PP2Cα positively regulates neuronal insulin signalling and aggravates neuronal insulin resistance.

PP2Cα is one of the newly identified isoforms of metal-dependent protein phosphatases (PPM). The role of this phosphatase in neuronal insulin signalling is completely unknown. In the present study, we show insulin-mediated rapid upregulation of a protein of the insulin signalling cascade, PP2Cα, in mouse N2a cells and human SH-SY5Y cells. By contrast, such PP2Cα upregulation is not observed in insulin-resistant conditions despite insulin stimulation. Here, we report that, under insulin-sensitive and insulin-resistant conditions, the translation of PP2Cα was regulated by insulin through c-Jun N-terminal kinase. PP2Cα in turn dephosphorylated a novel inhibitory site of insulin receptor substrate-1 at Ser522 and AMP-activated protein kinase, hence positively regulating neuronal insulin signalling and insulin resistance.