title: Kinomic profiling approach identifies Trk as a novel radiation modulator.
abstract: BACKGROUND
  Ionizing radiation treatment is used in over half of all cancer patients, thus determining the mechanisms of response or resistance is critical for the development of novel treatment approaches.
  
  
  METHODS
  In this report, we utilize a high-content peptide array platform that performs multiplex kinase assays with real-time kinetic readout to investigate the mechanism of radiation response in vascular endothelial cells. We applied this technology to irradiated human umbilical vein endothelial cells (HUVEC).
  
  
  RESULTS
  We identified 49 specific tyrosine phosphopeptides that were differentially affected by irradiation over a time course of 1h. In one example, the Tropomyosin receptor kinase (Trk) family members, TrkA and TrkB, showed transient activation between 2 and 15 min following irradiation. When we targeted TrkA and TrkB using small molecule inhibitors, HUVEC were protected from radiation damage. Conversely, stimulation of TrkA using gambogic amide promoted radiation enhancement.
  
  
  CONCLUSIONS
  Thus, we show that our approach not only can identify rapid changes in kinase activity but also identify novel targets such as TrkA. TrkA inhibition resulted in radioprotection that correlated with enhanced repair of radiation-induced damage while TrkA stimulation by gambogic amide produced radiation sensitization.
authors.affiliation: Department of Biochemistry and Molecular Genetics, The University of Alabama at Birmingham, Birmingham, AL 35249-6832, USA.
authors.forename: John S
authors.initials: JS
authors.lastname: Jarboe
authors.forename: Jerry J
authors.initials: JJ
authors.lastname: Jaboin
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Anderson
authors.forename: Somaira
authors.initials: S
authors.lastname: Nowsheen
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Stanley
authors.forename: Faris
authors.initials: F
authors.lastname: Naji
authors.forename: Rob
authors.initials: R
authors.lastname: Ruijtenbeek
authors.forename: Tianxiang
authors.initials: T
authors.lastname: Tu
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Hallahan
authors.forename: Eddy S
authors.initials: ES
authors.lastname: Yang
authors.forename: James A
authors.initials: JA
authors.lastname: Bonner
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Willey
mesh_terms: D002453:Cell Cycle / Q000528:radiation effects; D002460:Cell Line; D002470:Cell Survival / Q000528:radiation effects; D002478:Cells, Cultured; D004260:DNA Repair / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism / Q000528:radiation effects*; D006801:Humans; D010766:Phosphorylation; D040081:Protein Array Analysis; D011494:Protein Kinases / Q000378:metabolism; D011829:Radiation Dosage; D011836:Radiation Tolerance / Q000187:drug effects; D020917:Receptor, trkA / Q000819:agonists / Q000378:metabolism*; D020813:Receptor, trkB / Q000378:metabolism*; D044004:Xanthones / Q000494:pharmacology
chemical_list: D044004:Xanthones; D011494:Protein Kinases; D020917:Receptor, trkA; D020813:Receptor, trkB; C041311:tropomyosin kinase; C545053:gambogic amide