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

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.

Muscle specific kinase protects dystrophic mdx mouse muscles from eccentric contraction‐induced loss of force‐producing capacity

“…MuSK can thereby modify the transcriptome of the muscle cell (Yilmaz et al . ). Thus it is also possible that extrasynaptic MuSK might somehow tweak the gene expression profile of the mdx muscle fibres in a manner that helps protect them from EC challenge.…”

Tyrosine kinase Eph receptor A6 sensitizes glioma‐initiating cells towards bone morphogenetic protein‐induced apoptosis

“…In the mouse heart, EphA2 deficiency was associated with higher EphA6 expression and reduced cardiomyocyte survival after infarction . In addition to EPHA6, other RTK, including ROR2, MuSK, and TrkC, have been reported to associate with BMP receptors . ROR2 RTK and ALK‐6 form a protein complex, leading to transphosphorylation of ROR2 and activation of non‐SMAD pathways, whereas MuSK RTK binds to ALK‐3 or ALK‐6 and stimulates BMP‐SMAD signaling independently of its tyrosine kinase activity …”

“…44,45 In addition to EPHA6, other RTK, including ROR2, MuSK, and TrkC, have been reported to associate with BMP receptors. [46][47][48] ROR2 RTK and ALK-6 form a protein complex, leading to transphosphorylation of ROR2 and activation of non-SMAD pathways, 46 whereas MuSK RTK binds to ALK-3 or ALK-6 and stimulates BMP-SMAD signaling independently of its tyrosine kinase activity. 47 EPHA6 kinase activity was not necessary for apoptosis induction ( Figure 3), and for impeding tumor growth ( Figure 6).…”

“…[46][47][48] ROR2 RTK and ALK-6 form a protein complex, leading to transphosphorylation of ROR2 and activation of non-SMAD pathways, 46 whereas MuSK RTK binds to ALK-3 or ALK-6 and stimulates BMP-SMAD signaling independently of its tyrosine kinase activity. 47 EPHA6 kinase activity was not necessary for apoptosis induction ( Figure 3), and for impeding tumor growth ( Figure 6). Effects of EPHA6 on apoptosis are likely to be independent of ephrin ligand binding ( Figure S2).…”

Myotonic Discharges in Anti-MuSK Myasthenia

“…7 In addition, MuSK is expressed extrasynaptically in skeletal muscle of mice, and mediates the expression of genes in myoblasts and myotubes via bone morphogenetic proteins, which inhibit calcium signaling induced by muscarinic AchR. 8 Therefore, disruption of calcium signaling by MuSK antibodies, or an as-of-yet undefined role in the regulation of sodium or chloride channels in the muscle membrane, could lead to electrical myotonia.…”