Rho, but not Rho kinase, mediates inhibition of IGF I-induced Rac activation and chemotaxis by the G protein-coupled receptor EDG5

Abstract

Sphingosine-1-phosphate (S1P) is a bioactive lysophospholipid that induces a variety of biological responses in diverse cell types. Many of these responses are mediated by S1P receptors, S1P₁/EDG1, S1P₃/EDG3, and S1P₂/EDG5. We previously showed that S1P₂/EDG5, via G₁₂ and G₁₃ proteins, mediated inhibiton of insulin-like growth factor-I (IGF-I)-induced Rac activation and cell migration, whereas S1P₁/EDG1 and S1P₃/EDG3 each alone, via G_i protein, mediated Rac activation and stimulation of cell migration. However, it is not known how G₁₂and G₁₃ proteins mediate inhibition of Rac and cell migration in S1P₂/EDG5 signaling. We found that the pretreatment with C3 toxin, which inactivates Rho, and the expresson of dominat negative Rho A prevented S1P₂/EDG5-mediated inhibition of Rac and cell migration. On other hand, the expression of constitutively active Rho inhibited IGF-I induced Rac activation and cell migration. However, Rho kinase inhibitors did not affect S1P₂/EDG5-mediated inhibition of Rac or cell migration. These results indicate that Rho, but not Rho kinase, mediates inhibition of Rac activity and cell mobility on stimulation of S1P₂/EDG5. [Jpn J Physiol 54 Suppl:S77 (2004)]