UniProt functional annotation for O15146



	UniProt functional annotation for O15146

UniProt code: O15146.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: 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 (By similarity). {ECO:0000250, ECO:0000269|PubMed:25537362}.

Catalytic activity: Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl- [protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA- COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858, ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.10.1; Evidence={ECO:0000255|PROSITE-ProRule:PRU10028, ECO:0000269|PubMed:25029443};

Cofactor: Name=Mg(2+); Xref=ChEBI:CHEBI:18420; Evidence={ECO:0000269|PubMed:25029443};

Activity regulation: Positively regulated by CK2. {ECO:0000250}.

Subunit: 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 (By similarity). {ECO:0000250|UniProtKB:Q62838, ECO:0000305}.

Subcellular location: Cell junction, synapse, postsynaptic cell membrane {ECO:0000269|PubMed:23326516}; Single-pass type I membrane protein {ECO:0000305}. Note=Colocalizes with acetylcholine receptors (AChR) to the postsynaptic cell membrane of the neuromuscular junction. {ECO:0000269|PubMed:23326516}.

Ptm: Ubiquitinated by PDZRN3. Ubiquitination promotes endocytosis and lysosomal degradation (By similarity). {ECO:0000250}.

Ptm: Phosphorylated (By similarity). Phosphorylation is induced by AGRIN in a LRP4-dependent manner (By similarity). Autophosphorylated (PubMed:25029443). Autophosphorylation at Tyr-554 is required for interaction with DOK7 which in turn stimulates the phosphorylation and the activation of MUSK (By similarity). {ECO:0000250|UniProtKB:Q61006, ECO:0000269|PubMed:25029443}.

Ptm: Neddylated. {ECO:0000269|PubMed:20596523}.

Disease: Myasthenic syndrome, congenital, 9, associated with acetylcholine receptor deficiency (CMS9) [MIM:616325]: A form of congenital myasthenic syndrome, a group of disorders characterized by failure of neuromuscular transmission, including pre-synaptic, synaptic, and post-synaptic disorders that are not of autoimmune origin. Clinical features are easy fatigability and muscle weakness affecting the axial and limb muscles (with hypotonia in early-onset forms), the ocular muscles (leading to ptosis and ophthalmoplegia), and the facial and bulbar musculature (affecting sucking and swallowing, and leading to dysphonia). The symptoms fluctuate and worsen with physical effort. CMS9 is a disorder of postsynaptic neuromuscular transmission, due to deficiency of AChR at the endplate that results in low amplitude of the miniature endplate potential and current. {ECO:0000269|PubMed:15496425, ECO:0000269|PubMed:19949040, ECO:0000269|PubMed:20371544, ECO:0000269|PubMed:23326516, ECO:0000269|PubMed:24183479}. Note=The disease is caused by variants affecting the gene represented in this entry. MUSK mutations lead to decreased agrin-dependent AChR aggregation, a critical step in the formation of the neuromuscular junction.

Disease: Fetal akinesia deformation sequence 1 (FADS1) [MIM:208150]: A clinically and genetically heterogeneous group of disorders with congenital malformations related to impaired fetal movement. Clinical features include fetal akinesia, intrauterine growth retardation, polyhydramnios, arthrogryposis, pulmonary hypoplasia, craniofacial abnormalities, and cryptorchidism. FADS1 inheritance is autosomal recessive. {ECO:0000269|PubMed:25537362, ECO:0000269|PubMed:25612909}. Note=The disease is caused by variants affecting the gene represented in this entry.

Similarity: Belongs to the protein kinase superfamily. Tyr protein kinase family. {ECO:0000255|PROSITE-ProRule:PRU00159}.

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		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 (By similarity). {ECO:0000250, ECO:0000269\|PubMed:25537362}.


Catalytic activity:		Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl- [protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA- COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858, ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.10.1; Evidence={ECO:0000255\|PROSITE-ProRule:PRU10028, ECO:0000269\|PubMed:25029443};
Cofactor:		Name=Mg(2+); Xref=ChEBI:CHEBI:18420; Evidence={ECO:0000269\|PubMed:25029443};
Activity regulation:		Positively regulated by CK2. {ECO:0000250}.
Subunit:		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 (By similarity). {ECO:0000250\|UniProtKB:Q62838, ECO:0000305}.
Subcellular location:		Cell junction, synapse, postsynaptic cell membrane {ECO:0000269\|PubMed:23326516}; Single-pass type I membrane protein {ECO:0000305}. Note=Colocalizes with acetylcholine receptors (AChR) to the postsynaptic cell membrane of the neuromuscular junction. {ECO:0000269\|PubMed:23326516}.
Ptm:		Ubiquitinated by PDZRN3. Ubiquitination promotes endocytosis and lysosomal degradation (By similarity). {ECO:0000250}.
Ptm:		Phosphorylated (By similarity). Phosphorylation is induced by AGRIN in a LRP4-dependent manner (By similarity). Autophosphorylated (PubMed:25029443). Autophosphorylation at Tyr-554 is required for interaction with DOK7 which in turn stimulates the phosphorylation and the activation of MUSK (By similarity). {ECO:0000250\|UniProtKB:Q61006, ECO:0000269\|PubMed:25029443}.
Ptm:		Neddylated. {ECO:0000269\|PubMed:20596523}.
Disease:		Myasthenic syndrome, congenital, 9, associated with acetylcholine receptor deficiency (CMS9) [MIM:616325]: A form of congenital myasthenic syndrome, a group of disorders characterized by failure of neuromuscular transmission, including pre-synaptic, synaptic, and post-synaptic disorders that are not of autoimmune origin. Clinical features are easy fatigability and muscle weakness affecting the axial and limb muscles (with hypotonia in early-onset forms), the ocular muscles (leading to ptosis and ophthalmoplegia), and the facial and bulbar musculature (affecting sucking and swallowing, and leading to dysphonia). The symptoms fluctuate and worsen with physical effort. CMS9 is a disorder of postsynaptic neuromuscular transmission, due to deficiency of AChR at the endplate that results in low amplitude of the miniature endplate potential and current. {ECO:0000269\|PubMed:15496425, ECO:0000269\|PubMed:19949040, ECO:0000269\|PubMed:20371544, ECO:0000269\|PubMed:23326516, ECO:0000269\|PubMed:24183479}. Note=The disease is caused by variants affecting the gene represented in this entry. MUSK mutations lead to decreased agrin-dependent AChR aggregation, a critical step in the formation of the neuromuscular junction.
Disease:		Fetal akinesia deformation sequence 1 (FADS1) [MIM:208150]: A clinically and genetically heterogeneous group of disorders with congenital malformations related to impaired fetal movement. Clinical features include fetal akinesia, intrauterine growth retardation, polyhydramnios, arthrogryposis, pulmonary hypoplasia, craniofacial abnormalities, and cryptorchidism. FADS1 inheritance is autosomal recessive. {ECO:0000269\|PubMed:25537362, ECO:0000269\|PubMed:25612909}. Note=The disease is caused by variants affecting the gene represented in this entry.
Similarity:		Belongs to the protein kinase superfamily. Tyr protein kinase family. {ECO:0000255\|PROSITE-ProRule:PRU00159}.