ID MUSK_HUMAN Reviewed; 869 AA. AC O15146; Q32MJ8; Q32MJ9; Q5VZW7; Q5VZW8; DT 19-JUL-2004, integrated into UniProtKB/Swiss-Prot. DT 01-JAN-1998, sequence version 1. DT 13-FEB-2019, entry version 168. DE RecName: Full=Muscle, skeletal receptor tyrosine-protein kinase; DE EC=2.7.10.1 {ECO:0000269|PubMed:25029443}; DE AltName: Full=Muscle-specific tyrosine-protein kinase receptor; DE Short=MuSK; DE Short=Muscle-specific kinase receptor; DE Flags: Precursor; GN Name=MUSK; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND ALTERNATIVE SPLICING RP (ISOFORMS 2 AND 3). RX PubMed=7546737; DOI=10.1016/0896-6273(95)90146-9; RA Valenzuela D.M., Stitt T.N., DiStefano P.S., Rojas E., Mattsson K., RA Compton D.L., Nunez L., Park J.S., Stark J.L., Gies D.R., Thomas S., RA LeBeau M.M., Fernald A.A., Copeland N.G., Jenkins N.A., Burden S.J., RA Glass D.J., Yancopoulos G.D.; RT "Receptor tyrosine kinase specific for the skeletal muscle lineage: RT expression in embryonic muscle, at the neuromuscular junction, and RT after injury."; RL Neuron 15:573-584(1995). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15164053; DOI=10.1038/nature02465; RA Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E., RA Howe K.L., Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C., RA Ainscough R., Almeida J.P., Ambrose K.D., Ashwell R.I.S., RA Babbage A.K., Babbage S., Bagguley C.L., Bailey J., Banerjee R., RA Barker D.J., Barlow K.F., Bates K., Beasley H., Beasley O., Bird C.P., RA Bray-Allen S., Brown A.J., Brown J.Y., Burford D., Burrill W., RA Burton J., Carder C., Carter N.P., Chapman J.C., Chen Y., Clarke G., RA Clark S.Y., Clee C.M., Clegg S., Collier R.E., Corby N., Crosier M., RA Cummings A.T., Davies J., Dhami P., Dunn M., Dutta I., Dyer L.W., RA Earthrowl M.E., Faulkner L., Fleming C.J., Frankish A., RA Frankland J.A., French L., Fricker D.G., Garner P., Garnett J., RA Ghori J., Gilbert J.G.R., Glison C., Grafham D.V., Gribble S., RA Griffiths C., Griffiths-Jones S., Grocock R., Guy J., Hall R.E., RA Hammond S., Harley J.L., Harrison E.S.I., Hart E.A., Heath P.D., RA Henderson C.D., Hopkins B.L., Howard P.J., Howden P.J., Huckle E., RA Johnson C., Johnson D., Joy A.A., Kay M., Keenan S., Kershaw J.K., RA Kimberley A.M., King A., Knights A., Laird G.K., Langford C., RA Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C., Lloyd D.M., RA Lovell J., Martin S., Mashreghi-Mohammadi M., Matthews L., McLaren S., RA McLay K.E., McMurray A., Milne S., Nickerson T., Nisbett J., RA Nordsiek G., Pearce A.V., Peck A.I., Porter K.M., Pandian R., RA Pelan S., Phillimore B., Povey S., Ramsey Y., Rand V., Scharfe M., RA Sehra H.K., Shownkeen R., Sims S.K., Skuce C.D., Smith M., RA Steward C.A., Swarbreck D., Sycamore N., Tester J., Thorpe A., RA Tracey A., Tromans A., Thomas D.W., Wall M., Wallis J.M., West A.P., RA Whitehead S.L., Willey D.L., Williams S.A., Wilming L., Wray P.W., RA Young L., Ashurst J.L., Coulson A., Blocker H., Durbin R.M., RA Sulston J.E., Hubbard T., Jackson M.J., Bentley D.R., Beck S., RA Rogers J., Dunham I.; RT "DNA sequence and analysis of human chromosome 9."; RL Nature 429:369-374(2004). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2 AND 3). RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA RT project: the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [4] RP INTERACTION WITH DOK7. RX PubMed=20603078; DOI=10.1016/j.molcel.2010.06.007; RA Bergamin E., Hallock P.T., Burden S.J., Hubbard S.R.; RT "The cytoplasmic adaptor protein Dok7 activates the receptor tyrosine RT kinase MuSK via dimerization."; RL Mol. Cell 39:100-109(2010). RN [5] RP NEDDYLATION. RX PubMed=20596523; DOI=10.1371/journal.pone.0011332; RA Del Rincon S.V., Rogers J., Widschwendter M., Sun D., Sieburg H.B., RA Spruck C.; RT "Development and validation of a method for profiling post- RT translational modification activities using protein microarrays."; RL PLoS ONE 5:E11332-E11332(2010). RN [6] RP CATALYTIC ACTIVITY, COFACTOR, PHOSPHORYLATION, AND MUTAGENESIS OF RP GLY-584; LYS-609 AND ASP-743. RX PubMed=25029443; DOI=10.1371/journal.pone.0102695; RA Bainbridge T.W., DeAlmeida V.I., Izrael-Tomasevic A., Chalouni C., RA Pan B., Goldsmith J., Schoen A.P., Quinones G.A., Kelly R., Lill J.R., RA Sandoval W., Costa M., Polakis P., Arnott D., Rubinfeld B., RA Ernst J.A.; RT "Evolutionary divergence in the catalytic activity of the CAM-1, ROR1 RT and ROR2 kinase domains."; RL PLoS ONE 9:E102695-E102695(2014). RN [7] RP VARIANT CMS9 MET-790, AND INVOLVEMENT IN CMS9. RX PubMed=15496425; DOI=10.1093/hmg/ddh333; RA Chevessier F., Faraut B., Ravel-Chapuis A., Richard P., Gaudon K., RA Bauche S., Prioleau C., Herbst R., Goillot E., Ioos C., Azulay J.-P., RA Attarian S., Leroy J.-P., Fournier E., Legay C., Schaeffer L., RA Koenig J., Fardeau M., Eymard B., Pouget J., Hantai D.; RT "MUSK, a new target for mutations causing congenital myasthenic RT syndrome."; RL Hum. Mol. Genet. 13:3229-3240(2004). RN [8] RP VARIANTS [LARGE SCALE ANALYSIS] GLY-27; MET-100; GLU-107; GLY-159; RP SER-222; ILE-413; PHE-629; ALA-644; SER-664; LEU-696; ASP-782; RP SER-819; LEU-829 AND HIS-858. RX PubMed=17344846; DOI=10.1038/nature05610; RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., RA Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., RA O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., RA Bhamra G., Buck G., Choudhury B., Clements J., Cole J., Dicks E., RA Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., RA Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., RA Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., RA West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., RA Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., RA DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., RA Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., RA Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.; RT "Patterns of somatic mutation in human cancer genomes."; RL Nature 446:153-158(2007). RN [9] RP VARIANT CMS9 ARG-344. RX PubMed=19949040; DOI=10.1212/WNL.0b013e3181c3fce9; RA Mihaylova V., Salih M.A., Mukhtar M.M., Abuzeid H.A., El-Sadig S.M., RA von der Hagen M., Huebner A., Nurnberg G., Abicht A., Muller J.S., RA Lochmuller H., Guergueltcheva V.; RT "Refinement of the clinical phenotype in musk-related congenital RT myasthenic syndromes."; RL Neurology 73:1926-1928(2009). RN [10] RP VARIANTS CMS9 ILE-605 AND VAL-727, AND CHARACTERIZATION OF VARIANTS RP CMS9 ILE-605 AND VAL-727. RX PubMed=20371544; DOI=10.1093/hmg/ddq110; RA Maselli R.A., Arredondo J., Cagney O., Ng J.J., Anderson J.A., RA Williams C., Gerke B.J., Soliven B., Wollmann R.L.; RT "Mutations in MUSK causing congenital myasthenic syndrome impair MuSK- RT Dok-7 interaction."; RL Hum. Mol. Genet. 19:2370-2379(2010). RN [11] RP VARIANT CMS9 VAL-835, AND SUBCELLULAR LOCATION. RX PubMed=23326516; DOI=10.1371/journal.pone.0053826; RA Ben Ammar A., Soltanzadeh P., Bauche S., Richard P., Goillot E., RA Herbst R., Gaudon K., Huze C., Schaeffer L., Yamanashi Y., Higuchi O., RA Taly A., Koenig J., Leroy J.P., Hentati F., Najmabadi H., Kahrizi K., RA Ilkhani M., Fardeau M., Eymard B., Hantai D.; RT "A mutation causes MuSK reduced sensitivity to agrin and congenital RT myasthenia."; RL PLoS ONE 8:E53826-E53826(2013). RN [12] RP VARIANT FADS THR-575, INVOLVEMENT IN FADS, CHARACTERIZATION OF VARIANT RP FADS THR-575, AND FUNCTION. RX PubMed=25537362; DOI=10.1038/ejhg.2014.273; RA Tan-Sindhunata M.B., Mathijssen I.B., Smit M., Baas F., de Vries J.I., RA van der Voorn J.P., Kluijt I., Hagen M.A., Blom E.W., Sistermans E., RA Meijers-Heijboer H., Waisfisz Q., Weiss M.M., Groffen A.J.; RT "Identification of a Dutch founder mutation in MUSK causing fetal RT akinesia deformation sequence."; RL Eur. J. Hum. Genet. 23:1151-1157(2015). RN [13] RP VARIANT CMS9 GLU-38. RX PubMed=24183479; DOI=10.1016/j.nmd.2013.08.002; RA Gallenmuller C., Muller-Felber W., Dusl M., Stucka R., RA Guergueltcheva V., Blaschek A., von der Hagen M., Huebner A., RA Muller J.S., Lochmuller H., Abicht A.; RT "Salbutamol-responsive limb-girdle congenital myasthenic syndrome due RT to a novel missense mutation and heteroallelic deletion in MUSK."; RL Neuromuscul. Disord. 24:31-35(2014). RN [14] RP INVOLVEMENT IN FADS. RX PubMed=25612909; DOI=10.1136/jmedgenet-2014-102730; RA Wilbe M., Ekvall S., Eurenius K., Ericson K., Casar-Borota O., RA Klar J., Dahl N., Ameur A., Anneren G., Bondeson M.L.; RT "MuSK: a new target for lethal fetal akinesia deformation sequence RT (FADS)."; RL J. Med. Genet. 52:195-202(2015). CC -!- FUNCTION: Receptor tyrosine kinase which plays a central role in CC the formation and the maintenance of the neuromuscular junction CC (NMJ), the synapse between the motor neuron and the skeletal CC muscle (PubMed:25537362). Recruitment of AGRIN by LRP4 to the MUSK CC signaling complex induces phosphorylation and activation of MUSK, CC the kinase of the complex. The activation of MUSK in myotubes CC regulates the formation of NMJs through the regulation of CC different processes including the specific expression of genes in CC subsynaptic nuclei, the reorganization of the actin cytoskeleton CC and the clustering of the acetylcholine receptors (AChR) in the CC postsynaptic membrane. May regulate AChR phosphorylation and CC clustering through activation of ABL1 and Src family kinases which CC in turn regulate MUSK. DVL1 and PAK1 that form a ternary complex CC with MUSK are also important for MUSK-dependent regulation of AChR CC clustering. May positively regulate Rho family GTPases through CC FNTA. Mediates the phosphorylation of FNTA which promotes CC prenylation, recruitment to membranes and activation of RAC1 a CC regulator of the actin cytoskeleton and of gene expression. Other CC effectors of the MUSK signaling include DNAJA3 which functions CC downstream of MUSK. May also play a role within the central CC nervous system by mediating cholinergic responses, synaptic CC plasticity and memory formation (By similarity). {ECO:0000250, CC ECO:0000269|PubMed:25537362}. CC -!- CATALYTIC ACTIVITY: CC Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L- CC tyrosyl-[protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, CC Rhea:RHEA-COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, CC ChEBI:CHEBI:46858, ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; CC EC=2.7.10.1; Evidence={ECO:0000255|PROSITE-ProRule:PRU10028, CC ECO:0000269|PubMed:25029443}; CC -!- COFACTOR: CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420; CC Evidence={ECO:0000269|PubMed:25029443}; CC -!- ACTIVITY REGULATION: Positively regulated by CK2. {ECO:0000250}. CC -!- SUBUNIT: Monomer (By similarity). Homodimer (Probable). Interacts CC with LRP4; the heterodimer forms an AGRIN receptor complex that CC binds AGRIN resulting in activation of MUSK (By similarity). Forms CC a heterotetramer composed of 2 DOK7 and 2 MUSK molecules which CC facilitates MUSK trans-autophosphorylation on tyrosine residue and CC activation. Interacts (via cytoplasmic part) with DOK7 (via IRS- CC type PTB domain); requires MUSK phosphorylation. Interacts with CC DVL1 (via DEP domain); the interaction is direct and mediates the CC formation of a DVL1, MUSK and PAK1 ternary complex involved in CC AChR clustering (By similarity). Interacts with PDZRN3; this CC interaction is enhanced by agrin (By similarity). Interacts with CC FNTA; the interaction is direct and mediates AGRIN-induced CC phosphorylation and activation of FNTA (By similarity). Interacts CC with CSNK2B; mediates regulation by CK2 (By similarity). Interacts CC (via the cytoplasmic domain) with DNAJA3 (By similarity). CC Interacts with NSF; may regulate MUSK endocytosis and activity (By CC similarity). Interacts with CAV3; may regulate MUSK signaling (By CC similarity). Interacts with RNF31 (By similarity). CC {ECO:0000250|UniProtKB:Q62838, ECO:0000305}. CC -!- INTERACTION: CC P08238:HSP90AB1; NbExp=2; IntAct=EBI-6423196, EBI-352572; CC -!- SUBCELLULAR LOCATION: Cell junction, synapse, postsynaptic cell CC membrane {ECO:0000269|PubMed:23326516}; Single-pass type I CC membrane protein {ECO:0000305}. Note=Colocalizes with CC acetylcholine receptors (AChR) to the postsynaptic cell membrane CC of the neuromuscular junction. {ECO:0000269|PubMed:23326516}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; CC IsoId=O15146-1; Sequence=Displayed; CC Name=2; CC IsoId=O15146-2; Sequence=VSP_035958, VSP_035959, VSP_035960; CC Name=3; CC IsoId=O15146-3; Sequence=VSP_035959, VSP_035960; CC -!- PTM: Ubiquitinated by PDZRN3. Ubiquitination promotes endocytosis CC and lysosomal degradation (By similarity). {ECO:0000250}. CC -!- PTM: Phosphorylated (By similarity). Phosphorylation is induced by CC AGRIN in a LRP4-dependent manner (By similarity). CC Autophosphorylated (PubMed:25029443). Autophosphorylation at Tyr- CC 554 is required for interaction with DOK7 which in turn stimulates CC the phosphorylation and the activation of MUSK (By similarity). CC {ECO:0000250|UniProtKB:Q61006, ECO:0000269|PubMed:25029443}. CC -!- PTM: Neddylated. {ECO:0000269|PubMed:20596523}. CC -!- DISEASE: Myasthenic syndrome, congenital, 9, associated with CC acetylcholine receptor deficiency (CMS9) [MIM:616325]: A form of CC congenital myasthenic syndrome, a group of disorders characterized CC by failure of neuromuscular transmission, including pre-synaptic, CC synaptic, and post-synaptic disorders that are not of autoimmune CC origin. Clinical features are easy fatigability and muscle CC weakness affecting the axial and limb muscles (with hypotonia in CC early-onset forms), the ocular muscles (leading to ptosis and CC ophthalmoplegia), and the facial and bulbar musculature (affecting CC sucking and swallowing, and leading to dysphonia). The symptoms CC fluctuate and worsen with physical effort. CMS9 is a disorder of CC postsynaptic neuromuscular transmission, due to deficiency of AChR CC at the endplate that results in low amplitude of the miniature CC endplate potential and current. {ECO:0000269|PubMed:15496425, CC ECO:0000269|PubMed:19949040, ECO:0000269|PubMed:20371544, CC ECO:0000269|PubMed:23326516, ECO:0000269|PubMed:24183479}. CC Note=The disease is caused by mutations affecting the gene CC represented in this entry. MUSK mutations lead to decreased agrin- CC dependent AChR aggregation, a critical step in the formation of CC the neuromuscular junction. CC -!- DISEASE: Fetal akinesia deformation sequence (FADS) [MIM:208150]: CC A clinically and genetically heterogeneous group of disorders with CC congenital malformations related to impaired fetal movement. CC Clinical features include fetal akinesia, intrauterine growth CC retardation, polyhydramnios, arthrogryposis, pulmonary hypoplasia, CC craniofacial abnormalities, and cryptorchidism. CC {ECO:0000269|PubMed:25537362, ECO:0000269|PubMed:25612909}. CC Note=The disease is caused by mutations affecting the gene CC represented in this entry. CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein CC kinase family. {ECO:0000255|PROSITE-ProRule:PRU00159}. CC -!- WEB RESOURCE: Name=Wikipedia; Note=MuSK entry; CC URL="https://en.wikipedia.org/wiki/MuSK_protein"; CC ----------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC ----------------------------------------------------------------------- DR EMBL; AF006464; AAB63044.1; -; mRNA. DR EMBL; AL157881; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AL513328; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC109098; AAI09099.1; -; mRNA. DR EMBL; BC109099; AAI09100.1; -; mRNA. DR CCDS; CCDS48005.1; -. [O15146-1] DR CCDS; CCDS75874.1; -. [O15146-2] DR RefSeq; NP_001159752.1; NM_001166280.1. [O15146-2] DR RefSeq; NP_001159753.1; NM_001166281.1. [O15146-3] DR RefSeq; NP_005583.1; NM_005592.3. [O15146-1] DR UniGene; Hs.521653; -. DR ProteinModelPortal; O15146; -. DR SMR; O15146; -. DR BioGrid; 110679; 8. DR IntAct; O15146; 6. DR MINT; O15146; -. DR STRING; 9606.ENSP00000363571; -. DR BindingDB; O15146; -. DR ChEMBL; CHEMBL5684; -. DR GuidetoPHARMACOLOGY; 1847; -. DR iPTMnet; O15146; -. DR PhosphoSitePlus; O15146; -. DR BioMuta; MUSK; -. DR jPOST; O15146; -. DR PaxDb; O15146; -. DR PeptideAtlas; O15146; -. DR PRIDE; O15146; -. DR ProteomicsDB; 48471; -. DR ProteomicsDB; 48472; -. [O15146-2] DR ProteomicsDB; 48473; -. [O15146-3] DR DNASU; 4593; -. DR Ensembl; ENST00000189978; ENSP00000189978; ENSG00000030304. [O15146-2] DR Ensembl; ENST00000374448; ENSP00000363571; ENSG00000030304. [O15146-1] DR GeneID; 4593; -. DR KEGG; hsa:4593; -. DR UCSC; uc064vai.1; human. [O15146-1] DR CTD; 4593; -. DR DisGeNET; 4593; -. DR EuPathDB; HostDB:ENSG00000030304.13; -. DR GeneCards; MUSK; -. DR GeneReviews; MUSK; -. DR HGNC; HGNC:7525; MUSK. DR MalaCards; MUSK; -. DR MIM; 208150; phenotype. DR MIM; 601296; gene. DR MIM; 616325; phenotype. DR neXtProt; NX_O15146; -. DR OpenTargets; ENSG00000030304; -. DR Orphanet; 994; Fetal akinesia deformation sequence. DR Orphanet; 98913; Postsynaptic congenital myasthenic syndromes. DR PharmGKB; PA31326; -. DR eggNOG; ENOG410IMMJ; Eukaryota. DR eggNOG; COG0515; LUCA. DR GeneTree; ENSGT00940000158226; -. DR HOGENOM; HOG000044461; -. DR HOVERGEN; HBG052539; -. DR InParanoid; O15146; -. DR KO; K05129; -. DR OMA; CAPYNGK; -. DR OrthoDB; 1576308at2759; -. DR PhylomeDB; O15146; -. DR TreeFam; TF106465; -. DR Reactome; R-HSA-3000178; ECM proteoglycans. DR SignaLink; O15146; -. DR SIGNOR; O15146; -. DR ChiTaRS; MUSK; human. DR GenomeRNAi; 4593; -. DR PRO; PR:O15146; -. DR Proteomes; UP000005640; Chromosome 9. DR Bgee; ENSG00000030304; Expressed in 88 organ(s), highest expression level in small intestine Peyer's patch. DR ExpressionAtlas; O15146; baseline and differential. DR Genevisible; O15146; HS. DR GO; GO:0030054; C:cell junction; IEA:UniProtKB-KW. DR GO; GO:0005887; C:integral component of plasma membrane; ISS:UniProtKB. DR GO; GO:0031594; C:neuromuscular junction; ISS:UniProtKB. DR GO; GO:0045211; C:postsynaptic membrane; ISS:UniProtKB. DR GO; GO:0043235; C:receptor complex; IDA:MGI. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW. DR GO; GO:0004713; F:protein tyrosine kinase activity; ISS:UniProtKB. DR GO; GO:0004714; F:transmembrane receptor protein tyrosine kinase activity; IBA:GO_Central. DR GO; GO:0017147; F:Wnt-protein binding; IBA:GO_Central. DR GO; GO:0048856; P:anatomical structure development; IBA:GO_Central. DR GO; GO:0030154; P:cell differentiation; IEA:UniProtKB-KW. DR GO; GO:0007613; P:memory; ISS:UniProtKB. DR GO; GO:0007275; P:multicellular organism development; IEA:UniProtKB-KW. DR GO; GO:0007528; P:neuromuscular junction development; IDA:UniProtKB. DR GO; GO:0010628; P:positive regulation of gene expression; ISS:UniProtKB. DR GO; GO:2000541; P:positive regulation of protein geranylgeranylation; ISS:UniProtKB. DR GO; GO:0001934; P:positive regulation of protein phosphorylation; IMP:UniProtKB. DR GO; GO:0046777; P:protein autophosphorylation; ISS:UniProtKB. DR GO; GO:0008582; P:regulation of synaptic growth at neuromuscular junction; ISS:UniProtKB. DR GO; GO:0071340; P:skeletal muscle acetylcholine-gated channel clustering; ISS:UniProtKB. DR GO; GO:0007169; P:transmembrane receptor protein tyrosine kinase signaling pathway; IBA:GO_Central. DR Gene3D; 1.10.2000.10; -; 1. DR Gene3D; 2.60.40.10; -; 3. DR InterPro; IPR020067; Frizzled_dom. DR InterPro; IPR036790; Frizzled_dom_sf. DR InterPro; IPR007110; Ig-like_dom. DR InterPro; IPR036179; Ig-like_dom_sf. DR InterPro; IPR013783; Ig-like_fold. DR InterPro; IPR013098; Ig_I-set. DR InterPro; IPR003599; Ig_sub. DR InterPro; IPR003598; Ig_sub2. DR InterPro; IPR011009; Kinase-like_dom_sf. DR InterPro; IPR000719; Prot_kinase_dom. DR InterPro; IPR017441; Protein_kinase_ATP_BS. DR InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom. DR InterPro; IPR008266; Tyr_kinase_AS. DR InterPro; IPR020635; Tyr_kinase_cat_dom. DR Pfam; PF01392; Fz; 1. DR Pfam; PF07679; I-set; 2. DR Pfam; PF07714; Pkinase_Tyr; 1. DR PRINTS; PR00109; TYRKINASE. DR SMART; SM00409; IG; 3. DR SMART; SM00408; IGc2; 3. DR SMART; SM00219; TyrKc; 1. DR SUPFAM; SSF48726; SSF48726; 3. DR SUPFAM; SSF56112; SSF56112; 1. DR PROSITE; PS50038; FZ; 1. DR PROSITE; PS50835; IG_LIKE; 3. DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1. DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1. DR PROSITE; PS00109; PROTEIN_KINASE_TYR; 1. PE 1: Evidence at protein level; KW Alternative splicing; ATP-binding; Cell junction; Cell membrane; KW Complete proteome; Congenital myasthenic syndrome; KW Developmental protein; Differentiation; Disease mutation; KW Disulfide bond; Glycoprotein; Immunoglobulin domain; Kinase; KW Magnesium; Membrane; Metal-binding; Muscle protein; KW Nucleotide-binding; Phosphoprotein; Polymorphism; KW Postsynaptic cell membrane; Receptor; Reference proteome; Repeat; KW Signal; Synapse; Transferase; Transmembrane; Transmembrane helix; KW Tyrosine-protein kinase; Ubl conjugation. FT SIGNAL 1 23 {ECO:0000255}. FT CHAIN 24 869 Muscle, skeletal receptor tyrosine- FT protein kinase. FT /FTId=PRO_0000024446. FT TOPO_DOM 24 495 Extracellular. {ECO:0000255}. FT TRANSMEM 496 516 Helical. {ECO:0000255}. FT TOPO_DOM 517 869 Cytoplasmic. {ECO:0000255}. FT DOMAIN 28 116 Ig-like 1. FT DOMAIN 121 205 Ig-like 2. FT DOMAIN 212 302 Ig-like 3. FT DOMAIN 312 450 FZ. {ECO:0000255|PROSITE- FT ProRule:PRU00090}. FT DOMAIN 575 856 Protein kinase. {ECO:0000255|PROSITE- FT ProRule:PRU00159}. FT NP_BIND 581 589 ATP. {ECO:0000255|PROSITE- FT ProRule:PRU00159}. FT ACT_SITE 725 725 Proton acceptor. {ECO:0000255|PROSITE- FT ProRule:PRU00159, ECO:0000255|PROSITE- FT ProRule:PRU10028}. FT BINDING 609 609 ATP. {ECO:0000255|PROSITE- FT ProRule:PRU00159}. FT MOD_RES 554 554 Phosphotyrosine; by autocatalysis. FT {ECO:0000250|UniProtKB:Q61006}. FT MOD_RES 681 681 Phosphoserine; by CK2. FT {ECO:0000250|UniProtKB:Q61006}. FT MOD_RES 698 698 Phosphoserine; by CK2. FT {ECO:0000250|UniProtKB:Q61006}. FT MOD_RES 755 755 Phosphotyrosine; by autocatalysis. FT {ECO:0000250|UniProtKB:Q62838}. FT CARBOHYD 222 222 N-linked (GlcNAc...) asparagine. FT {ECO:0000255}. FT CARBOHYD 338 338 N-linked (GlcNAc...) asparagine. FT {ECO:0000250}. FT DISULFID 49 99 {ECO:0000250}. FT DISULFID 98 112 {ECO:0000250}. FT DISULFID 142 190 {ECO:0000250}. FT DISULFID 233 282 {ECO:0000250}. FT DISULFID 317 382 {ECO:0000250}. FT DISULFID 325 375 {ECO:0000250}. FT DISULFID 366 406 {ECO:0000250}. FT DISULFID 394 447 {ECO:0000250}. FT DISULFID 398 434 {ECO:0000250}. FT VAR_SEQ 209 209 E -> EEESEPEQDTK (in isoform 2). FT {ECO:0000303|PubMed:15489334}. FT /FTId=VSP_035958. FT VAR_SEQ 307 394 Missing (in isoform 2 and isoform 3). FT {ECO:0000303|PubMed:15489334}. FT /FTId=VSP_035959. FT VAR_SEQ 454 462 DYNKENLKT -> A (in isoform 2 and isoform FT 3). {ECO:0000303|PubMed:15489334}. FT /FTId=VSP_035960. FT VARIANT 27 27 A -> G (in dbSNP:rs56054734). FT {ECO:0000269|PubMed:17344846}. FT /FTId=VAR_041748. FT VARIANT 38 38 D -> E (in CMS9; dbSNP:rs775587809). FT {ECO:0000269|PubMed:24183479}. FT /FTId=VAR_072785. FT VARIANT 100 100 T -> M (in dbSNP:rs35142681). FT {ECO:0000269|PubMed:17344846}. FT /FTId=VAR_041749. FT VARIANT 107 107 G -> E (in dbSNP:rs55786136). FT {ECO:0000269|PubMed:17344846}. FT /FTId=VAR_041750. FT VARIANT 159 159 S -> G (in dbSNP:rs35176182). FT {ECO:0000269|PubMed:17344846}. FT /FTId=VAR_041751. FT VARIANT 222 222 N -> S (in dbSNP:rs55826142). FT {ECO:0000269|PubMed:17344846}. FT /FTId=VAR_041752. FT VARIANT 344 344 P -> R (in CMS9; dbSNP:rs387906803). FT {ECO:0000269|PubMed:19949040}. FT /FTId=VAR_072786. FT VARIANT 413 413 M -> I (in dbSNP:rs2274419). FT {ECO:0000269|PubMed:17344846}. FT /FTId=VAR_021930. FT VARIANT 575 575 I -> T (in FADS; reduces agrin-dependent FT AChR aggregation and tyrosine kinase FT activity in developing neuromuscular FT junction; dbSNP:rs751889864). FT {ECO:0000269|PubMed:25537362}. FT /FTId=VAR_072787. FT VARIANT 605 605 M -> I (in CMS9; affects interaction with FT DOK7 and impairs MUSK phosphorylation; FT altered AChR clustering; FT dbSNP:rs766640370). FT {ECO:0000269|PubMed:20371544}. FT /FTId=VAR_066604. FT VARIANT 629 629 L -> F (in dbSNP:rs34267283). FT {ECO:0000269|PubMed:17344846}. FT /FTId=VAR_041753. FT VARIANT 644 644 V -> A (in dbSNP:rs41279055). FT {ECO:0000269|PubMed:17344846}. FT /FTId=VAR_041754. FT VARIANT 664 664 N -> S (in dbSNP:rs55963442). FT {ECO:0000269|PubMed:17344846}. FT /FTId=VAR_041755. FT VARIANT 696 696 P -> L (in dbSNP:rs56126328). FT {ECO:0000269|PubMed:17344846}. FT /FTId=VAR_041756. FT VARIANT 727 727 A -> V (in CMS9; affects interaction with FT DOK7 and impairs MUSK phosphorylation; FT altered AChR clustering; FT dbSNP:rs397515450). FT {ECO:0000269|PubMed:20371544}. FT /FTId=VAR_066605. FT VARIANT 782 782 E -> D (in dbSNP:rs34614566). FT {ECO:0000269|PubMed:17344846}. FT /FTId=VAR_041757. FT VARIANT 790 790 V -> M (in CMS9; does not affect FT catalytic kinase activity; reduces FT protein expression and stability; FT dbSNP:rs199476083). FT {ECO:0000269|PubMed:15496425}. FT /FTId=VAR_023046. FT VARIANT 819 819 N -> S (in a lung neuroendocrine FT carcinoma sample; somatic mutation; FT dbSNP:rs757577755). FT {ECO:0000269|PubMed:17344846}. FT /FTId=VAR_041758. FT VARIANT 829 829 V -> L (in dbSNP:rs578430). FT {ECO:0000269|PubMed:17344846}. FT /FTId=VAR_033837. FT VARIANT 835 835 M -> V (in CMS9; reduces AChR aggregation FT in developing neuromuscular junction). FT {ECO:0000269|PubMed:23326516}. FT /FTId=VAR_072788. FT VARIANT 858 858 R -> H (in dbSNP:rs34115159). FT {ECO:0000269|PubMed:17344846}. FT /FTId=VAR_041759. FT MUTAGEN 584 584 G->C,D: Mild decrease in kinase activity. FT {ECO:0000269|PubMed:25029443}. FT MUTAGEN 609 609 K->R: Severe loss of kinase activity. FT {ECO:0000269|PubMed:25029443}. FT MUTAGEN 743 743 D->N: Severe loss of kinase activity. FT {ECO:0000269|PubMed:25029443}. SQ SEQUENCE 869 AA; 97056 MW; 3DDC20E179FA010C CRC64; MRELVNIPLV HILTLVAFSG TEKLPKAPVI TTPLETVDAL VEEVATFMCA VESYPQPEIS WTRNKILIKL FDTRYSIREN GQLLTILSVE DSDDGIYCCT ANNGVGGAVE SCGALQVKMK PKITRPPINV KIIEGLKAVL PCTTMGNPKP SVSWIKGDSP LRENSRIAVL ESGSLRIHNV QKEDAGQYRC VAKNSLGTAY SKVVKLEVEV FARILRAPES HNVTFGSFVT LHCTATGIPV PTITWIENGN AVSSGSIQES VKDRVIDSRL QLFITKPGLY TCIATNKHGE KFSTAKAAAT ISIAEWSKPQ KDNKGYCAQY RGEVCNAVLA KDALVFLNTS YADPEEAQEL LVHTAWNELK VVSPVCRPAA EALLCNHIFQ ECSPGVVPTP IPICREYCLA VKELFCAKEW LVMEEKTHRG LYRSEMHLLS VPECSKLPSM HWDPTACARL PHLDYNKENL KTFPPMTSSK PSVDIPNLPS SSSSSFSVSP TYSMTVIISI MSSFAIFVLL TITTLYCCRR RKQWKNKKRE SAAVTLTTLP SELLLDRLHP NPMYQRMPLL LNPKLLSLEY PRNNIEYVRD IGEGAFGRVF QARAPGLLPY EPFTMVAVKM LKEEASADMQ ADFQREAALM AEFDNPNIVK LLGVCAVGKP MCLLFEYMAY GDLNEFLRSM SPHTVCSLSH SDLSMRAQVS SPGPPPLSCA EQLCIARQVA AGMAYLSERK FVHRDLATRN CLVGENMVVK IADFGLSRNI YSADYYKANE NDAIPIRWMP PESIFYNRYT TESDVWAYGV VLWEIFSYGL QPYYGMAHEE VIYYVRDGNI LSCPENCPVE LYNLMRLCWS KLPADRPSFT SIHRILERMC ERAEGTVSV //