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 S1P2
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.