Ceramide 1-phosphate (C1P) promotes cell migration Involvement of a specific C1P receptor

Ceramide I-phosphate (C1P) is a bioactive sphingolipid that is implicated in the regulation of cell homeostasis and the control of inflammation. It is mitogenic for fibroblasts and macrophages, and has been described as potent inhibitor of apoptosis, Using RAW 264.7 macrophages we have now discovered a new biological activity of Cl P: stimulation of cell migration. This novel action can only be observed when Cl P is applied exogenously to the cells in culture, and not by increasing the intracellular levels of C1P. This fact led to identify a specific receptor through which Cl P stimulates cell migration. The receptor is coupled to G(i) proteins and causes phosphorylation of extracellularly regulated kinases 1 and 2. and protein kinase B (also known as Akt) upon ligation with C1P. Inhibition of either of these pathways completely abolished Cl P-stimulated macrophage migration. In addition, Cl P stimulated the DNA binding activity of nuclear factor kappa B, and blockade of this transcription factor resulted in complete inhibition of macrophage migration. This newly identified receptor could be an important drug target for treatment of illnesses that are associated to inflammatory processes, or to diseases in which cell migration is a major cause of pathology, as it occurs in metastatic tumors. (c) 2008 Elsevier Inc. All rights reserved.