Trop-2 inhibits prostate cancer cell adhesion to fibronectin through the β1 integrin-RACK1 axis

Trop‐2 is a transmembrane glycoprotein upregulated in several human carcinomas, including prostate cancer (PrCa). Trop‐2 has been suggested to regulate cell–cell adhesion, given its high homology with the other member of the Trop family, Trop‐1/EpCAM, and its ability to bind the tight junction proteins claudin‐1 and claudin‐7. However, a role for Trop‐2 in cell adhesion to the extracellular matrix has never been postulated. Here, we show for the first time that Trop‐2 expression in PrCa cells correlates with their aggressiveness. Using either shRNA‐mediated silencing of Trop‐2 in cells that endogenously express it, or ectopic expression of Trop‐2 in cells that do not express it, we show that Trop‐2 inhibits PrCa cell adhesion to fibronectin (FN). In contrast, expression of another transmembrane receptor, αvβ5 integrin, does not affect cell adhesion to this ligand. We find that Trop‐2 does not modulate either protein or activation levels of the prominent FN receptors, β1 integrins, but acts through increasing β1 association with the adaptor molecule RACK1 and redistribution of RACK1 to the cell membrane. As a result of Trop‐2 expression, we also observe activation of Src and FAK, known to occur upon β1‐RACK1 interaction. These enhanced Src and FAK activities are not mediated by changes in either the activity of IGF‐IR, which is known to bind RACK1, or IGF‐IR's ability to associate with β1 integrins. In summary, our data demonstrate that the transmembrane receptor Trop‐2 is a regulator of PrCa cell adhesion to FN through activation of the β1 integrin‐RACK1‐FAK‐Src signaling axis. J. Cell. Physiol. 227: 3670–3677, 2012. © 2012 Wiley Periodicals, Inc.