Molecular Mechanisms of podosome formation

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The great majority of cancers occur in epithelial tissues, yielding carcinomas. Given that epithelial cells are on the basement membrane underneath, they must degrade it to travel to distant sites. To initiate the invasion process, they must make contact with the extracellular matrices (ECM). Thus, the cell-matrix interactions must be one of the triggers that allow cancer cells to invade. To penetrate into the ECM, actin-rich adhesion structures called invadopodia or podosomes is thought to play pivotal roles for degrading it. I have studied the mechanism of invadopodium/podosome formation in Src-transformed NIH3T3 cells. In this study, based on the results of RNAi, identification of binding proteins by mass spectrometry, protein interaction and live-cell imaging analysis, I have established a stepwise mechanism for invadopodium formation. Invadopodia initiate from focal adhesions (FAs) due to changes in the phosphorylation status of proteins and in the composition of phosphoinositides on the plasma membrane. The onset of actin polymerization is triggered by PI(3,4)P2 production and Tks5 recruitment followed by N-WASP accumulation. This step involves intricate interactions of Tks5 with both PI(3,4)P2 and Grb2 at FAs