Phosphorylation and cytoskeletal anchoring of the acetylcholine receptor by Src class protein-tyrosine kinases. Activation by rapsyn.
Src class protein-tyrosine kinases bind to and phosphorylate the nicotinic acetylcholine receptor of skeletal muscle. This study provided evidence for the functional importance of Src kinases in regulating the nicotinic acetylcholine receptor at the neuromuscular junction. Three Src class kinases, Fyn, Fyk, and Src, each formed a complex with the endplate-specific cytoskeletal protein rapsyn. In addition, cellular phosphorylation by each kinase was stimulated by rapsyn in heterologous transfected cells. Several lines of evidence supported rapsyn as a substrate for Src kinases. Most importantly, rapsyn regulation of Fyn, Fyk, and Src resulted in phosphorylation of the nicotinic acetylcholine receptor beta and delta subunits and anchoring of the receptor to the cytoskeleton. Both nicotinic acetylcholine receptor phosphorylation and cytoskeletal anchoring were blocked by the Src kinase-selective inhibitor herbimycin A. Rapsyn alone also induced a modest increase in nicotinic acetylcholine receptor phosphorylation and cytoskeletal translocation. However, inhibition by herbimycin A and a catalytically inactive dominant negative Src demonstrated that the effects of rapsyn were mediated by endogenous Src kinases. These data support the importance of Src class kinases for stabilization of the nicotinic acetylcholine receptor at the endplate during synaptic differentiation at the neuromuscular junction.
Department of Neurology, Division of Neuroscience, Georgetown Institute for Cognitive and Computational Sciences, Georgetown University Medical Center, Washington, D.C. 20007-2197, USA.
A S
AS
Mohamed
S L
SL
Swope
D000595:Amino Acid Sequence; D000818:Animals; D001692:Biological Transport; D002460:Cell Line; D003599:Cytoskeleton / Q000378:metabolism*; D051379:Mice; D009124:Muscle Proteins / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D011950:Receptors, Cholinergic / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000378:metabolism*; D015398:Signal Transduction; D019061:src-Family Kinases / Q000378:metabolism*
D009124:Muscle Proteins; D011950:Receptors, Cholinergic; D011978:Receptors, Nicotinic; C051609:peripheral membrane protein 43K; D019061:src-Family Kinases