This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Mittaud, P.
Right arrow Articles by Fuhrer, C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Mittaud, P.
Right arrow Articles by Fuhrer, C.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, September 2004, p. 7841-7854, Vol. 24, No. 18
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.18.7841-7854.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

A Single Pulse of Agrin Triggers a Pathway That Acts To Cluster Acetylcholine Receptors

Peggy Mittaud,1,{dagger} Alain A. Camilleri,1,{dagger} Raffaella Willmann,1 Susanne Erb-Vögtli,1 Steven J. Burden,2 and Christian Fuhrer1*

Department of Neurochemistry, Brain Research Institute, University of Zürich, Zürich, Switzerland,1 Molecular Neurobiology Program, Skirball Institute for Biomolecular Medicine, New York University Medical School, New York, New York2

Received 31 October 2003/ Returned for modification 22 January 2004/ Accepted 22 June 2004

Agrin triggers signaling mechanisms of high temporal and spatial specificity to achieve phosphorylation, clustering, and stabilization of postsynaptic acetylcholine receptors (AChRs). Agrin transiently activates the kinase MuSK; MuSK activation has largely vanished when AChR clusters appear. Thus, a tyrosine kinase cascade acts downstream from MuSK, as illustrated by the agrin-evoked long-lasting activation of Src family kinases (SFKs) and their requirement for AChR cluster stabilization. We have investigated this cascade and report that pharmacological inhibition of SFKs reduces early but not later agrin-induced phosphorylation of MuSK and AChRs, while inhibition of Abl kinases reduces late phosphorylation. Interestingly, SFK inhibition applied selectively during agrin-induced AChR cluster formation caused rapid cluster dispersal later upon agrin withdrawal. We also report that a single 5-min agrin pulse, followed by extensive washing, triggered long-lasting MuSK and AChR phosphorylation and efficient AChR clustering. Following the pulse, MuSK phosphorylation increased and, beyond a certain level, caused maximal clustering. These data reveal novel temporal aspects of tyrosine kinase action in agrin signaling. First, during AChR cluster formation, SFKs initiate early phosphorylation and an AChR stabilization program that acts much later. Second, a kinase mechanism rapidly activated by agrin acts thereafter autonomously in agrin's absence to further increase MuSK phosphorylation and cluster AChRs.

* Corresponding author. Mailing address: Brain Research Institute, University of Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland. Phone: 41 1 635 33 10. Fax: 41 1 635 33 03. E-mail: chfuhrer{at}hifo.unizh.ch.

{dagger} P.M. and A.A.C. contributed equally to this work.

Molecular and Cellular Biology, September 2004, p. 7841-7854, Vol. 24, No. 18
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.18.7841-7854.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Chevessier, F., Girard, E., Molgo, J., Bartling, S., Koenig, J., Hantai, D., Witzemann, V. (2008). A mouse model for congenital myasthenic syndrome due to MuSK mutations reveals defects in structure and function of neuromuscular junctions. Hum Mol Genet 17: 3577-3595 [Abstract] [Full Text]  
  • Lu, Z., Je, H.-S., Young, P., Gross, J., Lu, B., Feng, G. (2007). Regulation of synaptic growth and maturation by a synapse-associated E3 ubiquitin ligase at the neuromuscular junction. JCB 177: 1077-1089 [Abstract] [Full Text]  
  • Jones, N., Hardy, W. R., Friese, M. B., Jorgensen, C., Smith, M. J., Woody, N. M., Burden, S. J., Pawson, T. (2007). Analysis of a Shc Family Adaptor Protein, ShcD/Shc4, That Associates with Muscle-Specific Kinase. Mol. Cell. Biol. 27: 4759-4773 [Abstract] [Full Text]  
  • Sadasivam, G., Willmann, R., Lin, S., Erb-Vogtli, S., Kong, X. C., Ruegg, M. A., Fuhrer, C. (2005). Src-Family Kinases Stabilize the Neuromuscular Synapse In Vivo via Protein Interactions, Phosphorylation, and Cytoskeletal Linkage of Acetylcholine Receptors. J. Neurosci. 25: 10479-10493 [Abstract] [Full Text]  
  • Charpantier, E., Wiesner, A., Huh, K.-H., Ogier, R., Hoda, J.-C., Allaman, G., Raggenbass, M., Feuerbach, D., Bertrand, D., Fuhrer, C. (2005). {alpha}7 Neuronal Nicotinic Acetylcholine Receptors Are Negatively Regulated by Tyrosine Phosphorylation and Src-Family Kinases. J. Neurosci. 25: 9836-9849 [Abstract] [Full Text]  
  • Martin, A. O., Alonso, G., Guerineau, N. C. (2005). Agrin mediates a rapid switch from electrical coupling to chemical neurotransmission during synaptogenesis. JCB 169: 503-514 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»