Research ArticleMUSCLE DEVELOPMENT

MuSK is a BMP co-receptor that shapes BMP responses and calcium signaling in muscle cells

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Sci. Signal.  06 Sep 2016:
Vol. 9, Issue 444, pp. ra87
DOI: 10.1126/scisignal.aaf0890

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Muscles need MuSK twice

Muscle-specific kinase (MuSK) is a receptor tyrosine kinase that is required for the formation and maintenance of neuromuscular junctions. Yilmaz et al. found that MuSK also functions as a co-receptor for bone morphogenetic proteins (BMPs) in myoblasts and in myotubes. MuSK bound to BMPs and BMP receptors in vitro and promoted signaling by BMPs in muscle cells. MuSK promoted the expression of distinct sets of BMP-induced transcripts in myoblasts and myotubes in a manner that was independent of its kinase activity. One of the transcripts stimulated by MuSK-BMP signaling in myoblasts was required for the ability of BMP4 to inhibit intracellular calcium release in response to activation of muscarinic acetylcholine receptors. Thus, in addition to playing a critical role in organizing the neuromuscular junction, MuSK also acts as a BMP co-receptor in developing muscles.

Abstract

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 Ca2+ 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.

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