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A DNA-PK phosphorylation site on MET regulates its signaling interface with the DNA damage response

Jonas P Koch1,2,3, Selina M Roth1,2,3, Aurélie Quintin1,2

  • 1Department for BioMedical Research, Radiation Oncology, Inselspital, Bern University Hospital, and University of Bern, Bern, Switzerland.

Oncogene
|May 15, 2023
PubMed

Insights

Researchers discovered a new MET receptor tyrosine kinase (RTK) phosphosite, Serine 1016 (S1016), crucial for the DNA damage response (DDR). This finding offers insights into targeted therapies for radiosensitization and maintaining genome stability.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Oncology

Background:

  • The DNA damage response (DDR) is closely linked to signaling pathways activated by oncogenic receptor tyrosine kinases (RTKs).
  • Understanding the molecular crosstalk between DDR and RTKs is essential for developing targeted therapies, particularly as radiosensitizers.

Purpose of the Study:

  • To characterize a novel MET RTK phosphosite, Serine 1016 (S1016), as a potential interface between the DDR and MET signaling.
  • To investigate the role of MET S1016 phosphorylation in cellular response to DNA damage and its implications for genome stability.

Main Methods:

  • Phosphoproteomic analysis to identify and characterize the MET S1016 phosphosite.
  • Irradiation experiments to assess changes in MET S1016 phosphorylation.
  • Site-directed mutagenesis (S1016A substitution) to study the functional impact of this phosphosite.
  • Cell cycle analysis and assessment of mitotic spindle formation.

Main Results:

  • A previously unreported MET RTK phosphosite, S1016, was identified and shown to be phosphorylated upon irradiation, primarily by DNA-dependent protein kinase (DNA-PK).
  • Abrogation of MET S1016 phosphorylation significantly impacts long-term cell cycle regulation following DNA damage, affecting proteins involved in cell cycle progression and mitotic spindle formation.
  • Cells lacking functional MET S1016 bypass G2 arrest upon irradiation, enter mitosis with compromised genome integrity, exhibit abnormal mitotic spindles, and show reduced proliferation.

Conclusions:

  • The study uncovers a novel signaling mechanism where the DDR utilizes the MET growth factor receptor system to regulate and maintain genome stability.
  • MET S1016 serves as a critical regulatory point connecting DNA damage signaling with cell cycle control and mitotic progression.
  • Targeting the MET S1016 phosphosite could represent a potential strategy for enhancing radiosensitization and improving cancer therapy outcomes.

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