Src kinase modulates the apoptotic p53 pathway by altering HIPK2 localization

Non-receptor tyrosine kinase Src is a master regulator of cell proliferation. Hyperactive Src is a potent oncogene and a driver of cellular transformation and carcinogenesis. Homeodomain-interacting protein kinase 2 (HIPK2) is a tumor suppressor mediating growth suppression and apoptosis upon genoto...

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Bibliographic Details
Published in:Cell cycle (Georgetown, Tex.) Tex.), 2014-01, Vol.13 (1), p.115-125
Main Authors: Polonio-Vallon, Timan, Kirckpatrick, Joanna, Krijgsveld, Jeroen, Hofmann, Thomas
Format: Article
Language:English
Subjects:
apoptosis
Apoptosis - genetics
Carrier Proteins - genetics
Carrier Proteins - metabolism
chemotherapeutic drug
DNA Damage
HCT116 Cells
HIPK2
Humans
Phosphorylation
Protein-Serine-Threonine Kinases - genetics
Protein-Serine-Threonine Kinases - metabolism
Serine - metabolism
Src
src-Family Kinases - genetics
src-Family Kinases - metabolism
Tumor Suppressor Protein p53 - genetics
Ubiquitin-Protein Ligases - genetics
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Summary:Non-receptor tyrosine kinase Src is a master regulator of cell proliferation. Hyperactive Src is a potent oncogene and a driver of cellular transformation and carcinogenesis. Homeodomain-interacting protein kinase 2 (HIPK2) is a tumor suppressor mediating growth suppression and apoptosis upon genotoxic stress through phosphorylation of p53 at Ser46. Here we show that Src phosphorylates HIPK2 and changes its subcellular localization. Using mass spectrometry we identified 9 Src-mediated Tyr-phosphorylation sites within HIPK2, 5 of them positioned in the kinase domain. By means of a phosphorylation-specific antibody we confirm that Src mediates phosphorylation of HIPK2 at Tyr354. We demonstrate that ectopic expression of Src increases the half-life of HIPK2 by interfering with Siah-1-mediated HIPK2 degradation. Moreover, we find that hyperactive Src binds HIPK2 and redistributes HIPK2 from the cell nucleus to the cytoplasm, where both kinases partially colocalize. Accordingly, we find that hyperactive Src decreases chemotherapeutic drug-induced p53 Ser46 phosphorylation and apoptosis activation. Together, our results suggest that Src kinase suppresses the apoptotic p53 pathway by phosphorylating HIPK2 and relocalizing the kinase to the cytoplasm.
ISSN:1538-4101
1551-4005
DOI:10.4161/cc.26857