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Vol. 20, Issue 24, 5156-5165, December 15, 2009

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Role of Rap1B and Tumor Suppressor PTEN in the Negative Regulation of Lysophosphatidic Acid—induced Migration by Isoproterenol in Glioma Cells

Enkhzol Malchinkhuu^*,, Koichi Sato^*,, Tomohiko Maehama, Shogo Ishiuchi, Yuhei Yoshimoto, Chihiro Mogi^*, Takao Kimura^*, Hitoshi Kurose^||, Hideaki Tomura^*, and Fumikazu Okajima^*

*Laboratory of Signal Transduction, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi 371-8512, Japan; Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, Tokyo 162-8640, Japan; Department of Neurosurgery, Gunma University Graduate School of Medicine, Maebashi 371-8511, Japan; and ^||Department of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan

Submitted August 14, 2009; Revised October 9, 2009; Accepted October 15, 2009
Monitoring Editor: Carole Parent

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.

These authors contributed equally to this work.

Address correspondence to: Koichi Sato (kosato{at}showa.gunma-u.ac.jp).

Abbreviations used: 8CPT-2Me-cAMP, 8-(4-chlorophenylthio)-2'-O-methyladenosine 3', 5'-cyclic monophosphate; Epac, exchange protein directly activated by cAMP; G-protein, GTP-binding regulatory protein; ISO, isoproterenol; LPA, 1-oleoyl-sn-glycero-3-phosphate or lysophosphatidic acid; PI3K, phosphatidylinositol 3-kinase; PKA, cAMP-dependent protein kinase; PTEN, phosphatase and tensin homolog deleted on chromosome 10; siRNA, small interfering RNA; S1P, sphingosine 1-phosphate.