Kinase- and rapsyn-independent activities of the muscle-specific kinase (MuSK).
The muscle-specific receptor tyrosine kinase (MuSK) is co-localized with nicotinic acetylcholine receptors (AChRs) in the postsynaptic membrane of the skeletal neuromuscular junction, and is required for all known aspects of postsynaptic differentiation. Studies in vitro have shown that Z(+)-agrin, a nerve-derived proteoglycan, activates MuSK's kinase activity to promote clustering of AChRs and MuSK itself with a cytoplasmic, receptor-associated protein, rapsyn. These studies, however, have used soluble forms of agrin, whereas agrin is cell- or matrix-attached in vivo. We show here that immobilized (particle- or cell-attached) agrin but not soluble agrin is able to aggregate MuSK in the absence of rapsyn and that this aggregation does not require MuSK's kinase activity but does require MuSK's cytoplasmic domain. Moreover, immobilized agrin can promote clustering of AChRs by a mechanism that requires MuSK and rapsyn but does not require MuSK's kinase activity. These results imply that rapsyn and signaling components activated by MuSK kinase may be dispensable for some early aspects of postsynaptic differentiation.
Bromann
P A
PA
Department of Anatomy and Neurobiology, Washington University Medical School, 660 South Euclid, St. Louis, MO 63110, USA.
Zhou
H
H
Sanes
J R
JR
D018171:Agrin / Q000494:pharmacology / Q000502:physiology; D000818:Animals; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D004622:Embryo, Mammalian; D004789:Enzyme Activation; D049452:Green Fluorescent Proteins; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008164:Luminescent Proteins / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D032446:Myoblasts / Q000187:drug effects / Q000378:metabolism*; D019006:Neural Cell Adhesion Molecules / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010770:Phosphotransferases / Q000378:metabolism*; D011940:Receptor Aggregation / Q000187:drug effects / Q000502:physiology; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D011950:Receptors, Cholinergic / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection / Q000379:methods
D018171:Agrin; D008164:Luminescent Proteins; D009124:Muscle Proteins; D019006:Neural Cell Adhesion Molecules; D011950:Receptors, Cholinergic; D011978:Receptors, Nicotinic; C051609:peripheral membrane protein 43K; D049452:Green Fluorescent Proteins; D010770:Phosphotransferases; D019869:Phosphatidylinositol 3-Kinases; C095714:MUSK protein, human; D020794:Receptor Protein-Tyrosine Kinases