Activated platelets rescue apoptotic cells via paracrine activation of EGFR and DNA-dependent protein kinase

Amanda E-Ling Au, Maithili Sashindranath, Rachael Jade Borg, Oded Kleifeld, Robert Keith Andrews, Elizabeth Ellen Gardiner, Robert Lindsay Medcalf, Andre Laval Samson

Research output: Contribution to journalArticleResearchpeer-review

15 Citations (Scopus)

Abstract

Platelet activation is a frontline response to injury, not only essential for clot formation but also important for tissue repair. Indeed, the reparative influence of platelets has long been exploited therapeutically where application of platelet concentrates expedites wound recovery. Despite this, the mechanisms of platelet-triggered cytoprotection are poorly understood. Here, we show that activated platelets accumulate in the brain to exceptionally high levels following injury and release factors that potently protect neurons from apoptosis. Kinomic microarray and subsequent kinase inhibitor studies showed that platelet-based neuroprotection relies upon paracrine activation of the epidermal growth factor receptor (EGFR) and downstream DNA-dependent protein kinase (DNA-PK). This same anti-apoptotic cascade stimulated by activated platelets also provided chemo-resistance to several cancer cell types. Surprisingly, deep proteomic profiling of the platelet releasate failed to identify any known EGFR ligand, indicating that activated platelets release an atypical activator of the EGFR. This study is the first to formally associate platelet activation to EGFR/DNA-PK--an endogenous cytoprotective cascade.
Original languageEnglish
Pages (from-to)1 - 13
Number of pages13
JournalCell Death and Disease
Volume5
DOIs
Publication statusPublished - 2014

Cite this

Au, Amanda E-Ling ; Sashindranath, Maithili ; Borg, Rachael Jade ; Kleifeld, Oded ; Andrews, Robert Keith ; Gardiner, Elizabeth Ellen ; Medcalf, Robert Lindsay ; Samson, Andre Laval. / Activated platelets rescue apoptotic cells via paracrine activation of EGFR and DNA-dependent protein kinase. In: Cell Death and Disease. 2014 ; Vol. 5. pp. 1 - 13.
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abstract = "Platelet activation is a frontline response to injury, not only essential for clot formation but also important for tissue repair. Indeed, the reparative influence of platelets has long been exploited therapeutically where application of platelet concentrates expedites wound recovery. Despite this, the mechanisms of platelet-triggered cytoprotection are poorly understood. Here, we show that activated platelets accumulate in the brain to exceptionally high levels following injury and release factors that potently protect neurons from apoptosis. Kinomic microarray and subsequent kinase inhibitor studies showed that platelet-based neuroprotection relies upon paracrine activation of the epidermal growth factor receptor (EGFR) and downstream DNA-dependent protein kinase (DNA-PK). This same anti-apoptotic cascade stimulated by activated platelets also provided chemo-resistance to several cancer cell types. Surprisingly, deep proteomic profiling of the platelet releasate failed to identify any known EGFR ligand, indicating that activated platelets release an atypical activator of the EGFR. This study is the first to formally associate platelet activation to EGFR/DNA-PK--an endogenous cytoprotective cascade.",
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Activated platelets rescue apoptotic cells via paracrine activation of EGFR and DNA-dependent protein kinase. / Au, Amanda E-Ling; Sashindranath, Maithili; Borg, Rachael Jade; Kleifeld, Oded; Andrews, Robert Keith; Gardiner, Elizabeth Ellen; Medcalf, Robert Lindsay; Samson, Andre Laval.

In: Cell Death and Disease, Vol. 5, 2014, p. 1 - 13.

Research output: Contribution to journalArticleResearchpeer-review

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