Differential intracellular localization and dynamic nucleocytoplasmic shuttling of homeodomain-interacting protein kinase family members.

The three canonical members of the family of homeodomain-interacting protein (HIP) kinases fulfill overlapping and distinct roles in cellular stress response pathways. Here we systematically compared all three endogenous HIPKs for their intracellular distribution and mutual interactions. The endogenous HIPKs are contained in high molecular weight complexes of ~700 kDa but do not directly interact physically. Under basal conditions, HIPK1 was mostly cytoplasmic, while HIPK3 was found in the nucleus and HIPK2 occurred in both compartments. Inhibition of nuclear export by leptomycin B resulted in the nuclear accumulation of mainly HIPK1 and HIPK2, indicating constitutive dynamic nucleocytoplasmic shuttling. The carcinogenic chemical stressor sodium arsenite caused the induction of HIPK2-dependent cell death and also resulted in a rapid and complete nuclear translocation of HIPK2, showing that the intracellular distribution of this kinase can undergo dynamic regulation.