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Kinomic profiling approach identifies Trk as a novel radiation modulator
John S Jarboe1, Jerry J Jaboin, Joshua C Anderson
1Department of Biochemistry and Molecular Genetics, The University of Alabama at Birmingham, Birmingham, AL 35249-6832, USA.
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.
Materials And 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.
Insights
Investigating radiation response in endothelial cells revealed Tropomyosin receptor kinase (Trk) family members, TrkA and TrkB, as key regulators. Inhibiting TrkA/TrkB protected cells from radiation damage, offering new therapeutic targets for cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Cellular Biology
Background:
- Ionizing radiation is a cornerstone of cancer therapy, used in over half of all patients.
- Understanding radiation response and resistance mechanisms is crucial for developing improved cancer treatments.
Purpose of the Study:
- To investigate the mechanisms of radiation response in vascular endothelial cells.
- To identify novel therapeutic targets for modulating radiation sensitivity.
Main Methods:
- Utilized a high-content peptide array platform for multiplex kinase assays with real-time kinetic readout.
- Applied the technology to irradiated human umbilical vein endothelial cells (HUVEC).
Main Results:
- Identified 49 differentially tyrosine phosphopeptides affected by irradiation within 1 hour.
- Observed transient activation of Tropomyosin receptor kinase (Trk) family members, TrkA and TrkB, between 2 and 15 minutes post-irradiation.
- TrkA/TrkB inhibition protected HUVEC from radiation damage, while TrkA stimulation enhanced radiation effects.
Conclusions:
- The study successfully identified rapid kinase activity changes and novel targets like TrkA.
- TrkA inhibition demonstrated radioprotective effects by enhancing DNA repair.
- TrkA stimulation via gambogic amide led to radiation sensitization, highlighting its therapeutic potential.
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