**6. Ceramide 1-phosphate and the control of cell migration**

Macrophage populations in tissues are determined by the rates of recruitment of monocytes from the bloodstream into the tissue, the rates of macrophage proliferation and apoptosis, and the rate of macrophage migration or efflux. Recently, our group demonstrated that exogenous addition of C1P to cultured Raw 264.7 macrophages stimulated cell migration (Granado et al., 2009b). Interestingly, this action could only be observed when C1P was applied to the cells exogenously, and not by increasing the intracellular levels of C1P (i.e. through agonist stimulation of CerK, or by using the ''caging" strategy to deliver C1P intracellularly (Lankalapalli et al., 2009)). This observation led us to identify a specific receptor through which C1P stimulates chemotaxis. This putative receptor seems to be located in the plasma membrane, has low affinity for C1P and has an apparent Kd of approximately 7.8 µM. The receptor is specific for C1P and is coupled to Gi proteins. Ligation of this receptor with C1P caused phosphorylation of ERK1–2, and PKB, and inhibition of either of these pathways completely abolished C1P-stimulated macrophage migration. Moreover, C1P stimulated the DNA binding activity of NF-kB, and blockade of this transcription factor resulted in full inhibition of macrophage migration. These observations suggest that MEK/ERK1-2, PI3-K/PKB (or Akt) and NF-kB are crucial signaling pathways for regulation of cell migration by C1P. It was concluded that this newly identified receptor could be an important drug target for treatment of illnesses in which cell migration is a major cause of pathology, as it occurs in atherosclerosis or in the metastasis of tumors.
