Figure 6: Proposed pathways by which NRG-1 stimulates GSH synthesis and Cbl metabolism. NRG-1 promotes megalin-involved Cbl uptake after which Cbl undergoes dealkylation or decyanation, giving rise to Cbl(II) and subsequently to OHCbl. NRG-1 also stimulates EAAT3-mediated cysteine uptake and promotes GSH synthesis by activating the PI3K signaling pathway. GSH reacts with OHCbl to form GSCbl, which then receives a methyl group from the methyl donor SAM to produce MeCbl. MeCbl functions as the cofactor for MS and increased MS activity promotes the methionine cycle of methylation. The dotted line indicates that multiple steps are involved.