Competition between pro- and anti-endocytic proteins steers cell movement by polarizing the activity of guidance cue receptors, say Quinones et al.
During Drosophila oogenesis, a cluster of border cells migrates across the flies' egg chamber toward the oocyte. This movement is guided by EGF and PDGF, which primarily activate their receptors at the border cells' leading edges. Quinones et al. found that this localized signaling and directional movement is disrupted in border cells lacking the protein missing-in-metastasis (MIM).
MIM is part of the BAR protein family, whose members normally promote endocytosis by linking membrane curvature to changes in the actin cytoskeleton. But Quinones et al. found that EGF receptor internalization was increased in the absence of MIM suggesting that, unlike its relatives, MIM inhibits endocytosis. MIM competed with the pro-endocytic BAR protein endophilin for binding to the actin-polymerizing factor cortactin. Cortactin drives endocytosis when bound to endophilin, and mutations in the protein also disrupt border cell migration. But cells lacking both cortactin and MIM migrated properly. Normal EGF receptor endocytosis was also restored, suggesting that the balance of pro- and anti-endocytic factors is critical for localizing signaling activity and guiding cell migration.
Other cell types also lost their bearings in the absence of Drosophila MIM. These cells all respond to different cues, so competition between MIM and other BAR proteins may be a general mechanism by which cells steer to their destinations. The authors now want to investigate how MIM affects the migration of cancer cells, because the protein is missing or up-regulated in a variety of human tumors.