title: Synergistic induction of cancer cell migration regulated by Gβγ and phosphatidylinositol 3-kinase.
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 Gβγ 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 Gβγ 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 Gβγ and PI3K signaling pathways for synergistic activation of Rac, thereby inducing maximum cancer cell migration and invasion.
authors.affiliation: MRC for Ischemic Tissue Regeneration, Medical Research Institute, Department of Pharmacology, Pusan National University, Yangsan 626-870, Korea.
authors.forename: Eun Kyoung
authors.initials: EK
authors.lastname: Kim
authors.forename: Sung Ji
authors.initials: SJ
authors.lastname: Yun
authors.forename: Jung Min
authors.initials: JM
authors.lastname: Ha
authors.forename: Young Whan
authors.initials: YW
authors.lastname: Kim
authors.forename: In Hye
authors.initials: IH
authors.lastname: Jin
authors.forename: Dae Han
authors.initials: DH
authors.lastname: Woo
authors.forename: Hye Sun
authors.initials: HS
authors.lastname: Lee
authors.forename: Hong Koo
authors.initials: HK
authors.lastname: Ha
authors.forename: Sun Sik
authors.initials: SS
authors.lastname: Bae
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D044387:GTP-Binding Protein beta Subunits / Q000378:metabolism*; D044388:GTP-Binding Protein gamma Subunits / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D006801:Humans; D008246:Lysophospholipids / Q000494:pharmacology; D009369:Neoplasms / Q000201:enzymology / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C118981:G-protein Beta gamma; D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; D020662:Guanine Nucleotide Exchange Factors; D008246:Lysophospholipids; D043562:Receptors, G-Protein-Coupled; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C032881:lysophosphatidic acid