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Src kinase phosphorylates RUNX3 at tyrosine residues and localizes the protein in the cytoplasm

Yun-Mi Goh1, Senthilkumar Cinghu1, Eileen Tan Hwee Hong2

  • 1Department of Biochemistry, School of Medicine, Institute for Tumor Research, Chungbuk National University, Cheongju 361-763, South Korea.

The Journal of Biological Chemistry
|January 27, 2010
PubMed

Insights

RUNX3, a tumor suppressor, is inactivated by cytoplasmic mislocalization in some cancers. Activated Src phosphorylates RUNX3, causing this mislocalization, which is reversible by inhibiting Src activity.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • RUNX3 acts as a tumor suppressor, with its down-regulation often linked to promoter hypermethylation in cancers.
  • Recent findings indicate that RUNX3 inactivation can also occur through cytoplasmic mislocalization.
  • The precise molecular mechanisms driving RUNX3 mislocalization remain largely unelucidated.

Purpose of the Study:

  • To investigate the role of Src in the cytoplasmic mislocalization of RUNX3.
  • To explore the molecular mechanisms linking Src activity to RUNX3 localization.
  • To determine if Src-mediated RUNX3 mislocalization is relevant in specific cancer types.

Main Methods:

  • Overexpression of Src in cellular models.
  • Analysis of tyrosine phosphorylation of RUNX3.
  • Assessment of RUNX3 subcellular localization using microscopy.
  • RNA interference (siRNA) to knockdown Src expression.
  • Inhibition of Src kinase activity using chemical inhibitors.

Main Results:

  • Src overexpression induced tyrosine phosphorylation and cytoplasmic localization of RUNX3.
  • Endogenous RUNX3 showed tyrosine phosphorylation and cytoplasmic localization in Src-activated cancer cell lines.
  • Src knockdown or kinase inhibition led to RUNX3 re-localization to the nucleus.
  • These findings were observed in gastric and breast cancer cell lines.

Conclusions:

  • Activated Src tyrosine phosphorylates RUNX3, leading to its cytoplasmic mislocalization.
  • Src-mediated RUNX3 phosphorylation is a key mechanism driving its inactivation in certain cancers.
  • Targeting Src activity may restore RUNX3 nuclear localization and tumor suppressor function in gastric and breast cancers.

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