84 日本生理学会 2007年3月20日〜22日(大阪

Sphingosine 1-phosphate (S1P)-induced inhibition of cell migration and Rac is independent of S1P-induced stimulation of PTEN

Naotoshi Sugimoto, Noriko Takuwa, Wa Du, Yoh Takuwa
Dept. Physiol., Grad. Med., Kanazawa Univ.

ABSTRACT
S1P is a bioactive lysophospholipid that induces a variety of biological responses in diverse cell types. We previously showed that S1P
2 receptor activates Rho, which in turn induces inhibition of Rac and cell migration in S1P2-expressing CHO cells. Phosphoinositide 3-kinases (PI3Ks) produce 3’-phosphoinositides (3’-PIs) including PI(3,4,5)P3 and PI(3,4)P2, whereas PTEN dephosphorylates 3’-PIs to decrease the contents of PI(3,4,5)P3 and PI(3,4)P2. Elevation of PI(3,4,5)P3 and PI(3,4)P2 contents induces activation of PDK1 and Akt, leading to stimulation of cell migration and cell survival. Recently, it has been shown that Rho and Rho-kinase stimulates PTEN, which mediates inhibition of Akt and cell migration in ??? and ??? cells. These observations led us to investigate the role of PTEN in S1P2-mediated inhibition of cell migration and Rac. IGF I stimulated Akt and chemotaxis in the PI3K inhibitor-sensitive manner. Interestingly, S1P partially inhibited IGF I-induced Akt activation and completely inhibited IGF I-induced chemotaxis and Rac activation in S1P2 overexpressing CHO cells. Either the dominant negative mutant of PTEN, the PTEN-specific siRNA or the Rho-kinase inhibitor Y27632 prevented S1P-inhibition of Akt activity, indicating that Rho kinase-PTEN mediates inhibition of Akt. However, either of these treatments failed to abrogate S1P-inhibition of chemotaxis and Rac. These data indicate that S1P2-mediated inhibition of either Rac or migration is not dependent on the tumor suppressor PTEN in these three cell types.