Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 279, Issue 47, Pages 49406-49413Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M408836200
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- NIGMS NIH HHS [GM49897] Funding Source: Medline
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Galpha(13), the alpha-subunit of the heterotrimeric G protein G13, has been shown to stimulate cell migration in addition to inducing oncogenic transformation. Cta, a Drosophila ortholog of G13, has been shown to be critical for cell migration leading to the ventral furrow formation in Drosophila embryos. Loss of Galpha(13) has been shown to disrupt cell migration associated with angiogenesis in developing mouse embryos. Whereas these observations point to the vital role of G13-orthologs in regulating cell migration, widely across the species barrier, the mechanism by which Galpha(13) couples to cytoskeleton and cell migration is largely unknown. Here we show that Galpha(13) physically interacts with Hax-1, a cytoskeleton-associated, cortactin-interacting intracellular protein, and this interaction is required for Galpha(13)-stimulated cell migration. Hax-1 interaction is specific to Galpha(13), and this interaction is more pronounced with the mutationally or functionally activated form of Galpha(13) as compared with the wild-type Galpha(13). Expression of Hax-1 reduces the formation of actin stress fibers and focal adhesion complexes in Galpha(13)-expressing NIH3T3 cells. Coexpression of Hax-1 also attenuates Galpha(13)-stimulated activity of Rho while potentiating Galpha(13)-stimulated activity of Rac. The presence of a quadnary complex consisting of Galpha(13), Hax-1, Rac, and cortactin indicates the role of Hax-1 in tethering Galpha(13) to the cytoskeletal component(s) involved in cell movement. Whereas the expression of Hax-1 potentiates Galpha(13)-mediated cell movement, silencing of endogenous Hax-1 with Hax-1-specific small interfering RNAs drastically reduces Galpha(13)-mediated cell migration. These findings, along with the observation that Hax-1 is overexpressed in metastatic tumors and tumor cell lines, suggest a novel role for the association of oncogenic Galpha(13) and Hax-1 in tumor metastasis.
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