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FLASH GENE

Symbol

MUSK

contributors: mct/pgu - updated : 08-07-2015

HGNC name	muscle, skeletal, receptor tyrosine kinase
HGNC id	7525

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	CMS1D congenital myasthenic syndrome, 1D FADSL fetal akinesia deformation sequence lethal
Location	9q31.3      Physical location : 113.431.050 - 113.563.278
Synonym name	protein-tyrosine kinase
	muscle-specific kinase receptor
Synonym symbol(s)	MGC126323, MGC126324, CMS9
EC.number	2.7.10.1

DNA

TYPE	functioning gene
STRUCTURE	132.23 kb     15 Exon(s)

10 Kb 5' upstream gene genomic sequence study

MAPPING

cloned

Y

linked

N

status

provisional

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_005592 15 - 2764 NP_005583 96.9 869 - 2008 18165682 NM_001166280 13 - 2496 NP_001159752 - 783 - 2008 18165682 NM_001166281 12 - 2466 NP_001159753 86.3 773 - 2008 18165682

EXPRESSION

Type	restricted

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Digestive mouth         Nervous brain limbic system hippocampus     Homo sapiens   brain forebrain cerebral cortex     Homo sapiens   brain hindbrain cerebellum     Homo sapiens Olfactory (smell) olfactory bulb         Homo sapiens

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Muscular striatum skeletal

cell lineage

cell lines

fluid/secretion

at STAGE

physiological period

embryo, fetal

Text	early myotomes and developing muscle

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	the most N-terminal Ig-like domain is essential for AGRN to stimulate MUSK phosphorylation
	a large ectodomain which comprises three immunoglobulin-like domains and a cysteine-rich domain (Fz-CRD) related to those in Frizzled proteins, the receptors for Wnts
	a spacer between domains 3 and 4, containing 6 conserved cysteines
	a kringle domain
	a soluble extracellular domain that potentiates Agrin-binding to LRP4-expressing cells

HOMOLOGY

Homologene

FAMILY	protein kinase superfamily
	Tyr protein kinase family

CATEGORY

enzyme , receptor membrane

SUBCELLULAR LOCALIZATION

plasma membrane,junction

basic FUNCTION	playing an essential role in stabilizing the muscle prepattern, and has a potent role in regulating the formation of synapses
	initial step in postsynaptic differentiation and formation of an end-plate band in cooperation with rapsyn
	essential receptor tyrosine kinase for the establishment and maintenance of the neuromuscular junction (NMJ)
	essential to initiate AChR clustering but also to restrict approaching growth cones to the muscle center, thereby coordinating pre- and postsynaptic development
	recruits docking protein-7 (DOK7), an adaptor protein that is expressed selectively in muscle (
	transmembrane tyrosine kinase vital for forming and maintaining the mammalian neuromuscular junction
	its activation initiates complex intracellular signalling events that coordinate the local synthesis and assembly of synaptic proteins
	LRP4 and MUSK act as scaffolds for multiple binding partners, resulting in a complex and dynamic network of interacting proteins that is required for ACHR clustering
	receptor tyrosine kinase that plays a central signaling role in the formation of neuromuscular junctions (NMJs)
	uses both classical and nonclassical endosomal pathways that involve a variety of different components of the endosomal machinery
	role of MUSK as a tyrosine kinase that orchestrates neuromuscular synaptogenesis

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

development

text	muscle development

PATHWAY

metabolism

signaling

a component

INTERACTION

DNA

RNA

small molecule

protein	rapsyn
	LRP4 and MUSK can interact and form a complex
	associate with SHC4 via its PTB domain (undergo tyrosine phosphorylation downstream of activated MUSK)
	PDZRN3 binds to MUSK and promotes its ubiquitination
	MUSK-interacting protein DOK7 is essential for neuromuscular synaptogenesis, although the mechanisms by which DOK7 regulates MUSK activity and promotes synapse formation have been unclear
	AGRN binds LRP4 and stimulates further MUSK phosphorylation, stabilizing nascent synapses
	LRP4 is a cis-acting ligand for MUSK, whereas AGRN functions as an allosteric and paracrine regulator to promote association between LRP4 and MUSK
	is a WNT4 receptor (WNT4 not only interacts with MUSK ectodomain but also mediates MUSK activation)
	LRP4 acts bi-directionally and coordinates synapse formation by binding AGRN, activating MUSK and stimulating postsynaptic differentiation
	ligand for MUSK is LRP4, a transmembrane protein in muscle, whose binding affinity for MUSK is potentiated by agrin, a neuronally derived heparan-sulfate proteoglycan 9)
	DOK7, a cytoplasmic adaptor protein, is also required for MUSK activation 9)
	MUSK activation by DOK7 mildly affects the localization of MUSK on the cell surface but has no effect on the rate of MUSK internalization
	MUSK activator agrin plays another role essential for the postnatal maintenance, but not for embryonic formation, of NMJs and also for the postnatal, but not prenatal, midmuscle localization of postsynaptic specializations
	DOK7 is essential for activation of the receptor kinase MUSK, which governs NMJ formation
	COLQ binds directly to LRP4 but not to MUSK and COLQ interacts indirectly with MUSK through LRP4

cell & other

REGULATION

activated by	AGRN to cluster acetylcholine receptors
	activation of muscle-specific receptor tyrosine kinase and binding to dystroglycan are regulated by alternative mRNA splicing of agrin AGRN)
	LRP4 (low-density lipoprotein receptor-related protein-4)

ASSOCIATED DISORDERS

corresponding disease(s)

CMS1D , FADSL

Susceptibility

Variant & Polymorphism

Candidate gene

Marker

Therapy target

ANIMAL & CELL MODELS