MuSK Kinase Activity is Modulated By A Serine Phosphorylation Site in The Kinase Loop.
The neuromuscular junction (NMJ) forms when a motor neuron contacts a muscle fibre. A reciprocal exchange of signals initiates a cascade of signalling events that result in pre- and postsynaptic differentiation. At the centre of these signalling events stands muscle specific kinase (MuSK). MuSK activation, kinase activity and subsequent downstream signalling are crucial for NMJ formation as well as maintenance. Therefore MuSK kinase activity is tightly regulated to ensure proper NMJ development. We have identified a novel serine phosphorylation site at position 751 in MuSK that is increasingly phosphorylated upon agrin stimulation. S751 is also phosphorylated in muscle tissue and its phosphorylation depends on MuSK kinase activity. A phosphomimetic mutant of S751 increases MuSK kinase activity in response to non-saturating agrin concentrations . In addition, basal MuSK and AChR phosphorylation as well as AChR cluster size are increased. We believe that the phosphorylation of S751 provides a novel mechanism to relief the autoinhibition of the MuSK activation loop. Such a lower autoinhibition could foster or stabilize MuSK kinase activation, especially during stages when no or low level of agrin are present. Phosphorylation of S751 might therefore represent a novel mechanism to modulate MuSK kinase activity during prepatterning or NMJ maintenance.
Center for Brain Research, Medical University of Vienna, Spitalgasse 4, 1090 Vienna, Austria.
B Z
BZ
Camurdanoglu
Center for Brain Research, Medical University of Vienna, Spitalgasse 4, 1090 Vienna, Austria.
C
C
Hrovat
Institute for Molecular Pathology (IMP), Dr. Bohr-Gasse 7, 1030 Vienna, Austria.|Institute of Molecular Biotechnology (IMBA), Dr. Bohr-Gasse 3, 1030 Vienna, Austria.|Gregor Mendel Institute (GMI), Austrian Academy of Sciences, Vienna Biocenter (VBC), Dr. Bohr-Gasse 3, 1030 Vienna, Austria.
G
G
Dürnberger
Institute for Molecular Pathology (IMP), Dr. Bohr-Gasse 7, 1030 Vienna, Austria.|Institute of Molecular Biotechnology (IMBA), Dr. Bohr-Gasse 3, 1030 Vienna, Austria.
M
M
Madalinski
Institute for Molecular Pathology (IMP), Dr. Bohr-Gasse 7, 1030 Vienna, Austria.|Institute of Molecular Biotechnology (IMBA), Dr. Bohr-Gasse 3, 1030 Vienna, Austria.
K
K
Mechtler
Center for Brain Research, Medical University of Vienna, Spitalgasse 4, 1090 Vienna, Austria.|Institute of Immunology, Medical University of Vienna, Lazarettgasse 19, 1090 Vienna, Austria.
R
R
Herbst
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