Inducible recruitment of Cdc42 or WASP to a cell-surface receptor triggers actin polymerization and filopodium formation

Abstract

This is the first demonstration that the local recruitment of activated Cdc42 or its downstream effector, WASP, to a membrane receptor in whole cells is sufficient to trigger actin polymerization that results in the formation of membrane protrusions. Our data suggest that Cdc42-induced actin-based protrusions result from the local and serial recruitment of cytoskeletal proteins including zyxin, VASP, and ezrin.

Regulation of endocytic traffic by Rho GTPases

“…RhoA is also recruited, but its necessity for this process is unclear [11]. Castellano et al [14] have used derivatized latex beads to trigger specific activation of Cdc42 or Rac separately at the plasma membrane. Interestingly, these experiments show that, whilst Cdc42 activation is required for significant filopodial extension [14], Rac activation is sufficient to mediate internalization [15].…”

“…Castellano et al [14] have used derivatized latex beads to trigger specific activation of Cdc42 or Rac separately at the plasma membrane. Interestingly, these experiments show that, whilst Cdc42 activation is required for significant filopodial extension [14], Rac activation is sufficient to mediate internalization [15]. The precise requirement for Cdc42, then, is unclear, but it may be that the increased surface contact afforded by filopodia projection increases the efficiency Figure 3 The most prominent family of Arp2/3 actin nucleation complex activators comprising Scar/WAVE proteins and members of WASP family [104] All these proteins exist in inhibited states.…”

Cutting Edge: The Wiskott-Aldrich Syndrome Protein Is Required for Efficient Phagocytosis of Apoptotic Cells

“…WASp can be activated by the Rho family GTPase Cdc42 to stimulate actin polymerization through the Arp2/3 complex, and the lack of functional WASp has been shown to lead to defects of immune cell polarization, signaling, and cell motility (5,6). Recently, both Cdc42 and Rac1 have been shown to regulate actin reorganization during Fc␥R-mediated phagocytosis by promoting pseudopod extension and phagosome closure, respectively (7)(8)(9)(10)(11)(12). For optimal efficiency, this process is also dependent on WASp, which actively relocates to the region of the evolving phagocytic cup, and is required for recruitment of the Arp2/3 complex (13,14).…”

Recruitment of Dbl by Ezrin and Dystroglycan Drives Membrane Proximal Cdc42 Activation and Filopodia Formation

“…Global over-expression of activated Cdc42 within the cell as a whole is sufficient to increase the levels of active Cdc42 at membrane-proximal sites leading to filopodia formation, 3 as does the direct targeting of activated Cdc42 to membrane sites by forcing association with a receptor complex. 8 We have shown recently that the cell adhesion receptor dystroglycan can induce filopodia formation in a Cdc42-and ezrindependent manner. 17,18 Dystroglycan has been most extensively characterised as a part of the dystrophin glycoprotein complex of skeletal muscle but also has roles in cell adhesion, cell polarity and morphogenesis in other tissues.…”

“…For example several reports have documented the induction of filopodia by the recruitment of WASP or N-WASP to peripheral sites. [7][8][9] Ena/VASP proteins either alone or in concert with WASP have also been implicated in formation of filopodial structures. 10,11 New actin polymerization is also critical to the generation of actin protrusions, and whilst not thought to be a component of filopodia itself, the Arp2/3 complex is an important driving force to generate new actin filaments that can then be bundled into filopodial structures through the actions of other proteins such as fascin, 12 or villin as in the case of microvilli.…”