Fig. 4.

STEP substrates. When dephosphorylated at Ser²²¹, STEP binds to and desphosphorylates ERK1/2, p38, Fyn, Pyk2, the NMDAR subunit GluN2B, and the AMPAR subunit GluA2. STEP dephosphorylates the regulatory active sites on ERK1/2 (Tyr^204/187), p38 (Tyr¹⁸²), Fyn (Tyr⁴²⁰) and Pyk2 (Tyr⁴⁰²) leading to their inactivation. STEP₆₁ regulates the phosphorylation of GluN2B-containing NMDARs by two parallel mechanisms. First, when Fyn is inactivated by STEP₆₁, Fyn-mediated phosphorylation of GluN2B Tyr¹⁴⁷² is reduced. Second, STEP₆₁ dephosphorylates GluN2B Tyr¹⁴⁷² directly. Dephosphorylation of Tyr¹⁴⁷² promotes the interaction of GluN2B with clathrin adaptor proteins and leads to endocytosis of these receptors. It is noteworthy that in this model, dephosphorylation of GluN2B Tyr¹⁴⁷² is depicted to occur extrasynaptically, where clathrin adaptor proteins reside to mediate receptor internalization. This event must occur with a prior signal triggering movement of GluN2B-containing receptors from synaptic sites to extrasynaptic sites. Another possibility is that GluN2B Tyr¹⁴⁷² dephosphorylation occurs synaptically, and this event acts as the signal to trigger lateral movement of GluN2B-containing receptors to extrasynaptic sites. Further work is required to address these two possibilities. In addition, Pyk2 is upstream of Fyn-mediated phosphorylation and enhancement of GluN2B-containing NMDARs. STEP₆₁ is also required for the internalization of GluA1/GluA2-containing AMPARs after mGluR stimulation. Although the molecular mechanisms underlying tyrosine-dependent internalization of AMPARs remains incompletely understood, STEP₆₁ seems to promote the endocytosis of AMPARs in a manner similar to that in which it promotes NMDARs, by dephosphorylating a key tyrosine residue.