Neuroendocrine Protein 7B2 Is Essential for Proteolytic Conversion and Activation of Proprotein Convertase 2in Vivo

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Abstract
The 7B2 protein is widely distributed in neural and endocrine tissues. Its biological function was found to be related to the processing enzyme proprotein convertase 2 (PC2), a mammalian subtilisin/kexin-like endoproteinase that cleaves at specific single or multiple basic amino-acid residues. In order to examine the proposed function of 7B2 on PC2 in in vivo models, we first compared the distribution of 7B2 and PC2 mRNAs in the rat brain. Expression of 7B2 mRNA was found to be pan-neuronal, but additionally, we observed 7B2 mRNA in ependymal cells and in the subcommissural organ. Although the expression of PC2 mRNA was exclusively neuronal, it was more restricted, sparing some regions expressing high levels of 7B2. This finding suggests that 7B2 has an additional function in non-PC2-expressing cells. No evidence of PC2-positive/7B2-negative cells could be obtained in the adult rat brain. However, in the developing rat brain (E17), such regions were easily observed, showing higher levels of pro-PC2 (75 kD). Similarly, in the animal model of insulin-induced hypoglycemic shock, where adrenomedullary 7B2 expression is decreased, the ratio of pro-PC2 to mature PC2 (75 kD:68 kD) was observed to be increased. Finally, the human neuroepithelioma SK-N-MCIXC expresses PC2 but not 7B2. Accordingly, only inactive pro-PC2 forms were observed: 75-kD intracellular and 71-kD extracellular. After stable transfection of SK-N-MCIXC cells with 27-kD pro-7B2, mature and active (68-kD) PC2 was secreted into the medium. Our data demonstrate a critical role of 7B2 in the proteolytic conversion and activation of PC2 in vivo.