Regulation of cellular actin dynamics is pivotal in driving cell motility. During cancer development, cells migrate to invade and spread; therefore, dysregulation of actin regulators is often associated with cancer progression. Here we report the role of ABRACL, a human homolog of the Dictyostelium actin regulator Costars, in migration and tumorigenic growth of cancer cells. We found a correlation between ABRACL expression and the migratory ability of cancer cells. Cell staining revealed the colocalization of ABRACL and F-actin signals at the leading edge of migrating cells. Analysis of the relative F-/G-actin contents in cells lacking or overexpressing ABRACL suggested that ABRACL promotes cellular actin distribution to the polymerized fraction. Physical interaction between ABRACL and cofilin was supported by immunofluorescence staining and proximity ligation. Additionally, ABRACL hindered cofilin-simulated pyrene F-actin fluorescence decay in vitro, indicating a functional interplay. Lastly, analysis on a colorectal cancer cohort demonstrated that high ABRACL expression was associated with distant metastasis, and further exploration showed that depletion of ABRACL expression in colon cancer cells resulted in reduced cell proliferation and tumorigenic growth. Together, results suggest that ABRACL modulates actin dynamics through its interaction with cofilin and thereby regulates cancer cell migration and participates in cancer pathogenesis.

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SummaryThrough analysis of a chemotaxis mutant obtained from a genetic screen in Dictyostelium discoideum, we have identified a new gene involved in regulating cell migration and have named it costars (cosA). The 82 amino acid Costars protein sequence appears highly conserved among diverse species, and significantly resembles the C-terminal region of the striated muscle activator of Rho signaling (STARS), a mammalian protein that regulates the serum response factor transcriptional activity through actin binding and Rho GTPase activation. The cosA-null (cosA -) cells formed smooth plaques on bacterial lawns, produced abnormally small fruiting bodies when developed on the non-nutrient agar and displayed reduced migration towards the cAMP source in chemotactic assays. Analysis of cell motion in cAMP gradients revealed decreased speed but wild-type-like directional persistence of cosA -cells, suggesting a defect in the cellular machinery for motility rather than for chemotactic orientation. Consistent with this notion, cosA -cells exhibited changes in the actin cytoskeleton, showing aberrant distribution of F-actin in fluorescence cell staining and an increased amount of cytoskeletonassociated actin. Excessive pseudopod formation was also noted in cosA -cells facing chemoattractant gradients. Expressing cosA or its human counterpart mCostars eliminated abnormalities of cosA -cells. Together, our results highlight a role for Costars in modulating actin dynamics and cell motility.

Dictyostelium cells lacking actin-binding protein G (AbpG) migrate at a reduced speed and display elevated F-actin levels. AbpG is enriched in the cortical/lamellipodial regions and colocalizes with F-actin. A novel protein domain in AbpG mediates the interaction with F-actin and is required for the cellular function of AbpG.