UniProt functional annotation for Q62838



	UniProt functional annotation for Q62838

UniProt code: Q62838.

Organism: Rattus norvegicus (Rat).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; Murinae; Rattus.

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:23326516). 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. {ECO:0000269|PubMed:16870737, ECO:0000269|PubMed:17011580, ECO:0000269|PubMed:23326516}.

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};

Cofactor: Name=Mg(2+); Xref=ChEBI:CHEBI:18420; Evidence={ECO:0000250|UniProtKB:O15146};

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. 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. 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). Interacts with DOK7 (PubMed:23326516). {ECO:0000250, ECO:0000269|PubMed:23326516, ECO:0000305}.

Subcellular location: Cell junction, synapse, postsynaptic cell membrane {ECO:0000305|PubMed:17011580}; Single-pass type I membrane protein {ECO:0000305|PubMed:17011580}. Note=Localizes to the postsynaptic cell membrane of the neuromuscular junction. {ECO:0000250|UniProtKB:O15146, ECO:0000305}.

Tissue specificity: Muscle specific. {ECO:0000269|PubMed:7546737}.

Developmental stage: From E14.0 day, expressed in developing myotomes. Once the muscle is innervated, localized to the neuromuscular junction (NMJ), where its expression is restricted to synaptic nuclei. Expression drops after birth. {ECO:0000269|PubMed:7546737}.

Induction: Up-regulated upon denervation (at protein level). {ECO:0000269|PubMed:7546737}.

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

Ptm: Phosphorylated (PubMed:23326516). Phosphorylation is induced by AGRIN in a LRP4-dependent manner (PubMed:23326516). Autophosphorylated (By similarity). Autophosphorylation at Tyr-553 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:23326516}.

Ptm: Neddylated. {ECO:0000250}.

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

Annotations taken from UniProtKB at the EBI.


Organism:		Rattus norvegicus (Rat).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; Murinae; Rattus.



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:23326516). 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. {ECO:0000269\|PubMed:16870737, ECO:0000269\|PubMed:17011580, ECO:0000269\|PubMed:23326516}.


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};
Cofactor:		Name=Mg(2+); Xref=ChEBI:CHEBI:18420; Evidence={ECO:0000250\|UniProtKB:O15146};
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. 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. 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). Interacts with DOK7 (PubMed:23326516). {ECO:0000250, ECO:0000269\|PubMed:23326516, ECO:0000305}.
Subcellular location:		Cell junction, synapse, postsynaptic cell membrane {ECO:0000305\|PubMed:17011580}; Single-pass type I membrane protein {ECO:0000305\|PubMed:17011580}. Note=Localizes to the postsynaptic cell membrane of the neuromuscular junction. {ECO:0000250\|UniProtKB:O15146, ECO:0000305}.
Tissue specificity:		Muscle specific. {ECO:0000269\|PubMed:7546737}.
Developmental stage:		From E14.0 day, expressed in developing myotomes. Once the muscle is innervated, localized to the neuromuscular junction (NMJ), where its expression is restricted to synaptic nuclei. Expression drops after birth. {ECO:0000269\|PubMed:7546737}.
Induction:		Up-regulated upon denervation (at protein level). {ECO:0000269\|PubMed:7546737}.
Ptm:		Ubiquitinated by PDZRN3. Ubiquitination promotes endocytosis and lysosomal degradation (By similarity). {ECO:0000250}.
Ptm:		Phosphorylated (PubMed:23326516). Phosphorylation is induced by AGRIN in a LRP4-dependent manner (PubMed:23326516). Autophosphorylated (By similarity). Autophosphorylation at Tyr-553 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:23326516}.
Ptm:		Neddylated. {ECO:0000250}.
Similarity:		Belongs to the protein kinase superfamily. Tyr protein kinase family. {ECO:0000255\|PROSITE-ProRule:PRU00159}.