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Src kinase modulates the apoptotic p53 pathway by altering HIPK2 localization
Tilman Polonio-Vallon1, Joanna Kirkpatrick2, Jeroen Krijgsveld2
1German Cancer Research Center (DKFZ); Research Group Cellular Senescence; DKFZ-ZMBH Alliance; Heidelberg, Germany.
Cell Cycle (Georgetown, Tex.)
|November 8, 2013
Summary
The Src kinase phosphorylates HIPK2, altering its location and stability. This interaction suppresses the p53 apoptotic pathway, impacting cancer cell growth and response to chemotherapy.
Area of Science:
- Cellular biology
- Molecular oncology
- Signal transduction
Background:
- Non-receptor tyrosine kinase Src is a key regulator of cell proliferation and a potent oncogene.
- Homeodomain-interacting protein kinase 2 (HIPK2) acts as a tumor suppressor by inducing apoptosis via p53 phosphorylation.
Purpose of the Study:
- To investigate the regulatory relationship between Src and HIPK2.
- To determine how Src influences HIPK2's function in apoptosis signaling.
Main Methods:
- Mass spectrometry to identify Src-mediated phosphorylation sites on HIPK2.
- Phosphorylation-specific antibody to confirm Tyr354 phosphorylation.
- Western blotting and co-immunoprecipitation to assess HIPK2 stability, degradation, and localization.
Main Results:
- Src phosphorylates HIPK2 at multiple tyrosine sites, including Tyr354.
- Src enhances HIPK2 stability by inhibiting Siah-1-mediated degradation.
- Src binding redistributes HIPK2 from the nucleus to the cytoplasm, reducing p53 Ser46 phosphorylation and apoptosis.
Conclusions:
- Src kinase suppresses the apoptotic p53 pathway by phosphorylating and cytoplasmic relocalization of HIPK2.
- This mechanism offers a potential target for cancer therapy by modulating Src-HIPK2 interactions.
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