The plasma membrane is generally associated with underling actin cytoskeleton. When the plasma membrane detaches from actin filaments, it is expanded by the intracellular pressure and the spherical membrane protrusion which lacks underlying actin cortex, termed bleb, is formed. Bleb is widely used for migration across species; however, the molecular mechanism underlying membrane blebbing remains largely unknown. Our recent study revealed that 2 small GTPases, Rnd3 and RhoA, are important regulators of membrane blebbing. In the expanding blebs, Rnd3 is recruited to the plasma membrane and inhibits RhoA activity by activating RhoGAP. On the other hand, RhoA is activated at the retracting membrane and removes Rnd3 from plasma membrane by the activity of ROCK (Rho-associated protein kinase). ROCK is also important for the rapid reassembly of actin cortex and retraction of membrane blebs by activating Ezrin. We propose that a Rnd3 and RhoA cycle underlies the core machinery of continuous membrane blebbing. The plasma membrane is generally associated with underling actin cytoskeleton. The interaction between plasma membrane and actin cytoskeleton is mediated by some anchor proteins such as ezrin/radixin/moesin (ERM) family proteins. When the plasma membrane detaches from actin filaments, spherical membrane protrusion is formed by the intracellular pressure. [1][2][3] This membrane protrusion termed bleb is observed during cytokinesis 4 and cell migration. 5 Some cancer cells use membrane blebbing as a mode of motility during metastasis. 6 When cancer cells are cultured on rigid substrates, cells move with forming actin-rich plasma membrane protrusions, such as lammellipodia and filopodia. On the other hand, cells migrate by forming membrane blebs when embedded in the 3D extracellular matrix such as collagen gels. [7][8][9] Recently, several groups reported that cancer cells start to use membrane blebbing-associated cell migration in response to the physical changes of extracellular conditions. Down-regulation of cell adhesion to the extracellular matrix and up-regulation of physical confinement induce the formation of large polarized blebs in cancer cells. [10][11][12] This bleb-based migration is the faster mode of migration as compared to the migration using lammellipodia and filopodiaThe blebbing-associated cell migration is not only observed in cancer cells, but also under physiological conditions. For example, primordial germ cells (PGCs) migrate with forming membrane blebs in zebrafish 13 and Drosophila melanogaster embryos. 14 Dictyostelium also use membrane blebbing for migration during chemotaxis. 15 Thus, membrane blebbing is widely used for migration across species.
The regulation of actin cytoskeleton during membrane blebbingThe process of expansion and retraction of blebs is largely depends on actin cytoskeleton organized underneath plasma membrane. Bleb forms when plasma membrane is detached from actin cytoskeleton. This is caused by the local increase of intracellular pressure or by the local ru...