Resumen de Truncación de GSK-3 por calpaína implicaciones fisiológicas y patológicas

Paloma Goñi Oliver

• GSK-3 activity can be regulated by phosphorylation and through interaction with GSK-3-binding proteins; here we describe N-terminal proteolysis as a novel way to regulate GSK-3. GSK-3¿ and GSK-3ß were truncated by calpain, generating two fragments of 40 and 30 kDa, a proteolytic process that was inhibited by specific calpain inhibitors. The 30 kDa fragment was originated by cleavage of the 49Asp - 50Arg peptide bound. These truncated isoforms were active kinases. We also found that lithium, a GSK-3 inhibitor, inhibits full-length and cleaved GSK-3 isoforms with the same IC50 value. When cultured cortical neurons were exposed with ionomycin, glutamate, or NMDA, GSK-3 was truncated. This truncation was blocked by the calpain inhibitor calpeptin, at the same concentration at which it inhibits calpain-mediated cleavage of other well-known calpain substrates. Truncated GSK-3 forms did not accumulate, suggesting that a short-lived product is formed. GSK-3 truncation mediated by calpain prevents its binding to 14-3-3¿. In addition, overexpression of the truncated GSK-3 form ([50-420]-GSK-3ß) in COS-7 cells showed that the N-terminal is involved in nuclear import, since the truncated form is only present in the cytoplasm.