Synergistic induction of cancer cell migration regulated by Gbetagamma and phosphatidylinositol 3-kinase.
- Author:
Eun Kyoung KIM
1
;
Sung Ji YUN
;
Jung Min HA
;
Young Whan KIM
;
In Hye JIN
;
Dae Han WOO
;
Hye Sun LEE
;
Hong Koo HA
;
Sun Sik BAE
Author Information
1. MRC for Ischemic Tissue Regeneration, Medical Research Institute, Department of Pharmacology, Pusan National University, Yangsan 626-870, Korea. sunsik@pusan.ac.kr
- Publication Type:Original Article ; Research Support, Non-U.S. Gov't
- Keywords:
cell movement;
GTP-binding protein beta subunits;
GTP-binding protein gamma subunits;
phosphatidylinositol 3-kinase;
P-Rex1 protein;
receptor protein-tyrosine kinases;
receptors, G-protein-coupled
- MeSH:
Cell Line, Tumor;
*Cell Movement/drug effects;
Enzyme Activation/drug effects;
GTP-Binding Protein beta Subunits/*metabolism;
GTP-Binding Protein gamma Subunits/*metabolism;
Guanine Nucleotide Exchange Factors/metabolism;
Humans;
Lysophospholipids/pharmacology;
Neoplasms/enzymology/*metabolism;
Phosphatidylinositol 3-Kinases/*metabolism;
Proto-Oncogene Proteins c-akt/metabolism;
Receptors, G-Protein-Coupled/metabolism;
Signal Transduction
- From:Experimental & Molecular Medicine
2012;44(8):483-491
- CountryRepublic of Korea
- Language:English
-
Abstract:
Phosphatidylinositol 3-kinase (PI3K) is essential for both G protein-coupled receptor (GPCR)- and receptor tyrosine kinase (RTK)-mediated cancer cell migration. Here, we have shown that maximum migration is achieved by full activation of phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 1 (P-Rex1) in the presence of Gbetagamma and PI3K signaling pathways. Lysophosphatidic acid (LPA)-induced migration was higher than that of epidermal growth factor (EGF)-induced migration; however, LPA-induced activation of Akt was lower than that stimulated by EGF. LPA-induced migration was partially blocked by either Gbetagamma or RTK inhibitor and completely blocked by both inhibitors. LPA-induced migration was synergistically increased in the presence of EGF and vice versa. In correlation with these results, sphingosine-1-phosphate (S1P)-induced migration was also synergistically induced in the presence of insulin-like growth factor-1 (IGF-1). Finally, silencing of P-Rex1 abolished the synergism in migration as well as in Rac activation. Moreover, synergistic activation of MMP-2 and cancer cell invasion was attenuated by silencing of P-Rex1. Given these results, we suggest that P-Rex1 requires both Gbetagamma and PI3K signaling pathways for synergistic activation of Rac, thereby inducing maximum cancer cell migration and invasion.
