Role for the pleckstrin homology domain-containing protein CKIP-1 in AP-1 regulation and apoptosis

The oncogenic transcription factor c- Jun plays an important role in cell proliferation, transformation and differentiation. All identified c- Jun- interacting proteins are localized to the nucleus or cytoplasm and function in their intact forms. Here we show that the pleckstrin homology domain- containing protein CKIP- 1 ( casein kinase 2- interacting protein- 1) functions as a plasma membrane-bound AP- 1 regulator. During apoptosis, CKIP- 1 is cleaved by caspase- 3 and translocated to the cytoplasm and then to the nucleus. C- terminal fragments of cleaved CKIP- 1 strongly repress AP- 1 activity. Importantly, CKIP- 1 overexpression promotes apoptosis by forming a positive feedback loop between CKIP- 1 and caspase- 3. RNA interference of CKIP- 1 or overexpression of c- Jun attenuates the sensitivity to apoptosis, indicating a novel role of CKIP- 1 in apoptosis. CKIP- 1 is the first case of a c- Jun- interacting protein that regulates AP- 1 activity via caspase- 3- dependent cleavage and translocation.