The Rockefeller University Press

Directed cell movement is instrumental for organismal devel-opment, immune responses, and the progression of diseases, such as cancer (Gardel et al., 2010). To achieve directed move-ment, an individual cell must establish front-to-back polarity, where there is coordinated protrusion of its front and retraction of its back (Fig. 1 A; Vicente-Manzanares et al., 2007). How polymerizing actin filaments drive protrusion of the front is un-derstood in exquisite detail (Pollard and Borisy, 2003; Pollard, 2007). The mechanisms defining how actin filament contraction defines the back of the cell (Yam et al., 2007) have been more difficult to elucidate. Contraction of actin filaments in crawl-ing cells is driven by nonmuscle myosin II (NMII; Vicente-Manzanares et al., 2009). NMII has three isoforms, NMII-A, NMII-B, and NMII-C, all of which can bind and contract actin filaments to generate force. Importantly, NMII-A and NMII-B have different cellular localizations, which could drive their functions (Kolega, 1998; Vicente-Manzanares et al., 2007). NMII-A localizes primarily to the front, protrusive edge and is required for adhesion maturation. In contrast, NMII-B local-izes behind NMII-A, primarily to large and stable actin stress fibers in the middle and back of the cell (Kolega, 1998; Vicente-Manzanares et al., 2007). NMII-B is required for front-to-back polarity, as cells lacking NMII-B lose large stress fibers and fail to define their rear (Vicente-Manzanares et al., 2007). The major question of what drives the polarized localization of NMII-B is unknown. In this issue, Juanes-Garcia et al. report that a short serine-rich motif in NMII-B is responsible for both its localiza-tion and the establishment of front-to-back cellular polarity. Though NMII-A and NMII-B are genetically and struc-turally very similar, Juanes-Garcia et al. (2015) identified a serine-rich sequence (SFSSSRS) in the C terminus of NMII-B (Fig. 1 B). The authors effectively used cells depleted of NMII-B A migrating cell must establish front-to-back polarity in order to move. In this issue, Juanes-Garcia et al. (2015. J. Cell Biol