Positive and negative regulation of the actin machinery for migration and invasion.

Cancer cell migration and invasion requires engagement of protrusive and matrix-remodeling machinery. Protrusions in 3D matrix involve a combination of actin nucleation promoting proteins, such as N-WASP and the Scar/WAVE Complex. Both N-WASP and Scar/WAVE Complex are regulated by the Rho GTPases Rac1 and Cdc42, but how their activities are coordinated during migration and invasion is still a subject of intense study. Although multiple positive signals are presumed to regulate the SCAR/WAVE complex and N-WASP in addition to active Rac1 or Cdc42, the requirement for balanced activation by negative regulatory signals and the possible mechanisms for this, remain elusive.

We have identified and characterized a highly conserved protein of unknown function, which we name RIPS (Rac1 Interacting Pseudopod Splitter). RIPS-depleted cells show a distinct accumulation of WAVE2 at the leading edge and mimic the cell shape change and invasive phenotype of constitutively active Rac1.  We speculate that RIPS is a negative regulator of the Rac1-Scar/WAVE complex axis and that its function is to provide negative feedback for this pathway.  Actin dynamics pathways involve competition and collaboration between the major nucleators to modulate protrusion and invasion and our challenge is to determine how RIPS fits into our picture of signaling to actin dynamics.