Localized Src Signals in the Synapse

Abstract

Synaptogenesis at the neuromuscular junction requires that agrin, a neurally released soluble factor, binds to its postsynaptic receptor tyrosine kinase, called muscle-specific kinase (MuSK). However, the sequence of signaling events downstream of MuSK activation is not clear, particularly when those signals that regulate the aggregation of acetylcholine receptors (AChRs) are involved. Though a role for Src family kinases has been implicated in AChR subunit phosphorylation and clustering, Mittaud et al. now show that in mammalian myotubes, Src family kinases are constitutively associated with the AChR, independently of agrin. Stimulation of myotubes with agrin specifically activated only Src family kinases associated with AChRs, and not the total cellular kinase pool, suggesting a highly localized response to agrin. Agrin-induced aggregation of AChRs correlated with receptor phosphorylation, and use of inhibitors indicated that the AchRs are substrates for Src kinases and not MuSK. This phosphorylation event was also dependent on the presence of rapsyn, a protein that is known to act downstream of MuSK and is also associated with AChRs. The study supports a model in which MuSK acts as a synaptic scaffold protein, organizing molecules that regulate the phosphorylation of AChRs by Src and assembling AChRs into functional clusters. P. Mittaud, P. A. Marangi, S. Erb-Vögtli, C. Fuhrer, Agrin-induced activation of acetylcholine receptor-bound Src family kinases. J. Biol. Chem. 276 , 14505-14513 (2001). [Abstract] [Full Text]