Cyclin Dependent Kinase 5 regulates neuronal cell death via FBXW7-dependent ubiquitination of anti-apoptotic protein
Yeon Uk Ko, Dana Kim and Young J. Oh Department of Systems Biology, Yonsei University College of Life Science and Biotechnology, Seoul 03722, Republic of Korea
Cyclin dependent kinase 5 (CDK5) is a proline-directed serine/threonine kinase and plays a crucial role in proper neuronal development. However, dysregulated CDK5 activity is directly associated with pathogenesis of various neurodegeneration. The CDK5 activity is regulated by association with neuronal specific activator p35 or p39. It is revealed that when neuronal cell was exposed to toxic stimuli, p35 is cleaved to p25 and p10 by activated calpain. Consequently, truncated p25 has been implicated with neurodegeneration as it induces hyperactivity of CDK5. In an effort to find novel endogenous substrates of CDK5 that is involved in neurodegeneration. In this study, we demonstrated that F-Box/WD repeat-containing protein (FBWX7) is a novel CDK5 substrate. Phosphorylation of FBWX7 by CDK5 is determined by in vitro assay and cell-based assay. In presence of p25 activator, levels of the CDK5-mediated phosphorylated FBWX7 was further enhanced. Furthermore, structural mutant analyses indicated that phosphorylation of FBXW7 is dependent on kinase activity and ATP binding pocket of CDK5. FBXW7 is a component of SCFs (SKP1-cullin-F-box) which is known to function in ubiquitination. In subsequent study, we found that MCL-1 is one of the ubiquitinated target protein by FBXW7 component. Ectopic expression study showed that expression level of MCL-1 is reduced in presence of phosphorylated FBXW7 by CDK5. As a results, it is proposed that CDK5 induces cell death through phosphorylation of FBXW7 and phosphorylated FBW7 subsequently reduces expression level of MCL-1 via UPS-mediated degradation. Considering previous reports demonstrating that MCL-1 is a well-known anti-apoptotic bcl-2 family and consistent level of MCL1 is necessary to maintain cellular homeostasis. Our data suggest the interesting cell death regulatory loop of CDK5-FBXW7-MCL1. As a results, it is hypothesized that CDK5 induces cell death through phosphorylation of FBXW7 and phosphorylated FBW7 reduces level of MCL-1.
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