Loss of Scar/WAVE Complex Promotes N-WASP- and FAK-Dependent Invasion

SummaryBackgroundThe Scar/WAVE regulatory complex (WRC) drives lamellipodia assembly via the Arp2/3 complex, whereas the Arp2/3 activator N-WASP is not essential for 2D migration but is increasingly implicated in 3D invasion. It is becoming ever more apparent that 2D and 3D migration utilize the actin cytoskeletal machinery differently.ResultsWe discovered that WRC and N-WASP play opposing roles in 3D epithelial cell migration. WRC depletion promoted N-WASP/Arp2/3 complex activation and recruitment to leading invasive edges and increased invasion. WRC disruption also altered focal adhesion dynamics and drove FAK activation at leading invasive edges. We observed coalescence of focal adhesion components together with N-WASP and Arp2/3 complex at leading invasive edges in 3D. Unexpectedly, WRC disruption also promoted FAK-dependent cell transformation and tumor growth in vivo.ConclusionsN-WASP has a crucial proinvasive role in driving Arp2/3 complex-mediated actin assembly in cooperation with FAK at invasive cell edges, but WRC depletion can promote 3D cell motility.

Graphical AbstractFigure optionsDownload high-quality image (131 K)Download as PowerPoint slideHighlights
► Arp2/3 complex drives epithelial cell invasion in the absence of WRC
► Loss of WRC promotes N-WASP-dependent invasion and degradative focal adhesions
► Loss of WRC promotes FAK activation and enhances anchorage-independent growth
► WRC suppresses cell transformation and tumor formation