MuSK is a BMP co-receptor that shapes BMP responses and calcium signaling in muscle cells.
Bone morphogenetic proteins (BMPs) function in most tissues but have cell type-specific effects. Given the relatively small number of BMP receptors, this exquisite signaling specificity requires additional molecules to regulate this pathway's output. The receptor tyrosine kinase MuSK (muscle-specific kinase) is critical for neuromuscular junction formation and maintenance. Here, we show that MuSK also promotes BMP signaling in muscle cells. MuSK bound to BMP4 and related BMPs with low nanomolar affinity in vitro and to the type I BMP receptors ALK3 and ALK6 in a ligand-independent manner both in vitro and in cultured myotubes. High-affinity binding to BMPs required the third, alternatively spliced MuSK immunoglobulin-like domain. In myoblasts, endogenous MuSK promoted BMP4-dependent phosphorylation of SMADs and transcription of Id1, which encodes a transcription factor involved in muscle differentiation. Gene expression profiling showed that MuSK was required for the BMP4-induced expression of a subset of genes in myoblasts, including regulator of G protein signaling 4 (Rgs4). In myotubes, MuSK enhanced the BMP4-induced expression of a distinct set of genes, including transcripts characteristic of slow muscle. MuSK-mediated stimulation of BMP signaling required type I BMP receptor activity but was independent of MuSK tyrosine kinase activity. MuSK-dependent expression of Rgs4 resulted in the inhibition of Ca(2+) signaling induced by the muscarinic acetylcholine receptor in myoblasts. These findings establish that MuSK has dual roles in muscle cells, acting both as a tyrosine kinase-dependent synaptic organizing molecule and as a BMP co-receptor that shapes BMP transcriptional output and cholinergic signaling.
Department of Neuroscience, Brown University, Providence, RI 02912, USA. Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI 02912, USA.
Atilgan
A
Yilmaz
Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, Medical Sciences Building, Cincinnati, OH 45267, USA.
Chandramohan
C
Kattamuri
Department of Molecular Pharmacology, Physiology and Biotechnology, Brown University, Providence, RI 02912, USA.
Rana N
RN
Ozdeslik
Department of Neuroscience, Brown University, Providence, RI 02912, USA.
Carolyn
C
Schmiedel
Department of Neuroscience, Brown University, Providence, RI 02912, USA.
Sarah
S
Mentzer
Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI 02912, USA.
Christoph
C
Schorl
Department of Molecular Pharmacology, Physiology and Biotechnology, Brown University, Providence, RI 02912, USA.
Elena
E
Oancea
Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, Medical Sciences Building, Cincinnati, OH 45267, USA.
Thomas B
TB
Thompson
Department of Neuroscience, Brown University, Providence, RI 02912, USA. justin_fallon@brown.edu.
Justin R
JR
Fallon
D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics / Q000378:metabolism*; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D032446:Myoblasts / Q000166:cytology / Q000378:metabolism*; D020710:RGS Proteins / Q000235:genetics / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011950:Receptors, Cholinergic / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism
C525809:BMP4 protein, human; C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; C497453:ID1 protein, human; C497455:Idb1 protein, mouse; D051798:Inhibitor of Differentiation Protein 1; D020710:RGS Proteins; D011950:Receptors, Cholinergic; D051785:Smad Proteins; C098799:RGS4 protein; C095714:MUSK protein, human; C511695:MuSK protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; C498212:Bmpr1a protein, mouse; C498215:Bmpr1b protein, mouse; D052005:Bone Morphogenetic Protein Receptors, Type I