title: Keratin 8 phosphorylation regulates keratin reorganization and migration of epithelial tumor cells.
abstract: Cell migration and invasion are largely dependent on the complex organization of the various cytoskeletal components. Whereas the role of actin filaments and microtubules in cell motility is well established, the role of intermediate filaments in this process is incompletely understood. Organization and structure of the keratin cytoskeleton, which consists of heteropolymers of at least one type 1 and one type 2 intermediate filament, are in part regulated by post-translational modifications. In particular, phosphorylation events influence the properties of the keratin network. Sphingosylphosphorylcholine (SPC) is a bioactive lipid with the exceptional ability to change the organization of the keratin cytoskeleton, leading to reorganization of keratin filaments, increased elasticity, and subsequently increased migration of epithelial tumor cells. Here we investigate the signaling pathways that mediate SPC-induced keratin reorganization and the role of keratin phosphorylation in this process. We establish that the MEK-ERK signaling cascade regulates both SPC-induced keratin phosphorylation and reorganization in human pancreatic and gastric cancer cells and identify Ser431 in keratin 8 as the crucial residue whose phosphorylation is required and sufficient to induce keratin reorganization and consequently enhanced migration of human epithelial tumor cells.
authors.affiliation: Department of Internal Medicine I, University of Ulm, Ulm, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Busch
authors.forename: Milena
authors.initials: M
authors.lastname: Armacki
authors.forename: Tim
authors.initials: T
authors.lastname: Eiseler
authors.forename: Golsa
authors.initials: G
authors.lastname: Joodi
authors.forename: Claudia
authors.initials: C
authors.lastname: Temme
authors.forename: Julia
authors.initials: J
authors.lastname: Jansen
authors.forename: Götz
authors.initials: G
authors.lastname: von Wichert
authors.forename: M Bishr
authors.initials: MB
authors.lastname: Omary
authors.forename: Joachim
authors.initials: J
authors.lastname: Spatz
authors.forename: Thomas
authors.initials: T
authors.lastname: Seufferlein
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects* / Q000235:genetics; D003599:Cytoskeleton / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007382:Intermediate Filaments / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D053533:Keratin-8 / Q000235:genetics / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D010767:Phosphorylcholine / Q000031:analogs & derivatives / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology; D013274:Stomach Neoplasms / Q000378:metabolism / Q000473:pathology
chemical_list: D053533:Keratin-8; D047428:Protein Kinase Inhibitors; C005356:sphingosine phosphorylcholine; D010767:Phosphorylcholine; D012694:Serine; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases; D013110:Sphingosine