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KMID : 0620920120440080483
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Experimental & Molecular Medicine
2012 Volume.44 No. 8 p.483 ~ p.491
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Synergistic induction of cancer cell migration regulated by Gβγ and phosphatidylinositol 3-kinase
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Kim Eun-Kyoung
Yun Sung-Ji
Ha Jung-Min
Kim Young-Whan
Jin In-Hye
Woo Dae-Han
Lee Hye-Sun
Ha Hong-Koo
Bae Sun-Sik
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Abstract
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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.
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KEYWORD
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cell movement, GTP-binding protein β subunits, GTP-binding protein γ subunits, phosphatidylinositol 3-kinase, P-Rex1 protein, receptor protein-tyrosine kinases, receptors, G-protein-coupled
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