%0 Journal Article
%A Reuven, Nina
%A Adler, Julia
%A Porat, Ziv
%A Polonio-Vallon, Tilman
%A Hofmann, Thomas
%A Shaul, Yosef
%T The Tyrosine Kinase c-Abl Promotes Homeodomain-interacting Protein Kinase 2 (HIPK2) Accumulation and Activation in Response to DNA Damage.
%J The journal of biological chemistry
%V 290
%N 27
%@ 1083-351X
%C Bethesda, Md.
%I Soc.
%M DKFZ-2017-03399
%P 16478 - 16488
%D 2015
%X The non-receptor tyrosine kinase c-Abl is activated in response to DNA damage and induces p73-dependent apoptosis. Here, we investigated c-Abl regulation of the homeodomain-interacting protein kinase 2 (HIPK2), an important regulator of p53-dependent apoptosis. c-Abl phosphorylated HIPK2 at several sites, and phosphorylation by c-Abl protected HIPK2 from degradation mediated by the ubiquitin E3 ligase Siah-1. c-Abl and HIPK2 synergized in activating p53 on apoptotic promoters in a reporter assay, and c-Abl was required for endogenous HIPK2 accumulation and phosphorylation of p53 at Ser(46) in response to DNA damage by γ- and UV radiation. Accumulation of HIPK2 in nuclear speckles and association with promyelocytic leukemia protein (PML) in response to DNA damage were also dependent on c-Abl activity. At high cell density, the Hippo pathway inhibits DNA damage-induced c-Abl activation. Under this condition, DNA damage-induced HIPK2 accumulation, phosphorylation of p53 at Ser(46), and apoptosis were attenuated. These data demonstrate a new mechanism for the induction of DNA damage-induced apoptosis by c-Abl and illustrate network interactions between serine/threonine and tyrosine kinases that dictate cell fate.
%K Carrier Proteins (NLM Chemicals)
%K Tumor Suppressor Protein p53 (NLM Chemicals)
%K HIPK2 protein, human (NLM Chemicals)
%K Proto-Oncogene Proteins c-abl (NLM Chemicals)
%K Protein-Serine-Threonine Kinases (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:25944899
%2 pmc:PMC4505402
%R 10.1074/jbc.M114.628982
%U https://inrepo02.dkfz.de/record/127374