Keratin 8 phosphorylation regulates keratin reorganization and migration of epithelial tumor cells

Keratin 8 (K8) and Keratin 18 (K18) are the major components of intermediate filaments of simple epithelia as found in the intestine, liver and exocrine pancreas. The expression pattern of these proteins is generally persistent in carcinomas arising from tissues that normally express K8 and K18. The structure and function of keratins are very likely regulated through posttranslational modifications, particularly phosphorylation on serine residues. Previously we have shown that sphingosylphosphorylcholine (SPC), a naturally occurring bioactive lipid, can induce a perinuclear reorganization of the keratin cytoskeleton in human pancreatic cancer. This reorganization is accompanied by keratin phosphorylation, including phosphorylation at K18-S52 and K8-S431, and an increase in cellular elasticity and enhanced migration of cancer cells. Here we investigate the signaling pathways that mediate SPC-induced keratin reorganization and the role of keratin phosphorylation in this process. We can establish that the MEK-ERK signalling cascade regulates both SPC-induced keratin phosphorylation and reorganization in human pancreatic and gastric cancer cells. Furthermore, we identified Ser431 in K8 as the critical residue whose phosphorylation is required and sufficient to induce keratin reorganization and consequently enhanced migration of human epithelial tumor cells. Thus, we provide a novel mechanism how ERKs can regulate tumor cell migration and identify keratin phosphorylation as an interesting novel therapeutic target to prevent invasion and potentially metastasis.