Mystery of Cell-Cell Repulsion Solved

The protein srGAP2, which initiates the repulsion that is known as the contact inhibition of locomotion, is heavily concentrated at the front of the cell, depicted here in red, yellow, and green. [Department of Biomedicine, University of Basel]

Call it The Case of the Colliding Fibroblasts. It started more than 50 years ago, when English researcher Michael Abercrombie first observed the contact inhibition of locomotion (CIL). He was tailing fibroblasts, the motile constituents of connective tissue. He saw fibroblasts bump into each other and then move off in different directions. What furtive exchange, Abercrombie wondered, could prompt fibroblasts to take a powder?

After further sleuthing, Abercrombie saw that many invasive cancer cells that contact normal cells lose their direction-changing CIL property. Instead of dusting out, these cancer cells settle down. They just keep growing over normal cells, driving malignant diseases such as melanoma.

CIL has attracted the attention of scientific shamuses who have managed to implicate various proteins in the cell-dispersion process. But overall, the molecular basis of CIL has remained something of a puzzle. In particular, it was unclear which repulsion signals were involved in the process, how these signals entered the cells from the outside, and how they influenced the cytoskeleton, which in turn regulates the cell’s movement.

These questions have now been answered by scientists based at the University of Basel. These investigators, led by Olivier Pertz, have identified a coherent signaling axis consisting of three proteins called Slit2, Robo4, and srGAP2.

The details appeared October 1 in the journal Developmental Cell, in an article entitled, “SrGAP2-Dependent Integration of Membrane Geometry and Slit-Robo-Repulsive Cues Regulates Fibroblast Contact Inhibition of Locomotion.” According to this article, the colorfully named signaling proteins operate as follows:

• The repulsion factor Slit2 binds to the receptor Robo4, whereupon the signal enters the cell's interior and activates srGAP2.
• This molecule consequently inhibits the regulator Rac1, which coordinates the cytoskeleton.
• The inactivation of Rac1 causes the cell to retract—such that the two cells repel one another.

If the function of Slit2, Robo4, or srGAP2 is deactivated, colliding cells will stick to one another and will not separate as easily.

“SrGAP2 specifically controls the duration of Rac1 activity in contact protrusions, but not in contact-free protrusions,” wrote the article’s authors. “We propose that srGAP2 integrates cell edge curvature and Slit-Robo-mediated repulsive cues to fine-tune Rac1 activation dynamics in contact protrusions to spatiotemporally coordinate CIL.”

Intriguingly, the repulsion machinery is localized at the front – even in freely moving cells. By assembling this kind of a 'molecular bumper', the cell is prepared for collision with another cell. Where exactly this bumper must be positioned—namely, only in parts of the cell that are moving forwards—is determined by the cell's geometry, which in turn is deciphered by srGAP2.

The integration of membrane curvature and repulsion signals ensures that cell-cell repulsion takes place at the correct location. This repulsive reaction could play an important role in cancer metastasis. This is supported by the fact that the expression of Slit and Robo isoforms is deregulated in several tumor types.