Diacylglycerol kinase alpha, an enzyme integral to the production of phosphatidic acid, was required to fuel the invasion of tumor cells, according to study results published in The Journal of Cell Biology.
Based on prior study results, researchers observed that in normal cells, adhesive integrin proteins continually cycle to and from the cell surface. However, invasive cancer cells carry mutant forms of the tumor suppressor p53 that alters the cycle, increasing the recycling of an integrin that provides a better hold on the fibronectin fibers found in tumors. Researchers found that to make this alteration, mutant p53 requires the Rab-coupling protein (RCP) to connect the integrins to the Rab GTPases that promote membrane recycling.
In metastasizing tumor cells, vesicles sporting RCP are bound to the tips of the advancing pseudopods. However, researchers observed that few of these vesicles collected if diacylglycerol kinase alpha (DGK-alpha) was absent, indicating that vesicle-binding may require phosphatidic acid. Although specific tumor cells did not boost levels of DGK-alpha in order to metastasize, researchers theorized that DGK-alpha — and the production of phosphatidic acid — was required for RCP to be gathered together and bound to the tips of invasive pseudopods.
According to study results, DGK-alpha was required for RCP to be mobilized to and tethered at the tips of invasive pseudopods and to allow RCP-dependent alpha-5-beta-1 recycling and the resulting invasiveness of tumor cells. In addition, researchers found that expression of a constitutive-active mutant of DGK-alpha fueled the invasion of RCP-dependent tumor cells in the absence of mutant p53 expression — an RCP mutant lacking the PA-binding C2 domain was not capable of being tethered at pseudopod tips.
“These findings not only offer mechanistic insight into the control of tumor cell invasion and motility but also provide evidence for an essential role for DGK-alpha and specific molecular species of PA in delivery of recycling vesicles to the plasma membrane at the tips of invasive pseudopodial structures,” the researchers wrote. “Whether DGK-alpha–dependent integrin recycling impacts tumor invasion in vivo remains to be determined, but the contribution made by this kinase to integrin trafficking and signaling needs to be considered in the context of cancer metastasis.”
Disclosure: The researchers reported financial support from Cancer Research UK, the Association for International Cancer Research, Fondazione Cariplo, the Science Foundation Ireland Programme, the European Molecular Biology Organization and the Biotechnology and Biosciences Research Committee.