Abstract
The neuromuscular junction (NMJ) forms when a motor neuron contacts a muscle fibre. A reciprocal exchange of signals initiates a cascade of signalling events that result in pre- and postsynaptic differentiation. At the centre of these signalling events stands muscle specific kinase (MuSK). MuSK activation, kinase activity and subsequent downstream signalling are crucial for NMJ formation as well as maintenance. Therefore MuSK kinase activity is tightly regulated to ensure proper NMJ development. We have identified a novel serine phosphorylation site at position 751 in MuSK that is increasingly phosphorylated upon agrin stimulation. S751 is also phosphorylated in muscle tissue and its phosphorylation depends on MuSK kinase activity. A phosphomimetic mutant of S751 increases MuSK kinase activity in response to non-saturating agrin concentrations . In addition, basal MuSK and AChR phosphorylation as well as AChR cluster size are increased. We believe that the phosphorylation of S751 provides a novel mechanism to relief the autoinhibition of the MuSK activation loop. Such a lower autoinhibition could foster or stabilize MuSK kinase activation, especially during stages when no or low level of agrin are present. Phosphorylation of S751 might therefore represent a novel mechanism to modulate MuSK kinase activity during prepatterning or NMJ maintenance.
Highlights
The vertebrate neuromuscular junction (NMJ) represents a special chemical synapse between a motor neuron and a skeletal muscle fibre
In addition to muscle specific kinase (MuSK) tyrosine phosphorylation, we identified a novel phosphorylation site on S751, which is upregulated during late agrin stimulation
S751 is located in the activation loop of the MuSK kinase domain between Y750 and Y754/Y755, which are critical for MuSK activation
Summary
The vertebrate neuromuscular junction (NMJ) represents a special chemical synapse between a motor neuron and a skeletal muscle fibre. Several lines of evidence have shown that MuSK kinase activity and MuSK scaffolding ability are crucial for NMJ formation: (1) expression of MuSK mutants with a defective kinase domain inhibits agrin-induced AChR clustering[11]; (2) tyrosine kinase inhibitors block agrin-induced AChR clustering[12]; (3) specific residues in the MuSK cytoplasmic domain, in particular a NPXY motif in the juxtamembrane region, are required for down-stream signalling[13,14]; (4) several molecules including scaffolding proteins, adaptor proteins, kinases and phosphatases have been identified that are downstream from MuSK1 We found an increased AChR cluster size in response to agrin further supporting the notion that S751 modulates MuSK kinase activity upon agrin stimulation
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