Abstract
Cell migration requires dynamic remodeling of the actomyosin network. We report here that an adapter protein, ArgBP2, is a component of α-actinin containing stress fibers and inhibits migration. ArgBP2 is undetectable in many commonly studied cancer-derived cell lines. COS-7 and HeLa cells express ArgBP2 (by Western analysis), but expression was detectable only in approximately half the cells by immunofluorescence. Short term clonal analysis demonstrated 0.2-0.3% of cells switch ArgBP2 expression (on or off) per cell division. ArgBP2 can have a fundamental impact on the actomyosin network: ArgBP2 positive COS-7 cells, for example, are clearly distinguishable by their denser actomyosin (stress fiber) network. ArgBP2γ binding to α-actinin appears to underlie its ability to localize to stress fibers and decrease cell migration. We map a small α-actinin binding region in ArgBP2 (residues 192-228) that is essential for these effects. Protein kinase A phosphorylation of ArgBP2γ at neighboring Ser-259 and consequent 14-3-3 binding blocks its interaction with α-actinin. ArgBP2 is known to be down-regulated in some aggressively metastatic cancers. Our work provides a biochemical explanation for the anti-migratory effect of ArgBP2.
Highlights
Arg kinase-binding pprotein 2 (ArgBP2) is a cytoskeletal adaptor protein down-regulated in tumors
Because ArgBP2 is localized to these structures and may be regulated by phosphorylation mediated 14-3-3 binding, we wanted to test if ArgBP2 might play a role in regulating the actomyosin network
The epigenetic regulation of ArgBP2 by HDAC7 was demonstrated [20] that may underlie our observation here. Given this natural heterogeneity in ArgBP2 expression, we focused on COS-7 and HeLa cells to assay differences in cell behavior based on the presence or absence of detectable ArgBP2
Summary
ArgBP2 is a cytoskeletal adaptor protein down-regulated in tumors. Results: ArgBP2 binds to ␣-actinin through a conserved protein domain. Conclusion: ArgBP2 inhibits cell migration via its interaction with ␣-actinin, which links it to the actomyosin network; this is negatively regulated by PKA. Arg kinase-binding pprotein 2 (ArgBP2) is an adapter protein that can localize to both focal adhesions and actomyosin filaments [3] and has recently emerged as a potential tumor suppressor capable of blocking cancer metastasis [4]. A novel highly conserved region of ArgBP2 found in the N-terminal half of the protein is necessary and sufficient for its localization to the enlarged puncta along actin stress fibers. This domain was required for ArgBP2 interaction with ␣-actinin. We propose a model for the ArgBP2-mediated inhibition of cell migration by increased cross-linking of the actomyosin network
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