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Analysis of a Shc family Print E-mail
Written by Jones, N.   
Wednesday, 31 January 2007

Analysis of a Shc family adaptor protein, ShcD/Shc4, that associates with muscle-specific kinase

Jones N, Hardy WR, Friese MB, Jorgensen C, Smith MJ, Woody NM, Burden SJ, Pawson T.

Mol Cell Biol. 2007 July 27(13): 4759-4773.

PMID: 17452444

DOI: 10.1128/MCB.00184-07

Shc family proteins serve as phosphotyrosine adaptor molecules in various receptor-mediated signaling pathways. In mammals, three distinct Shc genes have been described that encode proteins characterized by two phosphotyrosine-interaction modules, an amino-terminal phosphotyrosine binding (PTB) domain and a carboxy-terminal Src homology 2 domain. Here we report the analysis of an uncharacterized fourth Shc family protein, ShcD/Shc4, that is expressed in adult brain and skeletal muscle. Consistent with this expression pattern, we find that ShcD can associate via its PTB domain with the phosphorylated Muscle-Specific Kinase (MuSK) receptor tyrosine kinase, and undergo tyrosine phosphorylation downstream of activated MuSK. Interestingly, additional sites of tyrosine phosphorylation, including a novel Grb2 binding site, are present on ShcD that are not found in other Shc family proteins. Activation of MuSK upon agrin binding at the neuromuscular junction (NMJ) induces clustering and tyrosine phosphorylation of acetylcholine receptors (AChRs) required for synaptic transmission. ShcD is co-expressed with MuSK in the postsynaptic region of the NMJ, and in cultured myotubes stimulated with agrin, expression of ShcD appears to be important for early tyrosine phosphorylation of the AChR. Thus we have characterized a new member of the Shc family of docking proteins, which may mediate a specific aspect of signaling downstream of the MuSK receptor.



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