| First Author | Xu J | Year | 2015 |
| Journal | J Neurochem | Volume | 134 |
| Issue | 4 | Pages | 629-41 |
| PubMed ID | 25951993 | Mgi Jnum | J:224941 |
| Mgi Id | MGI:5689775 | Doi | 10.1111/jnc.13160 |
| Citation | Xu J, et al. (2015) Striatal-enriched protein tyrosine phosphatase regulates the PTPalpha/Fyn signaling pathway. J Neurochem 134(4):629-41 |
| abstractText | The tyrosine kinase Fyn has two regulatory tyrosine residues that when phosphorylated either activate (Tyr(420)) or inhibit (Tyr(531)) Fyn activity. Within the central nervous system, two protein tyrosine phosphatases (PTPs) target these regulatory tyrosines in Fyn. PTPalpha dephosphorylates Tyr(531) and activates Fyn, while STEP (STriatal-Enriched protein tyrosine Phosphatase) dephosphorylates Tyr(420) and inactivates Fyn. Thus, PTPalpha and STEP have opposing functions in the regulation of Fyn; however, whether there is cross talk between these two PTPs remains unclear. Here, we used molecular techniques in primary neuronal cultures and in vivo to demonstrate that STEP negatively regulates PTPalpha by directly dephosphorylating PTPalpha at its regulatory Tyr(789). Dephosphorylation of Tyr(789) prevents the translocation of PTPalpha to synaptic membranes, blocking its ability to interact with and activate Fyn. Genetic or pharmacologic reduction in STEP61 activity increased the phosphorylation of PTPalpha at Tyr(789), as well as increased translocation of PTPalpha to synaptic membranes. Activation of PTPalpha and Fyn and trafficking of GluN2B to synaptic membranes are necessary for ethanol (EtOH) intake behaviors in rodents. We tested the functional significance of STEP61 in this signaling pathway by EtOH administration to primary cultures as well as in vivo, and demonstrated that the inactivation of STEP61 by EtOH leads to the activation of PTPalpha, its translocation to synaptic membranes, and the activation of Fyn. These findings indicate a novel mechanism by which STEP61 regulates PTPalpha and suggest that STEP and PTPalpha coordinate the regulation of Fyn. STEP61 , PTPalpha, Fyn, and NMDA receptor (NMDAR) have been implicated in ethanol intake behaviors in the dorsomedial striatum (DMS) in rodents. Here, we report that PTPalpha is a novel substrate for STEP61. Upon ethanol exposure, STEP61 is phosphorylated and inactivated by protein kinase A (PKA) signaling in the DMS. As a result of STEP61 inhibition, there is an increase in the phosphorylation of PTPalpha, which translocates to lipid rafts and activates Fyn and subsequent NMDAR signaling. The results demonstrate a synergistic regulation of Fyn-NMDAR signaling by STEP61 and PTPalpha, which may contribute to the regulation of ethanol-related behaviors. NMDA, N-methyl-D-aspartate; PTPalpha, receptor-type protein tyrosine phosphatase alpha; STEP, STriatal-Enriched protein tyrosine Phosphatase. |
