Figure 9

A model for Shp2-dependent regulation of AChR redistribution. Synaptogenic stimuli initiate two SIRPα1/Shp2-involving signaling cascades. Agrin/MuSK stimulates src family tyrosine kinases that, in addition to phosphorylating MuSK, phosphorylate SIRPα1 to activate Shp2, which then dephosphorylates (on tyr527) and stimulates more src, and thus more SIRPα1/Shp2, etc., to propagate the dispersal signal that disassembles pre-patterned AChR clusters at extrasynaptic sites. Locally at postsynaptic sites, SIRPα1/Shp2 signaling triggered by MuSK/src acts through a feedback loop to restrain the MuSK-initiated AChR clustering signal, which helps generate new AChR clusters selectively at postsynaptic sites. This form of regenerative signaling through src, SIRPα1 and Shp2 also has built-in self-regulation because Shp2 can dephosphorylate SIRPα1 to control its own activation state.