Activation of Phosphotyrosine-Mediated Signaling Pathways in the Cortex and Spinal Cord of SOD1^G93A, a Mouse Model of Familial Amyotrophic Lateral Sclerosis

Figure 5

Schematic representation of STEP-mediated signaling cascade in ALS. Exposure to mutant SOD1 (mSOD1)/oxidative stress leads to inactivation of STEP, reasonably through inactivation of PP2B (calcineurin)/PP1 pathway, and activation of src kinases, both of which drive the tyrosine phosphorylation of the GluN2B subunit. In addition, as a consequence of STEP downregulation, Pyk2 becomes hyperphosphorylated and activated. Phospho-Pyk2 (pPyk2), in turn, upregulates NMDAR function by further activating src kinase, thus contributing to the potentiation of the activation loop. Red points and triangle represent phosphate groups at tyrosine and serine residues, respectively.