TY - JOUR
T1 - Role of Rap1B and tumor suppressor PTEN in the negative regulation of lysophosphatidic acid - Induced migration by isoproterenol in glioma cells
AU - Malchinkhuu, Enkhzol
AU - Sato, Koichi
AU - Maehama, Tomohiko
AU - Ishiuchi, Shogo
AU - Yoshimoto, Yuhei
AU - Mogi, Chihiro
AU - Kimura, Takao
AU - Kurose, Hitoshi
AU - Tomura, Hideaki
AU - Okajima, Fumikazu
PY - 2009
Y1 - 2009
N2 - The clarification of mechanisms that negatively regulate the invasive behavior of human glioma cells is of great importance in order to find new methods of treatment. In this study, we have focused on the negative regulation of lysophosphatidic acid (LPA)-induced migration in glioma cells. Using small interference RNA and dominant-negative gene strategies in addition to pharmacological tools, we found that isoproterenol (ISO) and sphingosine-1-phosphate (S1P) negatively but differently regulate the LPA-induced migration. ISO-induced suppression of the migration of glioma cells occurs via β2-adrenergic receptor/cAMP/Epac/Rap1B/inhibition of Rac, whereas S1P has been shown to suppress the migration of the cells through S1P2 receptor/Rho-mediated down-regulation of Rac1. The expression of tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is required for the inhibitory ISO-induced and Rap1B-mediated actions on the migration, Rac1 activation, and Akt activation in response to LPA. Thus, the PTEN-mediated down-regulation of phosphatidylinositol 3-kinase activity may be involved in the regulation of Rap1B-dependent inhibition of Rac1 activity. These findings suggest that there are at least two distinct inhibitory pathways, which are mediated by the S1P2 receptor and β2- adrenergic receptor, to control the migratory, hence invasive, behavior of glioma cells.
AB - The clarification of mechanisms that negatively regulate the invasive behavior of human glioma cells is of great importance in order to find new methods of treatment. In this study, we have focused on the negative regulation of lysophosphatidic acid (LPA)-induced migration in glioma cells. Using small interference RNA and dominant-negative gene strategies in addition to pharmacological tools, we found that isoproterenol (ISO) and sphingosine-1-phosphate (S1P) negatively but differently regulate the LPA-induced migration. ISO-induced suppression of the migration of glioma cells occurs via β2-adrenergic receptor/cAMP/Epac/Rap1B/inhibition of Rac, whereas S1P has been shown to suppress the migration of the cells through S1P2 receptor/Rho-mediated down-regulation of Rac1. The expression of tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is required for the inhibitory ISO-induced and Rap1B-mediated actions on the migration, Rac1 activation, and Akt activation in response to LPA. Thus, the PTEN-mediated down-regulation of phosphatidylinositol 3-kinase activity may be involved in the regulation of Rap1B-dependent inhibition of Rac1 activity. These findings suggest that there are at least two distinct inhibitory pathways, which are mediated by the S1P2 receptor and β2- adrenergic receptor, to control the migratory, hence invasive, behavior of glioma cells.
UR - http://www.scopus.com/inward/record.url?scp=73849133645&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=73849133645&partnerID=8YFLogxK
U2 - 10.1091/mbc.E09-08-0692
DO - 10.1091/mbc.E09-08-0692
M3 - Article
C2 - 19864456
AN - SCOPUS:73849133645
SN - 1059-1524
VL - 20
SP - 5156
EP - 5165
JO - Molecular Biology of the Cell
JF - Molecular Biology of the Cell
IS - 24
ER -