1. Activation of p21-activated kinase 1 is required for lysophosphatidic acid-induced focal adhesion kinase phosphorylation and cell motility in human melanoma A2058 cells
- Author
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Dong-Wan Seo, Hoi Young Lee, Chang Gyo Park, Jeung Whan Han, Yong Kee Kim, Hyang Woo Lee, Jangsoon Lee, In Duk Jung, Kyung Bok Lee, and Dongeun Park
- Subjects
rac1 GTP-Binding Protein ,Mitogen-activated protein kinase kinase ,GTP-Binding Protein alpha Subunits, Gi-Go ,Protein Serine-Threonine Kinases ,Transfection ,Biochemistry ,MAP2K7 ,Phosphatidylinositol 3-Kinases ,Cell Movement ,Cell Line, Tumor ,Class Ib Phosphatidylinositol 3-Kinase ,Humans ,ASK1 ,Phosphorylation ,cdc42 GTP-Binding Protein ,Melanoma ,Focal Adhesions ,biology ,MAP kinase kinase kinase ,Cyclin-dependent kinase 4 ,Chemistry ,Cyclin-dependent kinase 5 ,Cyclin-dependent kinase 2 ,Protein-Tyrosine Kinases ,Cell biology ,Enzyme Activation ,Isoenzymes ,p21-Activated Kinases ,Focal Adhesion Kinase 1 ,Focal Adhesion Protein-Tyrosine Kinases ,biology.protein ,lipids (amino acids, peptides, and proteins) ,Cyclin-dependent kinase 9 ,biological phenomena, cell phenomena, and immunity ,Lysophospholipids ,Signal Transduction - Abstract
Lysophosphatidic acid (LPA), one of the naturally occurring phospholipids, stimulates cell motility through the activation of Rho family members, but the signaling mechanisms remain to be elucidated. In the present study, we investigated the roles of p21-activated kinase 1 (PAK1) on LPA-induced focal adhesion kinase (FAK) phosphorylation and cell motility. Treatment of human melanoma cells A2058 with LPA increased phosphorylation and activation of PAK1, which was blocked by treatment with pertussis toxin and by inhibition of phosphoinositide 3-kinase (PI3K) with an inhibitor LY294002 or by overexpression of catalytically inactive mutant of PI3Kgamma, indicating that LPA-induced PAK1 activation was mediated via a Gi protein and the PI3Kgamma signaling pathway. In addition, we demonstrated that Rac1/Cdc42 signals acted as upstream effector molecules of LPA-induced PAK activation. However, Rho-associated kinase, MAP kinase kinase 1/2 or phospholipase C might not be involved in LPA-induced PAK1 activation or cell motility stimulation. Furthermore, PAK1 was necessary for FAK phosphorylation by LPA, which might cause cell migration, as transfection of the kinase deficient mutant of PAK1 or PAK auto-inhibitory domain significantly abrogated LPA-induced FAK phosphorylation. Taken together, these findings strongly indicated that PAK1 activation was necessary for LPA-induced cell motility and FAK phosphorylation that might be mediated by sequential activation of Gi protein, PI3Kgamma and Rac1/Cdc42.
- Published
- 2004