title: Activated platelets rescue apoptotic cells via paracrine activation of EGFR and DNA-dependent protein kinase.
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.
authors.affiliation: Australian Centre for Blood Diseases, Department of Clinical Haematology, Monash University, Victoria 3004, Australia.
authors.forename: A E-L
authors.initials: AE
authors.lastname: Au
authors.affiliation: Australian Centre for Blood Diseases, Department of Clinical Haematology, Monash University, Victoria 3004, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Sashindranath
authors.affiliation: Australian Centre for Blood Diseases, Department of Clinical Haematology, Monash University, Victoria 3004, Australia.
authors.forename: R J
authors.initials: RJ
authors.lastname: Borg
authors.affiliation: Department of Biochemistry, Monash University, Victoria 3800, Australia.
authors.forename: O
authors.initials: O
authors.lastname: Kleifeld
authors.affiliation: Australian Centre for Blood Diseases, Department of Clinical Haematology, Monash University, Victoria 3004, Australia.
authors.forename: R K
authors.initials: RK
authors.lastname: Andrews
authors.affiliation: Australian Centre for Blood Diseases, Department of Clinical Haematology, Monash University, Victoria 3004, Australia.
authors.forename: E E
authors.initials: EE
authors.lastname: Gardiner
authors.affiliation: Australian Centre for Blood Diseases, Department of Clinical Haematology, Monash University, Victoria 3004, Australia.
authors.forename: R L
authors.initials: RL
authors.lastname: Medcalf
authors.affiliation: 1] Australian Centre for Blood Diseases, Department of Clinical Haematology, Monash University, Victoria 3004, Australia [2] Department of Biochemistry, Monash University, Victoria 3800, Australia.
authors.forename: A L
authors.initials: AL
authors.lastname: Samson
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D017209:Apoptosis; D001792:Blood Platelets / Q000201:enzymology* / Q000378:metabolism; D001921:Brain / Q000166:cytology / Q000201:enzymology; D001930:Brain Injuries / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D051747:DNA-Activated Protein Kinase / Q000235:genetics / Q000378:metabolism*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009474:Neurons / Q000166:cytology*; D015539:Platelet Activation; D055815:Young Adult
chemical_list: D066246:ErbB Receptors; D051747:DNA-Activated Protein Kinase