Function and regulation of HIPK2
The evolutionary conserved serine/threonine kinase and tumor suppressor Homeodomain-interacting protein kinase 2 (HIPK2) is an important regulator of cell growth, cell death and differentiation. Tumor cells tend to inactivate HIPK2 through different mechanisms, involving HIPK2 downregulation, mutation and mislocalization.
Using protein-protein interaction screens we identified numerous novel HIPK2 client proteins which are currently functionally characterized. Using this approach, we hope to gain insight in the molecular mechanisms of HIPK2īs tumor suppressive function.
Our previous work showed that HIPK2 activates the tumor suppressor p53 in response to various forms of DNA damage (Hofmann et al, 2002; Dauth et al., 2007). Upon lethal damage HIPK2 site-specifically phosphorylates p53 at serine residue 46 and thereby activates the apoptotic program finally leading to cell death. Remarkably, HIPK2 activation also causes apoptosis in the absence of p53 (Hofmann et al., 2003), which is frequently mutated or functionally inactivated in human cancer.
More recent work of our group addressed the mechanism of HIPK2 activation. We found that the checkpoint kinase ATM is strictly required for DNA damage-induced HIPK2 activation and p53 Ser46 phosphorylation by facilitating HIPK2 accumulation (Dauth et al., 2007).
Very recent data from our lab provided a more detailed molecular framework of HIPK2 regulation in unstressed and in DNA-damged cells. We could demonstrate that HIPK2 protein levels are kept low in unstressed cells through interaction with the E3 ubiquitin ligase Siah-1, which facilitates HIPK2 poly-ubiquitination and proteasome-dependent degradation. In response to DNA damage, the checkpoint kinases ATM and ATR, which are essential for HIPK2 activation, mediate disruption of the HIPK2-Siah-1 complex thus allowing HIPK2 stabilization and activation. Mechanistically, disruption of the HIPK2-Siah-1 complex involves phosphorylation of Siah-1 at serine residue 19 by ATM and ATR. Once stabilized, HIPK2 can activate the apoptotic machinery in response to severe damage, whereas HIPK2 is again rapidly degraded via a p53-driven Siah-1-dependent trail in cells that recover from DNA damage (Winter et al., 2008).
Since HIPK2 appears to be essential for induction of cell death upon DNA damage, which is the mode of action of most anti-cancer therapies, the HIPK2-Siah-1 complex might be a promising target in cancer treatment.
For selective reading:
Winter et al., Nature Cell Biology, 2008.
Dauth et al., Cancer Research, 2007.
Hofmann et al., J.Biol.Chem., 2005.
Hofmann et al., Cancer Research, 2003.
Hofmann et al., Nature Cell Biology, 2002.
