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How local interactions of actin regulators yield large-scale organization of cell shape and movement is not well understood. Here we investigate how the WAVE complex organizes sheet-like lamellipodia. Using super-resolution microscopy, we find that the WAVE complex forms actin-independent 230-nm-wide rings that localize to regions of saddle membrane curvature. This pattern of enrichment could explain several emergent cell behaviors, such as expanding and self-straightening lamellipodia and the ability of endothelial cells to recognize and seal transcellular holes. The WAVE complex recruits IRSp53 to sites of saddle curvature but does not depend on IRSp53 for its own localization. Although the WAVE complex stimulates actin nucleation via the Arp2/3 complex, sheet-like protrusions are still observed in ARP2-null, but not WAVE complex-null, cells. Therefore, the WAVE complex has additional roles in cell morphogenesis beyond Arp2/3 complex activation. Our work defines organizing principles of the WAVE complex lamellipodial template and suggests how feedback between cell shape and actin regulators instructs cell morphogenesis.
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This content will become publicly available on September 1, 2026
WAVE complex forms linear arrays at negative membrane curvature to instruct lamellipodia formation
Different actin nucleation-promoting factors (NPFs) orchestrate different patterns of cell protrusions, likely reflecting their distinct patterns of self-organization. Here, we leveraged in vivo biochemical approaches to investigate how the WAVE complex instructs the formation of sheet-like lamellipodia. We show that the WAVE complex is a core constituent of a linear multilayered protein array at the plasma membrane, expected for an NPF that builds sheet-like actin-based protrusions. Negative membrane curvature is both necessary and sufficient for WAVE complex linear membrane association in the presence of upstream activators (Rac, Arf1/6, and PIP3) and the PRDs of both WAVE2 and Abi2, providing a potential mechanistic basis for templating of lamellipodia and their emergent behaviors, including barrier avoidance. Through computational modeling, we demonstrate that WAVE complex’s linear organization and preference for negative curvature both play important roles in robust lamellipodia formation. Our data reveal key features of mesoscale WAVE complex patterning and highlight an integral relation between NPF self-organization and cell morphogenesis.
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- Award ID(s):
- 2019598
- PAR ID:
- 10621822
- Publisher / Repository:
- Journal of Cell Biology
- Date Published:
- Journal Name:
- Journal of Cell Biology
- Volume:
- 224
- Issue:
- 9
- ISSN:
- 0021-9525
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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