Roles of tyrosine kinases and phosphatases in the formation and dispersal of acetylcholine receptor clusters

The formation of acetylcholine receptor (AChR) clusters at the postsynaptic muscle membrane in response to motor innervation is a key event in the development of the neuromuscular junction. The synaptic AChR clustering process is initiated by motor axon-released agrin, which activates a tyrosine kinase-based signaling pathway to cause AChR aggregation. In cultured muscle cells, AChR clustering is elicited by diverse nonneural signals, and this process is also mediated by tyrosine kinases. Conversely, the formation of new AChR clusters induced by innervation or nonneural stimuli is unfailingly associated with the dispersal of pre-existing AChR clusters, and this process is mediated by tyrosine phosphatases. In this review, we address how local kinase activation leads to global phosphatase action in muscle. More specifically, we discuss the roles of Src kinase and the SH2 domain-containing tyrosine phosphatase Shp-2 in establishing a regenerative mechanism to propagate the AChR cluster dispersing signal extrasynaptically and in defining the boundary of cluster formation subsynaptically.