医学英文文献VIP专享

RAPSYN CARBOXYL TERMINAL DOMAINS MEDIATE MUSCLESPECIFIC KINASE–INDUCED PHOSPHORYLATION OFTHE MUSCLE ACETYLCHOLINE RECEPTORY. LEE, J. RUDELL, S. YECHIKHOV, R. TAYLOR,S. SWOPE AND M. FERNS*Departments of Anesthesiology and Physiology and Membrane Biol-ogy, One Shields Avenue, University of California Davis, Davis, CA95616, USAAbstract—At the developing vertebrate neuromuscular junc-tion, postsynaptic localization of the acetylcholine receptor(AChR) is regulated by agrin signaling via the muscle specifickinase (MuSK) and requires an intracellular scaffolding pro-tein called rapsyn. In addition to its structural role, rapsyn isalso necessary for agrin-induced tyrosine phosphorylation ofthe AChR, which regulates some aspects of receptor local-ization. Here, we have investigated the molecular mechanismby which rapsyn mediates AChR phosphorylation at the ro-dent neuromuscular junction. In a heterologous COS cellsystem, we show that MuSK and rapsyn induced phosphor-ylation of ␤ subunit tyrosine 390 (Y390) and ␦ subunit Y393,as in muscle cells. Mutation of ␤ Y390 or ␦ Y393 did not inhibitMuSK/rapsyn-induced phosphorylation of the other subunitin COS cells, and mutation of ␤ Y390 did not inhibit agrin-induced phosphorylation of the ␦ subunit in Sol8 musclecells; thus, their phosphorylation occurs independently,downstream of MuSK activation. In COS cells, we furthershow that MuSK-induced phosphorylation of the ␤ subunitwas mediated by rapsyn, as MuSK plus rapsyn increased ␤Y390 phosphorylation more than rapsyn alone and MuSKalone had no effect. Intriguingly, MuSK also induced tyrosinephosphorylation of rapsyn itself. We then used deletion mu-tants to map the rapsyn domains responsible for activation ofcytoplasmic tyrosine kinases that p...