Agrin and laminin induce acetylcholine receptor clustering by convergent, Rho GTPase-dependent signaling pathways.
During neuromuscular junction formation, extracellular matrix-mediated signals cause muscle surface acetylcholine receptors (AChRs) to aggregate at synaptic sites. Two extracellular matrix proteins, agrin and laminin, have each been shown to initiate signaling pathways that culminate in AChR clustering in cultured muscle cells. Here we present evidence that laminin-induced AChR clustering is mediated by the activation of the Rho GTPases Cdc42, Rac and Rho. Clustering in response to laminin is blocked by the dominant negative mutants Cdc42N17, RacN17 and RhoN19, as well as by the Rho inhibitor C3 transferase. Moreover, laminin-induced AChR clustering is impaired by the Rho kinase inhibitor Y-27632. Agrin-induced AChR clustering has previously been shown to require activation of Cdc42, Rac and Rho. Therefore, although agrin and laminin use distinct transmembrane receptors to initiate AChR clustering, their signaling pathways converge at the level of Rho GTPase activation.
Weston
Christi A
CA
Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY 11794, USA.
Teressa
Getu
G
Weeks
Benjamin S
BS
Prives
Joav
J
D036002:ADP Ribose Transferases / Q000494:pharmacology; D018171:Agrin / Q000494:pharmacology*; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001905:Botulinum Toxins / Q000494:pharmacology; D002478:Cells, Cultured; D019204:GTP-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007797:Laminin / Q000494:pharmacology*; D051379:Mice; D008856:Microscopy, Fluorescence; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009469:Neuromuscular Junction / Q000187:drug effects / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011950:Receptors, Cholinergic / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D014162:Transfection; D020764:cdc42 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
D018171:Agrin; D051017:Apoptosis Regulatory Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007797:Laminin; D011950:Receptors, Cholinergic; C498395:Rtkn protein, mouse; D036002:ADP Ribose Transferases; C063007:exoenzyme C3, Clostridium botulinum; D020928:Mitogen-Activated Protein Kinases; D001905:Botulinum Toxins; D019204:GTP-Binding Proteins; D020764:cdc42 GTP-Binding Protein; D020744:rac GTP-Binding Proteins; D020741:rho GTP-Binding Proteins