Localization and functional relevance of cytoplasmic SPTAN1. SPTAN1 can have diverse functions in the cell depending on its localization. (a) SPTAN1 (green bars) serves as cytoskeletal scaffolding protein and, under physiological calcium levels, together with SPTBN1 (yellow bars) and other proteins, it forms a stabilizing mesh beneath the cell membrane allowing cell polarity. Shown are epithelial cells expressing SPTAN1 apically and laterally in the cell. Upon cell-cell contact (orange bars), SPTAN1 interacts with E-cadherin, ankyrin, and Na/K-ATPase and thus might influence EMT and metastasis. (b) SPTAN1 can affect tumor growth and outcome by enhancing cell proliferation and migration (upper panel), which are impaired in case of reduced SPTAN1 levels (lower panel). High levels of cytoplasmic SPTAN1 in proliferating cells could be used as marker for neoplasia. Moreover, migration might be influenced by the interaction of SPTAN1 and SPTBN1 with actin filaments. (c) SPTAN1 has also a role in survival, angiogenesis, apoptosis, and other cellular mechanisms through expression of alternative spliced forms and cleavage products. A SPTAN1 spliceform including a 20 amino acid (aa) motif contributes to gap junctions (orange dumbbells) through association of this motif with Connexin 43 (Cx43). This association is regulated by JNK-mediated phosphorylation. Expression of this spliceform is repressed during hypoxia, thus leading to a decrease in gap junctions. SPTAN1 is involved in apoptosis if cleaved by calpain and caspases. This is regulated by phosphorylation of Y1176 and dephosphorylation enhances the proteolytic susceptibility of SPTAN1 to calpain and caspases 2, 3, and 7. Cleavage leads to membrane blebbing and irreversible cell death. Caspase-mediated cleavage can be inhibited by calmodulin (CaM) binding and indicates again the influence of calcium homeostasis. SPTAN1 cleavage products can further lead to cell rounding and detachment by degrading FAK and paxillin (PXN) and can activate further yet unknown cellular mechanisms.