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Volume 17, Number 13, Issue of July 1, 1997 pp. 5038-5045
Copyright ©1997 Society for Neuroscience

Tyrosine Phosphorylation of Nicotinic Acetylcholine Receptor Mediates Grb2 Binding

Received Feb. 10, 1997; revised April 8, 1997; accepted April 14, 1997.

Marcie Colledge and Stanley C. Froehner

Department of Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599

Tyrosine phosphorylation of the nicotinic acetylcholine receptor (AChR) is associated with an altered rate of receptor desensitization and also may play a role in agrin-induced receptor clustering. We have demonstrated a previously unsuspected interaction between Torpedo AChR and the adaptor protein Grb2. The binding is mediated by the Src homology 2 (SH2) domain of Grb2 and the tyrosine-phosphorylated  subunit of the AChR. Dephosphorylation of the  subunit abolishes Grb2 binding. A cytoplasmic domain of the  subunit contains a binding motif (pYXNX) for the SH2 domain of Grb2. Indeed, a phosphopeptide corresponding to this region of the  subunit binds to Grb2 SH2 fusion proteins with relatively high affinity, whereas a peptide lacking phosphorylation on tyrosine exhibits no binding. Grb2 is colocalized with the AChR on the innervated face of Torpedo electrocytes. Furthermore, Grb2 specifically copurifies with AChR solubilized from postsynaptic membranes. These data suggest a novel role for tyrosine phosphorylation of the AChR in the initiation of a Grb2-mediated signaling cascade at the postsynaptic membrane.

Key words: acetylcholine receptor; tyrosine phosphorylation; Grb2; SH2 domain; postsynaptic specialization; signal transduction

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