PAR-1 kinase phosphorylates Dlg and regulates its postsynaptic targeting at the Drosophila neuromuscular junction

Targeting of synaptic molecules to their proper location is essential for synaptic differentiation and plasticity. PSD-95/Dig proteins have been established as key components of the post-synapse. However, the molecular mechanisms regulating the synaptic targeting, assembly, and disassembly of PSD-95/Dlg are not well understood. Here we show that PAR-1 kinase, a conserved cell polarity regulator, is critically involved in controlling the postsynaptic localization of Dig. PAR-1 is prominently localized at the Drosophila neuromuscular junction (NMJ). Loss of PAR-1 function leads to increased synapse formation and synaptic transmission, whereas overexpression of PAR-1 has the opposite effects. PAR-1 directly phosphorylates Dig at a conserved site and negatively regulates its mobility and targeting to the postsynapse. The ability of a nonphosphorylatable Dig to largely rescue PAR-1-induced synaptic defects supports the idea that Dig is a major synaptic substrate of PAR-1. Control of Dig synaptic targeting by PAR-1-mediated phosphorylation thus constitutes a critical event in synaptogenesis.