Solution to 50-Year-Old Riddle of Why Colliding Connective Tissue Fibroblasts Repel Each; “Molecular Bumper” Mechanism May Play Role in Metastasis

When fibroblast cells from the connective tissue collide, they repel one another – this phenomenon was discovered more than 50 years ago. It is only now, however, that researchers at the University of Basel in Switzerland have discovered the molecular basis for this process, as they report online on October 1, 2015 in Developmental Cell. The article is titled “SrGAP2-Dependent Integration of Membrane Geometry and Slit-Robo-Repulsive Cues Regulate Fibroblast Contact Inhibition of Locomotion.” Their findings could have important implications for cancer research. Fibroblasts are motile constituents of the connective tissue and also regulate its stiffness. Moreover, fibroblasts play an important role in malignant skin diseases such as melanoma. In research, they serve as a model system for studying cell migration. In the early 1950s, the English researcher Michael Abercrombie discovered that colliding fibroblasts repel one another and, in the process, change their direction of motion. He called this phenomenon “contact inhibition of locomotion.” Although individual proteins were identified as key factors in this process, the molecular basis of this reaction remained something of a mystery. 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.Professor Olivier Pertz’s research group at the University of Basel has now precisely answered these questions. The group identified a coherent signaling axis consisting of three proteins called Slit2, Robo4, and srGAP2 which operates as follows. The repulsion factor Slit2 binds to the receptor Robo4, whereupon the signal enters the cell’s interior and activates srGAP2.
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