| First Author | Nagappan-Chettiar S | Year | 2018 |
| Journal | J Biol Chem | Volume | 293 |
| Issue | 31 | Pages | 12026-12042 |
| PubMed ID | 29914984 | Mgi Jnum | J:267152 |
| Mgi Id | MGI:6197445 | Doi | 10.1074/jbc.RA117.001488 |
| Citation | Nagappan-Chettiar S, et al. (2018) Tyrosine phosphorylation of the transmembrane protein SIRPalpha: Sensing synaptic activity and regulating ectodomain cleavage for synapse maturation. J Biol Chem 293(31):12026-12042 |
| abstractText | Synapse maturation is a neural activity-dependent process during brain development, in which active synapses preferentially undergo maturation to establish efficient neural circuits in the brain. Defects in this process are implicated in various neuropsychiatric disorders. We have previously reported that a postsynaptic transmembrane protein, signal regulatory protein-alpha (SIRPalpha), plays an important role in activity-dependently directing synapse maturation. In the presence of synaptic activity, the ectodomain of SIRPalpha is cleaved and released and then acts as a retrograde signal to induce presynaptic maturation. However, how SIRPalpha detects synaptic activity to promote its ectodomain cleavage and synapse maturation is unknown. Here, we show that activity-dependent tyrosine phosphorylation of SIRPalpha is critical for SIRPalpha cleavage and synapse maturation. We found that during synapse maturation and in response to neural activity, SIRPalpha is highly phosphorylated on its tyrosine residues in the hippocampus, a structure critical for learning and memory. Tyrosine phosphorylation of SIRPalpha was necessary for SIRPalpha cleavage and presynaptic maturation, as indicated by the fact that a phosphorylation-deficient SIRPalpha variant underwent much less cleavage and could not drive presynaptic maturation. However, SIRPalpha phosphorylation did not affect its synaptic localization. Finally, we show that inhibitors of the Src and JAK kinase family suppress neural activity-dependent SIRPalpha phosphorylation and cleavage. Together, our results indicate that SIRPalpha phosphorylation serves as a mechanism for detecting synaptic activity and linking it to the ectodomain cleavage of SIRPalpha, which in turn drives synapse maturation in an activity-dependent manner. |
