Like a car with snow tires, metastasizing cancer cells often carry integrins that provide better traction. Rainero et al. reveal how a lipid-converting enzyme helps the cells mobilize these integrins.
Integrins continually cycle to and from the plasma membrane. Invasive cancer cells that carry mutant forms of p53 often bias the process, increasing the recycling of the α5β1 integrin that offers a better grip on the fibronectin fibers found in tumors. To make this change, mutant p53 requires the Rab-coupling protein (RCP), which connects α5β1 integrins to the Rab GTPases that promote membrane recycling. In turn, RCP links up with a lipid called phosphatidic acid (PA).
Rainero et al. found that diacylglycerol kinase α (DGK-α), an enzyme that makes PA, helps cancer cells to get moving. Tumor cells that were short on DGK-α didn't recycle α5β1 integrin and didn't penetrate into slabs of extracellular matrix.
In metastasizing tumor cells, vesicles sporting RCP are tethered to the tips of the advancing pseudopods. Few of these vesicles built up if DGK-α was absent, however, indicating that vesicle tethering requires PA. The researchers found that the particular tumor cells they studied didn't boost levels of DGK-α in order to metastasize. Instead, the team thinks that DGK-α permits cancer cells to move following the acquisition of p53 mutations. By manufacturing PA that binds to RCP, DGK-α enables the tumor cells to tether vesicles containing α5β1integrins close to the plasma membrane, where the integrins can readily recycle.