Abstract
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.
Highlights
The formation of specialized contacts between cells is known to involve the integration of cues from different signaling pathways
Laminin-induced acetylcholine receptors (AChRs) clustering is impaired by the Rho kinase inhibitor Y-27632
Agrin and laminin use distinct transmembrane receptors to initiate AChR clustering, their signaling pathways converge at the level of Rho GTPase activation
Summary
The formation of specialized contacts between cells is known to involve the integration of cues from different signaling pathways. A prominent aspect of this specialization that is crucial for synapse function is the concentration of high densities of nicotinic acetylcholine receptors (AChR) in the postsynaptic membrane (Sanes and Lichtman, 1999; Sanes and Lichtman, 2001). There is evidence that multiple incoming signals are integrated to produce the clustering of AChR and associated components at these sites (Burden, 1998; Sanes and Lichtman, 2001). The ECM glycoprotein, laminin, is known to play a role in postsynaptic membrane organization including AChR clustering (Colognato and Yurchenco, 2000; Patton et al, 1997; Vogel et al, 1983). Laminin-induced AChR clustering, probably uses a different transmembrane signaling pathway than agrin. Soluble laminin has been reported to transduce AChR clustering through the ␣71 integrin and ␣-
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