CYFIP2-containing WAVE complexes inhibit cell migration by a competition mechanism

Branched actin networks polymerized by the Arp2/3 complex are critical for cell migration. The WAVE complex is the major Arp2/3 activator at the leading edge of migrating cells. However, multiple distinct WAVE complexes can be assembled in a cell, due to the combinatorial complexity of paralogous subunits. When systematically analyzing the contribution of each WAVE complex subunit to the metastasis-free survival of breast cancer patients, we found that overexpression of the CYFIP2 subunit was surprisingly associated with good prognosis. Gain and loss of function experiments in transformed and untransformed mammary epithelial cells, as well as in prechordal plate cells in gastrulating zebrafish embryos, revealed that lamellipodium protrusion and cell migration were always inversely related to CYFIP2 levels. The role of CYFIP2 was systematically opposite to the role of the paralogous subunit CYFIP1 or of the NCKAP1 subunit, which determines levels of WAVE complexes. CYFIP2 showed no difference from CYFIP1 in assembling WAVE complexes or binding to active RAC1. CYFIP2-containing WAVE complexes, however, were less able to activate the Arp2/3 complex in response to RAC1 binding. CYFIP1- and CYFIP2-containing WAVE complexes thus compete for active RAC1 and produce different outcomes. Therefore, cell migration, lamellipodium protrusion and Arp2/3 activity are controlled by relative levels of CYFIP1 and CYFIP2.