4.7 Article

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

期刊

DEVELOPMENTAL CELL
卷 43, 期 2, 页码 186-+

出版社

CELL PRESS
DOI: 10.1016/j.devcel.2017.09.012

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资金

  1. China Scholarship Council
  2. Cancer Prevention and Research Institute of Texas (CPRIT) [RP130425, RP160775]
  3. NIH [R01HL119478, R01GM114260, R01CA112403, R01CA193455]

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Little is known about the cellular events promoting metastasis. We show that knockout of phospholipase D-2 (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.

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