title: LPA-mediated migration of ovarian cancer cells involves translocalization of Gαi2 to invadopodia and association with Src and β-pix.
abstract: Lysophosphatidic acid (LPA) plays a critical role in the migration and invasion of ovarian cancer cells. However, the downstream spatiotemporal signaling events involving specific G protein(s) underlying this process are largely unknown. In this report, we demonstrate that LPA signaling causes the translocation of Gαi2 into the invadopodia leading to its interaction with the tyrosine kinase Src and the Rac/CDC42-specific guanine nucleotide exchange factor, β-pix. Our results establish that Gαi2 activates Rac1 through a p130Cas-dependent pathway in ovarian cancer cells. Moreover, our report reveals that knockdown of Gαi2 leads to loss of β-pix and active-Rac association in the invadopodia. We also show that knockdown of Gαi2 leads to the complete loss of translocation to p130Cas to focal adhesions. Finally, when Gαi2 is knocked down, this led to the total distribution of Src being shifted primarily from invadopodia and the leading edge of the cells to the perinuclear region, suggesting that Src is inactive in the absence of Gαi2. Overall, our report provides tantalizing evidence that Gαi2 is a critical signaling component of a large signaling complex in the invadopodia that if disrupted could serve as an excellent target for therapy in ovarian and potentially other cancers.
authors.affiliation: Stephenson Cancer Center, Department of Cell Biology, The University of Oklahoma Health Sciences Center, 975 NE 10th Street, Oklahoma City, OK 73104, USA.
authors.forename: Jeremy D
authors.initials: JD
authors.lastname: Ward
authors.affiliation: Stephenson Cancer Center, Department of Cell Biology, The University of Oklahoma Health Sciences Center, 975 NE 10th Street, Oklahoma City, OK 73104, USA.
authors.forename: Ji Hee
authors.initials: JH
authors.lastname: Ha
authors.affiliation: Stephenson Cancer Center, Department of Cell Biology, The University of Oklahoma Health Sciences Center, 975 NE 10th Street, Oklahoma City, OK 73104, USA.
authors.forename: Muralidharan
authors.initials: M
authors.lastname: Jayaraman
authors.affiliation: Stephenson Cancer Center, Department of Cell Biology, The University of Oklahoma Health Sciences Center, 975 NE 10th Street, Oklahoma City, OK 73104, USA. Electronic address: danny-dhanasekaran@ouhsc.edu.
authors.forename: Danny N
authors.initials: DN
authors.lastname: Dhanasekaran
mesh_terms: D015153:Blotting, Western; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D022081:Cell Surface Extensions / Q000187:drug effects*; D005260:Female; D022001:Focal Adhesions / Q000187:drug effects; D051960:GTP-Binding Protein alpha Subunit, Gi2 / Q000378:metabolism*; D006801:Humans; D008246:Lysophospholipids / Q000494:pharmacology*; D009361:Neoplasm Invasiveness; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D021381:Protein Transport / Q000187:drug effects*; D064067:Rho Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: C576606:ARHGEF7 protein, human; D008246:Lysophospholipids; D064067:Rho Guanine Nucleotide Exchange Factors; D019061:src-Family Kinases; D051960:GTP-Binding Protein alpha Subunit, Gi2; C032881:lysophosphatidic acid
keywords: Cell migration; G protein; Gα(i2); LPA; Ovarian cancer; Src