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.