engleski

Polarity of the actin cytoskeleton in amoeboid cell migration

The transition from mesenchymal to amoeboid mode of motility is a hallmark of the metastatic spread of tumor cells. Amoeboid cell migration, compared to mesenchymal type of migration, is characterized by higher speeds of movement, more flexible cell shape, diminished adhesion to the extracellular matrix, abrupt switches in cell polarity, simultaneous appearance of multiple pseudopods and conditional blebbing. Cells of the protist Dictyostelium discoideum represent a suitable model to study regulation of the actin cytoskeleton during amoeboid cell migration. Dictyostelium cells undergo the fastest spontaneous repolarization among eukaryotic cells, being capable of completely reversing their orientation within 30 seconds. They can also translocate approximately one cell length in a minute using the basic constituents of the actin cytoskeleton common to all eukaryotes. For example, formins and the Arp2/3 complex are the major promoters of actin assembly in Dictyostelium as in other eukaryotic cells. Formins nucleate and elongate linear actin filaments that are abundant e.g. in filopodia. On the other hand, Arp2/3 complex creates branches on the sides of existing actin filaments and thereby generates a dense actin meshwork in lamellipodia. Activity of these proteins at the leading edge of polarized cells is regulated by small GTPases from the Rho family by well-studied and evolutionary conserved mechanisms. For instance, the SCAR/WAVE complex mediates the upstream Rac signaling to the activation of Arp2/3 complex in evolutionary distant organisms from Dictyostelium to human. However, much less is known about the regulation of the actin cytoskeleton at the lateral and rear segments of the cell cortex that underlies the plasma membrane. In my talk I will discuss the signaling pathways that govern the organization and dynamics of actin filaments in polarized Dictyostelium cell, with an emphasis on the less studied rear end of the cell. We recently discovered that actin polymerization mediated by Diaphanous-related formin ForA is the main mechanism of de novo generation of actin filaments at the back of polarized cells. Further stabilization of the posterior actin cortex is accomplished by actin crosslinkers and IQGAP-related proteins, and their localization and activity is regulated by small GTPases and phosphoinositide lipids. Interestingly, small GTPase Rac1A both activates the SCAR/WAVE complex, which promotes actin polymerization at the cell front, and induces formation of a complex between the IQGAP-related protein DGAP1 and actin-bundling proteins cortexillins at the cell back. Competition between DGAP1 and SCAR/WAVE for a common activator Rac1 might provide the basis for the oscillatory re-polarization typically seen in randomly migrating Dictyostelium cells. Such signaling mechanisms may be of general importance in regulating spatiotemporal dynamics of the actin cytoskeleton by small GTPases.

amoeboid migration; cell polarity; actin cytoskeleton; small GTPases; formins

nije evidentirano