Toxins affecting cell signalling and alteration of cytoskeletal structure

Many natural toxins act by modifying key functions of the phosphorylation-based signalling machinery. Microcystins comprise a good example of highly specific, signalling-targeted toxicants. These liver-specific cyanobacterial peptide toxins act as potent inhibitors of serine/threonine (ser/thr) protein phosphatases, in particular type-1 (PP1) and type-2A (PP2A). PP1 and PP2A regulate the phosphorylation of a large number of key elements in various signalling processes. Furthermore, they are crucial in maintaining cytoskeletal integrity. Consequently, microcystins disrupt the liver structure by abrogating cytoskeletal regulation. Microcystin-induced protein phosphatase inhibition in liver cells leads to rapid reorganization of all three major cytoskeletal components, microfilaments, microtubules and intermediate filaments (IFs). The inhibited dephosphorylation induces an especially marked phosphorylation of the liver IF proteins, keratins 8 and 18. The elevated phosphorylation of these proteins causes disassembly and reorganization of keratin filaments, indicating that their assembly state in vivo is regulated by a continuous phosphate turnover. In this review on microcystin-induced cellular effects, we attempt to illustrate the potentially grave consequences when phosphorylation processes are disturbed by toxicants. The aim is also to show how such signalling-targeted toxicants can be used as biochemical tools to establish the biological roles of specific signalling or regulatory processes.