A functional genetic screen reveals new regulators of β1-integrin activity

beta 1 integrins constitute a large group of widely distributed adhesion receptors, which regulate the ability of cells to interact with their surroundings. This regulation of the expression and activity of integrins is crucial for tissue homeostasis and development and contributes to inflammation and cancer. We report an RNA interference screen to uncover genes involved in the regulation of beta 1-integrin activity using cell spot microarray technology in cancer cell lines. Altogether, ten cancer and two normal cell lines were used to identify regulators of beta 1 integrin activity. Cell biological analysis of the identified beta 1-integrin regulatory genes revealed that modulation of integrin activity can influence cell invasion in a three-dimensional matrix. We demonstrate with loss-of-function and rescue experiments that CD9 activates and MMP8 inactivates beta 1 integrins and that both proteins associate with beta 1 integrins in cells. Furthermore, CD9 and MMP8 regulate cancer cell extravasation in vivo. Our discovery of new regulators of beta 1-integrin activity highlight the complexity of integrin activity regulation and provide a set of new genes involved in regulation of integrin function.