Role of Striatal-Enriched Tyrosine Phosphatase in Neuronal Function

Figure 1

STEP signaling pathways associated with Alzheimer’s disease. The binding of Aβ to α7nAChRs results in activation of calcineurin (PP2B), inhibition of DARPP-32, and activation of PP1. PP1 dephosphorylates STEP₆₁ at a regulatory serine within the substrate-binding domain (Ser²²¹). Dephosphorylation of this serine residue increases the affinity of STEP for its substrates. In a parallel pathway, Aβ inhibits the proteasome, thereby blocking the degradation of STEP₆₁. Both mechanisms result in an accumulation of active STEP₆₁. The increase in active STEP₆₁ results in increased dephosphorylation of GluN2B Tyr¹⁴⁷² and internalization of GluN2B-containing NMDARs. In addition, dephosphorylation of Fyn results in its inactivation. Thus, active STEP₆₁ directly dephosphorylates GluN2B and at the same time inactivates the kinase that phosphorylates STEP₆₁ at Tyr¹⁴⁷².