PI3Kβ links integrin activation and PI(3,4)P2 production during invadopodial maturation

The invasion of tumor cells from the primary tumor is mediated by invadopodia, actin-rich protrusive organelles that secrete matrix metalloproteases and degrade the extracellular matrix. This coupling between protrusive activity and matrix degradation facilitates tumor invasion. We previously reported that the PI3K beta isoform of PI 3-kinase, which is regulated by both receptor tyrosine kinases and G protein-coupled receptors, is required for invasion and gelatin degradation in breast cancer cells. We have now defined the mechanism by which PI3K beta regulates invadopodia. We find that PI3K beta is specifically activated downstream from integrins, and is required for integrin-stimulated spreading and haptotaxis as well as integrin-stimulated invadopodia formation. Surprisingly, these integrin-stimulated and PI3K beta-dependent responses require the production of PI(3,4)P-2 by the phosphoinositide 5'-phosphatase SHIP2. Thus, integrin activation of PI3K beta is coupled to the SHIP2-dependent production of PI(3,4)P-2, which regulates the recruitment of PH domain-containing scaffolds such as lamellipodin to invadopodia. These findings provide novel mechanistic insight into the role of PI3K beta in the regulation of invadopodia in breast cancer cells.