Figure 4.

Proposed model for the interaction between S-nitrosylation of Ras and other targets of S-nitrosylation in neuronal cells. Ras can be activated following the stimulation of RTK with the consequent transduction of three main signaling pathways: RalGEF, PI3K and MAPK. Ras can also be activated by S-nitrosylation, independent of the stimulation of the RTK. In this case, several members of the PI3K and MAPK cascades are also S-nitrosylated. S-nitrosylation of RalGEF elements in neuronal cells are not known. S-Nitrosylation of 14-3-3 proteins enhances the ERK1/2 MAPK signaling by interacting with the most upstream protein, Raf. S-Nitrosylation of PEBP-1 releases its inhibitory effect upon the Raf/MEK1/2/ERK1/2, promoting the activation of this pathway. hnRNP K S-nitrosylation also contributes to the activation of this MAPK signaling by interacting with ERK1/2. S-Nitrosylated PTEN is signaled to degradation via the UPS, promoting the activation of the Akt cascade. S-Nitrosylation of Akt results in a diminished proliferation of cells. AKT: protein kinase B (PKB), ERK1/2: extracellular signal-related kinases 1 and 2, GDP: guanosine diphosphate, GTP: guanosine triphosphate, hnRNP K: heterogeneous nuclear ribonucleoprotein K, MEK1/2: mitogen-activated protein kinase kinase 1 and 2, NF-kB: nuclear factor kappa B, NO: nitric oxide, NOS: nitric oxide synthase, PEBP-1: phosphatidylethanolamine binding protein 1, PI3K: phosphoinositide-3 kinase, PTEN: phosphatase and tensin homolog, RTK: receptor tyrosine kinase. Arrows (→) in the figure means activation and this symbol (⊥) means blockade.