Binding of PLD2-Generated Phosphatidic Acid to KIF5B Promotes MT1-MMP Surface Trafficking and Lung Metastasis of Mouse Breast Cancer Cells

Little is known about the cellular events promoting metastasis. We show that knockout of phospholipase D2 (PLD2), which generates the signaling lipid phosphatidic acid (PA), inhibits lung metastases in the mammary tumor virus (MMTV)-Neu transgenic mouse breast cancer model. PLD2 promotes local invasion through the regulation of the plasma membrane targeting of MT1-MMP and its associated invadopodia. A liposome pull-down screen identifies KIF5B, the heavy chain of the motor protein kinesin-1, as a new PA-binding protein. In vitro assays reveal that PA specifically and directly binds to the C terminus of KIF5B. The binding between PLD2-generated PA and KIF5B is required for the vesicular association of KIF5B, surface localization of MT1-MMP, invadopodia, and invasion in cancer cells. Taken together, these results identify a role of PLD2-generated PA in the regulation of kinesin-1 motor functions and breast cancer metastasis and suggest PLD2 as a potential therapeutic target for metastatic breast cancer. [Display omitted] •The lung metastasis of breast cancer cells is dependent on PLD2•PLD2 promotes invadopodia formation•PLD2-generated phosphatidic acid binds to and regulates the motor protein KIF5B•PLD2-PA-KIF5B signaling controls MT1-MMP surface localization and invasion The cellular events that regulate cancer metastasis are poorly understood. Wang et al. demonstrate that PLD2, through generating the signaling lipid phosphatidic acid (PA), promotes breast cancer lung metastasis. Direct PA binding to the motor protein KIF5B controls MT1-MMP plasma membrane trafficking, invadopodia formation, and local invasion.