A functional interaction between liprin-α1 and B56γ regulatory subunit of protein phosphatase 2A supports tumor cell motility

Scaffold liprin-alpha 1 is required to assemble dynamic plasma membrane-associated platforms (PMAPs) at the front of migrating breast cancer cells, to promote protrusion and invasion. We show that the N-terminal region of liprin-alpha 1 contains an LxxIxE motif interacting with B56 regulatory subunits of serine/threonine protein phosphatase 2A (PP2A). The specific interaction of B56 gamma with liprin-alpha 1 requires an intact motif, since two point mutations strongly reduce the interaction. B56 gamma mediates the interaction of liprin-alpha 1 with the heterotrimeric PP2A holoenzyme. Most B56 gamma protein is recovered in the cytosolic fraction of invasive MDA-MB-231 breast cancer cells, where B56 gamma is complexed with liprin-alpha 1. While mutation of the short linear motif (SLiM) does not affect localization of liprin-alpha 1 to PMAPs, localization of B56 gamma at these sites specifically requires liprin-alpha 1. Silencing of B56 gamma or liprin-alpha 1 inhibits to similar extent cell spreading on extracellular matrix, invasion, motility and lamellipodia dynamics in migrating MDA-MB-231 cells, suggesting that B56 gamma/PP2A is a novel component of the PMAPs machinery regulating tumor cell motility. In this direction, inhibition of cell spreading by silencing liprin-alpha 1 is not rescued by expression of B56 gamma binding-defective liprin-alpha 1 mutant. We propose that liprin-alpha 1-mediated recruitment of PP2A via B56 gamma regulates cell motility by controlling protrusion in migrating MDA-MB-231 cells.Liprin-alpha 1 interacts with and recruits B56 gamma-PP2A at the front of migrating breast cancer cells, to promote cell protrusion and motility.