TY  - JOUR
AU  - Reuven, Nina
AU  - Adler, Julia
AU  - Porat, Ziv
AU  - Polonio-Vallon, Tilman
AU  - Hofmann, Thomas
AU  - Shaul, Yosef
TI  - The Tyrosine Kinase c-Abl Promotes Homeodomain-interacting Protein Kinase 2 (HIPK2) Accumulation and Activation in Response to DNA Damage.
JO  - The journal of biological chemistry
VL  - 290
IS  - 27
SN  - 1083-351X
CY  - Bethesda, Md.
PB  - Soc.
M1  - DKFZ-2017-03399
SP  - 16478 - 16488
PY  - 2015
AB  - 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.
KW  - Carrier Proteins (NLM Chemicals)
KW  - Tumor Suppressor Protein p53 (NLM Chemicals)
KW  - HIPK2 protein, human (NLM Chemicals)
KW  - Proto-Oncogene Proteins c-abl (NLM Chemicals)
KW  - Protein-Serine-Threonine Kinases (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:25944899
C2  - pmc:PMC4505402
DO  - DOI:10.1074/jbc.M114.628982
UR  - https://inrepo02.dkfz.de/record/127374
ER  -