Among the most prominent structures driving cell migration are so called lamellipodia, flat and broad in dimension pushing the cell front forward. Lamellipodia are built of dense networks of polymers mostly comprising the protein actin, and they are dynamically renewed to translate pushing forces into forward movement. But how are these structures regulated at the molecular scale? “The role of the actin binding protein profilin in these processes has been controversial, but our results could largely clarify previous inconsistencies in the literature,” Klemens Rottner says.
Using genome editing by CRISPR/Cas9, the researchers first disrupted various players in the process, alone and in combination. Then they explored how this affected formation and function of lamellipodia as well as the relative distributions of remaining proteins. Doing this, they were able to establish the functional connections between the most relevant players in these structures in a step-wise manner, including the roles of four components as follows:
“We have succeeded in improving our understanding of how all those lamellipodial components interact with and influence each other – thereby collectively regulating forward movement,” Dr. Yubo Tang says, first author on the study. These interactions operate as follows: Profilin counteracts Ena/VASP and at the same time promotes Arp2/3 complex activity. Ena/VASP and capping protein antagonize each other. Combinations of gene disruptions have been particularly informative: Profilin was still crucial for Arp2/3 complex localization even in the absence of Ena/VASP, but this was not seen for CP. In the absence of Ena/VASP, the impact of profilin on CP vanished. These data showed that profilin influences Arp2/3 complex and CP through distinct and separable molecular pathways.
Taken together, the data establish profilin as master regulator of Arp2/3 complex-dependent actin networks. The results thus resolve several controversial issues: Previous research have either suggested profilin to funnel actin monomers into formin or Ena/VASP-dependent actin structures, and thus away from Arp2/3 complex, while others rather saw the opposite. “We are now clarifying this controversy by clearly showing profilin to operate upstream of Arp2/3 complex in lamellipodia and also how,” Klemens Rottner says. Mathematical modeling done in cooperation by Prof. Martin Falcke from Max Delbrück Center Berlin not only recapitulated all experimental results, but also implied that Ena/VASP and CP have to compete for a common recruitment mechanism in lamellipodia.
The work thus provides decisive insights into the molecular logics of building branched actin networks driving the forces for membrane protrusion. “We understand much better now how these molecular players operate with one another at lamellipodial edges,” Klemens Rottner says. “This mechanistic understanding forms the basis for examining what goes wrong in aberrant migration, ranging from cancer metastasis to cells suffering from infections – and how those processes can potentially be targeted.”
One important open question constitutes the molecular nature of the recruitment structure Ena/VASP and CP are competing for. This will constitute one of many important lines of future investigation in Rottner’s team.
Text: Dr. Christian Heinrich
Helmholtz Centre for Infection Research:
Scientists at the Helmholtz Centre for Infection Research (HZI) in Braunschweig and its other sites in Germany are engaged in the study of bacterial and viral infections and the body’s defense mechanisms. They have a profound expertise in natural compound research and its exploitation as a valuable source for novel anti-infectives. As member of the Helmholtz Association and the German Center for Infection Research (DZIF) the HZI performs translational research laying the ground for the development of new treatments and vaccines against infectious diseases. www.helmholtz-hzi.de/en
Nature Communications
Experimental study
Cells
Profilin promotes lamellipodium protrusion by tuning the antagonistic activities of capping protein and VASP
16-Sep-2026