ABSTRACT
The sphingolipids, sphingosine 1-phosphate (S1P) and sphingosylphosphorylcholine (SPC), can induce or inhibit cellular migration. The intermediate filament protein vimentin is an inducer of migration and a marker for epithelial-mesenchymal transition. Given that keratin intermediate filaments are regulated by SPC, with consequences for cell motility, we wanted to determine whether vimentin is also regulated by sphingolipid signalling and whether it is a determinant for sphingolipid-mediated functions. In cancer cells where S1P and SPC inhibited migration, we observed that S1P and SPC induced phosphorylation of vimentin on S71, leading to a corresponding reorganization of vimentin filaments. These effects were sphingolipid-signalling-dependent, because inhibition of either the S1P2 receptor (also known as S1PR2) or its downstream effector Rho-associated kinase (ROCK, for which there are two isoforms ROCK1 and ROCK2) nullified the sphingolipid-induced effects on vimentin organization and S71 phosphorylation. Furthermore, the anti-migratory effect of S1P and SPC could be prevented by expressing S71-phosphorylation-deficient vimentin. In addition, we demonstrated, by using wild-type and vimentin-knockout mouse embryonic fibroblasts, that the sphingolipid-mediated inhibition of migration is dependent on vimentin. These results imply that this newly discovered sphingolipid-vimentin signalling axis exerts brake-and-throttle functions in the regulation of cell migration.
Subject(s)
Cell Movement/physiology , Sphingolipids/metabolism , Vimentin/metabolism , Animals , Cell Line , Cell Line, Tumor , Fibroblasts/metabolism , Humans , Lysophospholipids/metabolism , Mice , Phosphorylation/physiology , Phosphorylcholine/analogs & derivatives , Phosphorylcholine/metabolism , Receptors, Lysosphingolipid/metabolism , Signal Transduction/physiology , Sphingosine/analogs & derivatives , Sphingosine/metabolism , Sphingosine-1-Phosphate Receptors , rho-Associated Kinases/metabolismABSTRACT
Intermediate filament (IF) proteins comprise a large family with more than 70 members. Initially, IFs were assumed to provide only structural reinforcement for the cell. However, IFs are now known to be dynamic structures that are involved in a wide range of cellular processes during all stages of life, from development to ageing, and during homeostasis and stress. This Commentary discusses some lesser-known functional and regulatory aspects of IFs. We specifically address the emerging roles of nestin in myogenesis and cancer cell migration, and examine exciting evidence on the regulation of nestin and lamin A by the notch signalling pathway, which could have repercussions for our understanding of the roles of IF proteins in development and ageing. In addition, we discuss the modulation of the post-translational modifications of neuronally expressed IFs and their protein-protein interactions, as well as IF glycosylation, which not only has a role in stress and ageing, but might also regulate IFs during development. Although many of these recent findings are still preliminary, they nevertheless open new doors to explore the functionality of the IF family of proteins.