New Study by the Team of Dr. Dehmelt Uncovers Fundamental Mechanism in Cell Migration
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In order to heal a wound or to elicit an effective immune response, cells have to migrate within complex tissues to reach their destination. To enable their movements, cells dynamically change their shape: they form protrusions in their front and contract, similar to a muscle, in their back region. In a physiological context, cells often move directionally to their targets, for example to close a wound. The disruption of this mechanism can lead to uncontrolled, non-directional cell migration, such as in cancer metastasis.
Until now, it was assumed that the directional movement of cells is controlled by mutual inhibition between certain signaling molecules of the Rho GTPase family. In order to verify this, Dr. Dehmelt’s group has further developed microscopy-based sensor techniques to visualize the activity of these signaling molecules inside living cells. The researchers have combined these techniques with fast-acting chemical and light-based perturbation methods to investigate the functional interaction between different Rho GTPase family members.
Signaling molecules interact and influence cell migration
Using these methods, the scientists were able to clearly show, that the Rho GTPase family member Rac1 is only active in cell protrusions and the related family member RhoA only in cell contractions. Contrary to previous assumptions, however, Rac1 and RhoA do not inhibit each other; instead, Rac1 positively influences RhoA and activates it. The team hypothesized that this unexpected coupling plays a role in generating dynamic cycles of alternating cell protrusion and cell retraction. To test this hypothesis, it was first necessary to decipher the mechanism by which Rac1 activates RhoA. The group found that this occurs via the signaling molecules Arhgef11 and Arhgef12, which are themselves activated by Rac1 and can then activate RhoA. By experimentally manipulating the concentration of these signaling molecules, the group demonstrated that these molecules indeed drive the dynamic cycles of cell protrusion and retraction.
With this research, the group was able to show that the interaction of the two signaling molecules Rac1 and RhoA influences the dynamic protrusion-retraction cycles during cell migration and thus also determines how directional cells move. Cells with fewer dynamic cycles change their direction less frequently and thus migrate in a more controlled and targeted manner. Since Arhgef11 and Arhgef12 are known tumor-associated genes, the scientists believe that the increased concentration of these two signaling molecules could couple Rac1 and RhoA too strongly and thus promote the uncontrolled migration of cancer cells.
A large part of this research was funded by the Heisenberg Program of the German Research Foundation and by the Mercator Foundation. In addition to Dr. Leif Dehmelt from the TU Dortmund University and Prof. Perihan Nalbant from the University of Duisburg-Essen, cooperation partners from Umeå University in Sweden were also involved.
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