Molecular Target Synopsis
Overview
Domains and Structures
Drugs and Clinical Candidates
Druggability
Chemistry
Ligand Efficiency Plot
Pathways
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Interaction Network
Gene Expression
Gene Copy Number Variation
RNAi
Mutations
Germline Genetics

MUSK (O15146) - Overview - Molecular Target Synopsis

Protein


MUSK, Muscle, skeletal receptor tyrosine-protein kinase
Enzyme Classification 2.7.10.1
UniProt O15146

Also Known as MUSK_HUMAN, MUSK

Receptor tyrosine kinase which plays a central role in the formation and the maintenance of the neuromuscular junction (NMJ), the synapse between the motor neuron and the skeletal muscle (PubMed:25537362). Recruitment of AGRIN by LRP4 to the MUSK signaling complex induces phosphorylation and activation of MUSK, the kinase of the complex. The activation of MUSK in myotubes regulates the formation of NMJs through the regulation of different processes including the specific expression of genes in subsynaptic nuclei, the reorganization of the actin cytoskeleton and the clustering of the acetylcholine receptors (AChR) in the postsynaptic membrane. May regulate AChR phosphorylation and clustering through activation of ABL1 and Src family kinases which in turn regulate MUSK. DVL1 and PAK1 that form a ternary complex with MUSK are also important for MUSK-dependent regulation of AChR clustering. May positively regulate Rho family GTPases through FNTA. Mediates the phosphorylation of FNTA which promotes prenylation, recruitment to membranes and activation of RAC1 a regulator of the actin cytoskeleton and of gene expression. Other effectors of the MUSK signaling include DNAJA3 which functions downstream of MUSK. May also play a role within the central nervous system by mediating cholinergic responses, synaptic plasticity and memory formation. Monomer (By similarity). Homodimer (Probable). Interacts with LRP4; the heterodimer forms an AGRIN receptor complex that binds AGRIN resulting in activation of MUSK (By similarity). Forms a heterotetramer composed of 2 DOK7 and 2 MUSK molecules which facilitates MUSK trans-autophosphorylation on tyrosine residue and activation. Interacts (via cytoplasmic part) with DOK7 (via IRS-type PTB domain); requires MUSK phosphorylation. Interacts with DVL1 (via DEP domain); the interaction is direct and mediates the formation of a DVL1, MUSK and PAK1 ternary complex involved in AChR clustering (By similarity). Interacts with PDZRN3; this interaction is enhanced by agrin (By similarity). Interacts with FNTA; the interaction is direct and mediates AGRIN-induced phosphorylation and activation of FNTA (By similarity). Interacts with CSNK2B; mediates regulation by CK2 (By similarity). Interacts (via the cytoplasmic domain) with DNAJA3 (By similarity). Interacts with NSF; may regulate MUSK endocytosis and activity (By similarity). Interacts with CAV3; may regulate MUSK signaling (By similarity). Interacts with RNF31.

Isoforms / Transcripts (Protein Coding)


Sub-cellular localization


UniProt: MUSK is active in the following subcellular-locations: cell junction, postsynaptic cell membrane, synapse.
GO terms: MUSK is active in the following subcellular-locations: cell junction, integral component of plasma membrane, neuromuscular junction, postsynaptic membrane, receptor complex.



UniProt
GO terms

Gene Copy Number Variation


In COSMIC - Cell Lines Project MUSK has gain in 1 cell-lines, loss in 2 cell-lines and no signal in 1002 cell-lines. (see details)

Gene Expression


In NCI60, the highest expressing cell lines are: TK_10, MCF7, HS578T

In Array Express (RNA-seq of 675 commonly used human cancer cell lines), the highest expressing cell lines are: LXFL529, SJCRH30, Hs 746T

In Array Express (RNA-seq of long poly adenylated RNA and long non poly adenylated RNA from ENCODE cell lines), the highest expressing cell lines are: HSMM, SK-N-SH, NHLF

(see details)

RNA Interference


MUSK was reported in the following RNAI studies:

Cell - Large Scale Profiling of Kinase Dependencies in Cancer Cell Lines, the highest RNAi cell lines are: PL5, CAOV3. (see details)

3D Structures


At greater than 90% identity similarity to MUSK there are:
2 structures (3 chains) solved
0 are solved in complex with at least one small molecule ligand



(see details)
Molecular Target 3D Synopsis

Screening and Chemistry


MUSK has been screened with 686 compounds (1280 bioactivities), 14 compounds have bioactivities that show binding affinity of <= 500nM (24 bioactivities). (see details)