1. Phosphorylation-regulated cleavage of the reticulon protein Nogo-B by caspase-7 at a noncanonical recognition site
- Author
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Thomas Oertle, Christine E. Bandtlow, Rüdiger Schweigreiter, Lukas A. Huber, Taras Stasyk, Igea Contarini, Lars Klimaschewski, and Silke Frauscher
- Subjects
Nogo Proteins ,Molecular Sequence Data ,Apoptosis ,CHO Cells ,Biochemistry ,Caspase 7 ,Substrate Specificity ,Phosphoserine ,Cricetulus ,Cyclin-dependent kinase ,Cricetinae ,mental disorders ,CDC2 Protein Kinase ,Animals ,Humans ,Amino Acid Sequence ,Enzyme Inhibitors ,Phosphorylation ,Molecular Biology ,Caspase ,Cyclin-dependent kinase 1 ,biology ,Kinase ,Cyclin-dependent kinase 2 ,Cyclin-Dependent Kinase 2 ,Molecular biology ,Caspase Inhibitors ,Sciatic Nerve ,Cell biology ,Rats ,Disease Models, Animal ,Reticulon ,biology.protein ,psychological phenomena and processes ,Myelin Proteins - Abstract
Reticulons (RTNs) are a large family of transmembrane proteins present throughout the eukaryotic domain in virtually every cell type. Despite their wide distribution, their function is still mostly unknown. RTN4, also termed Nogo, comes in three isoforms, Nogo-A, -B, and -C. While Nogo-A has been described as potent inhibitor of nerve growth, Nogo-B has been implicated in vascular remodeling and regulation of apoptosis. We show here that Nogo-B gets cleaved by caspase-7, but not caspase-3, during apoptosis at a caspase nonconsensus site. By a combination of MS and site-directed mutagenesis we demonstrate that proteolytic processing of Nogo-B is regulated by phosphorylation of Ser(16) within the cleavage site. We present cyclin-dependent kinase (Cdk)1 and Cdk2 as kinases that phosphorylate Nogo-B at Ser(16) in vitro. In vivo, cleavage of Nogo-B is markedly increased in Schwann cells in a lesion model of the rat sciatic nerve. Taken together, we identified an RTN protein as one out of a selected number of caspase targets during apoptosis and as a novel substrate for Cdk1 and 2. Furthermore, our data support a functionality of caspase-7 that is distinct from closely related caspase-3.
- Published
- 2007