The scaffold protein Tks4 is an integral part of EGF signalling. Situated upstream near the intracellular kinase domain of EGFR, held in place via interaction with the membrane through its N-terminal PX domain, and participating in many protein-protein interactions through the namesake four SH3 domains. To this day the functions of Tks4 had not been fully elucidated. It is known that it plays a major role in the formation of podosomes/invadopoida, which are dynamic protrusions of the ventral cell membrane, aiding movement. It also governs stromal cell differentiation into adipogenic and osteogenic lineages. Losing Tks4 results in a complex autosomal recessive disorder, known as Frank-ter Haar syndrome.

In our cooperation, we investigated Tks4-/- HCT116 human colorectal carcinoma cell lineages. To unfold the underlying mechanisms, that may cause the severe defects, first we compared movement capabilities of wild type cells and knock-out (KO) clones.

The results, showed that KO clones had increased mobility, despite the Tks4’s role in podosome formation. Further experiments showed that, the normally epithelial HCT116 cells began to express mesenchymal features. RT-PCR measurements confirmed a possible epithelial-mesenchymal transition (EMT), showing increased mRNA levels of EMT transcription factors SNAI1, SNAI2, and mesenchymal marker FN1. These results predict an inhibitory role of Tks4 in EMT.

László Buday - András Czirok

Report I. - 2018 April