Regulation of the proapoptotic activity of huntingtin interacting protein 1 by Dyrk1 and caspase-3 in hippocampal neuroprogenitor cells

Dual specific protein kinase Dyrks are thought to play a key role in the regulation of cell growth in a variety of cellular systems. Interestingly, human Dyrk1 is mapped to the Down's syndrome (DS) critical region on chromosome 21, and thought to be a candidate gene responsible for the mental retardation of DS patients. Huntingtin‐interacting protein 1 (Hip‐1), a proapoptotic mediator, is implicated as a molecular accomplice in the pathogenesis of Huntington's disease. In the present study we found that Dyrk1 selectively binds to and phosphorylates Hip‐1 during the neuronal differentiation of embryonic hippocampal neuroprogenitor (H19‐7) cells. The Dyrk1‐mediated phosphorylation of Hip‐1, in response to bFGF, resulted in the blockade of Hip‐1‐mediated neuronal cell death as well as the enhancement of neurite outgrowth. Furthermore, the addition of etoposide to proliferating H19‐7 cells caused the diminished binding of Hip‐1 to Dyrk1 and the levels of phosphorylated Hip‐1 remarkably decreased. Simultaneously, the dissociated Hip‐1 from Dyrk1 bound to caspase‐3 in response to etoposide, which led to its activation and consequently cell death in H19‐7 cells. These data suggest that the phosphorylation of Hip‐1 by Dyrk1 has a dual role in regulating neuronal differentiation and cell death. The interaction between Dyrk1 and Hip‐1 appeared to be differentially modulated by different kinds of stimuli, such as bFGF and etoposide in H19‐7 cells. © 2005 Wiley‐Liss, Inc.