Dynamic relocalization of NHERF1 mediates chemotactic migration of ovarian cancer cells toward lysophosphatidic acid stimulation

NHERF1/EBP50 (Na+/H+ exchanger regulating factor 1; Ezrin-binding phosphoprotein of 50 kDa) organizes stable protein complexes beneath the apical membrane of polar epithelial cells. By contrast, in cancer cells without any fixed polarity, NHERF1 often localizes in the cytoplasm. The regulation of cytoplasmic NHERF1 and its role in cancer progression remain unclear. In this study, we found that, upon lysophosphatidic acid (LPA) stimulation, cytoplasmic NHERF1 rapidly translocated to the plasma membrane, and subsequently to cortical protrusion structures, of ovarian cancer cells. This movement depended on direct binding of NHERF1 to C-terminally phosphorylated ERM proteins (cpERMs). Moreover, NHERF1 depletion downregulated cpERMs and further impaired cpERM-dependent remodeling of the cell cortex, suggesting reciprocal regulation between these proteins. The LPA-induced protein complex was highly enriched in migratory pseudopodia, whose formation was impaired by overexpression of NHERF1 truncation mutants. Consistent with this, NHERF1 depletion in various types of cancer cells abolished chemotactic cell migration toward a LPA gradient. Taken together, our findings suggest that the high dynamics of cytosolic NHERF1 provide cancer cells with a means of controlling chemotactic migration. This capacity is likely to be essential for ovarian cancer progression in tumor microenvironments containing LPA. Movement of a protein from the cell cytoplasm to the cell membrane may be linked to the progression of ovarian cancer. The finding comes from researchers in South Korea led by Yong-Seok Oh at DGIST and Pann-Ghill Suh at UNIST. The protein concerned is a "scaffolding protein" that allows other proteins to combine and change cell behavior. Its activity was observed in cultured ovary cancer cells exposed to lysophosphatidic acid (LPA), a signaling molecule associated with poor prognosis of the disease especially in cases with extensive metastasis. LPA exposure stimulated events that transported the protein to the cell membrane, where it became involved in changes allowing the cells to migrate toward regions of higher LPA concentration. This suggests molecular dynamics of the protein may control cell migration in the spread of ovarian cancer.