosylation. • SPPL3 affects cell migration speed by direct cleavage of novel substrates. • SPPL3 affects cell proliferation by changes in the glycome and/or by direct cleavage of unknown substrates. • Changes in SPPL3 expression affect migration, proliferation and invasion behavior of cancer cell lines Understanding the role of SPPL3 in regulating these important cellular processes will not only enlarge our basic knowledge on how cell growth, migration and interplay with immune cells are controlled but will also disclose the role of SPPL3 in, for instance, metastasizing cancers or defective wound healing, turning this protease into a potential target for treatment.

• DFG Programme: Research Grants