The Rho family GTPase Rif induces filopodia through mDia2

Eukaryotic cells produce a variety of specialized actin-rich surface protrusions. These include filopodia-thin, highly dynamic projections that help cells to sense their external environment [1]. Filopodia consist of parallel filaments of actin, bundled by actin cross-linking proteins. The filaments are oriented with their rapidly growing "barbed" ends at the protruding tip and their slowly growing "pointed" ends at the base [2]. Extension occurs by polymerization at the tip [3] and is controlled by regulation of filament capping [4]. The Rho GTPase Cdc42 is a key mediator of filopodia formation, which it regulates through binding CRIB domain-containing effectors [2]. Cdc42 binds and activates the WASP proteins, which in turn activate the actin-nucleating complex Arp2/3 [2]. It also binds and activates IRSp53, which recruits the Ena/WASP family protein Mena [5] to the filopodial tip and protects elongating actin filaments from capping [4]. Previously, we identified another Rho family GTPase, Rif, as a potent stimulator of filopodial protrusion through a mechanism that does not require Cdc42 [6]. Here we characterize the differences between filopodia induced by these two small GTPases and show that the Rif effector in this pathway is the Diaphanous-related formin mDia2. Thus, Rif and Cdc42 represent two distinct routes to the induction of filopodia-producing structures with both shared and unique properties.