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At neuromuscular synapses, agrin stabilizes postsynaptic acetylcholine receptor (AChR) clusters by signaling through the Muscle Specific Kinase (MuSK) complex.Imaging of cultured myotubes showed that the formation and disassembly of primitive AChR clusters is a dynamic and reversible process favored by agrin, and possibly other synaptic signals.Recent studies suggest that neuregulin-1-ErbB signaling can modulate agrin-induced AChR clustering independent of its effects on transcription.Our recent work has shown that when injected into muscles of embryonic mice, neuregulin1 increased the size of developing AChR clusters.We have investigated this phenomenon using cultured myotubes, and found that in the presence of agrin, neuregulin-1 potentiates AChR clustering by increasing the tyrosine phosphorylation of MuSK.This potentiation appears to be mediated by Shp2, a postsynaptic tyrosine phosphatase known to modulate the activity of MuSK.Our results provide new evidence that neuregulin-1 modulates the signaling activity of MuSK and hence may function as a second order regulator of postsynaptic AChR clustering at the neuromuscular synapse.Thus two classic synaptic signaling systems (neuregulin-1 and agrin) converge upon MuSK to regulate postsynaptic differentiation.