Phosphatidylinositol transfer protein-α in platelets is inconsequential for thrombosis yet is utilized for tumor metastasis

Liang Zhao, Chelsea L. Thorsheim, Aae Suzuki, Timothy J. Stalker, Sang H. Min, Lurong Lian, Gregory D. Fairn, Shamshad Cockcroft, Amy Durham, Sriram Krishnaswamy and Charles S. Abrams ()
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Liang Zhao: School of Medicine, University of Pennsylvania
Chelsea L. Thorsheim: School of Medicine, University of Pennsylvania
Aae Suzuki: School of Medicine, University of Pennsylvania
Timothy J. Stalker: School of Medicine, University of Pennsylvania
Sang H. Min: School of Medicine, University of Pennsylvania
Lurong Lian: School of Medicine, University of Pennsylvania
Gregory D. Fairn: St. Michael’s Hospital
Shamshad Cockcroft: University College London
Amy Durham: School of Veterinary Medicine, University of Pennsylvania
Sriram Krishnaswamy: Children’s Hospital of Philadelphia
Charles S. Abrams: School of Medicine, University of Pennsylvania

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: Abstract Platelets are increasingly recognized for their contributions to tumor metastasis. Here, we show that the phosphoinositide signaling modulated by phosphatidylinositol transfer protein type α (PITPα), a protein which shuttles phosphatidylinositol between organelles, is essential for platelet-mediated tumor metastasis. PITPα-deficient platelets have reduced intracellular pools of phosphoinositides and an 80% reduction in IP3 generation upon platelet activation. Unexpectedly, mice lacking platelet PITPα form thrombi normally at sites of intravascular injuries. However, following intravenous injection of tumor cells, mice lacking PITPα develop fewer lung metastases due to a reduction of fibrin formation surrounding the tumor cells, rendering the metastases susceptible to mucosal immunity. These findings demonstrate that platelet PITPα-mediated phosphoinositide signaling is inconsequential for in vivo hemostasis, yet is critical for in vivo dissemination. Moreover, this demonstrates that signaling pathways within platelets may be segregated into pathways that are essential for thrombosis formation and pathways that are important for non-hemostatic functions.

Date: 2017
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DOI: 10.1038/s41467-017-01181-4

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