Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTERKP1U)

• DOT Name: Muscle, skeletal receptor tyrosine-protein kinase (MUSK)
• Synonyms: EC 2.7.10.1; Muscle-specific tyrosine-protein kinase receptor; MuSK; Muscle-specific kinase receptor
• Gene Name: MUSK
• Related Disease:
  Congenital myasthenic syndrome 9
  Fetal akinesia deformation sequence 1
  Postsynaptic congenital myasthenic syndrome
• UniProt ID: MUSK_HUMAN
• PDB ID: 8S9P
• EC Number: 2.7.10.1
• Pfam ID: PF01392 ; PF07679 ; PF13927 ; PF07714
• Sequence:
  MRELVNIPLVHILTLVAFSGTEKLPKAPVITTPLETVDALVEEVATFMCAVESYPQPEIS
  WTRNKILIKLFDTRYSIRENGQLLTILSVEDSDDGIYCCTANNGVGGAVESCGALQVKMK
  PKITRPPINVKIIEGLKAVLPCTTMGNPKPSVSWIKGDSPLRENSRIAVLESGSLRIHNV
  QKEDAGQYRCVAKNSLGTAYSKVVKLEVEVFARILRAPESHNVTFGSFVTLHCTATGIPV
  PTITWIENGNAVSSGSIQESVKDRVIDSRLQLFITKPGLYTCIATNKHGEKFSTAKAAAT
  ISIAEWSKPQKDNKGYCAQYRGEVCNAVLAKDALVFLNTSYADPEEAQELLVHTAWNELK
  VVSPVCRPAAEALLCNHIFQECSPGVVPTPIPICREYCLAVKELFCAKEWLVMEEKTHRG
  LYRSEMHLLSVPECSKLPSMHWDPTACARLPHLDYNKENLKTFPPMTSSKPSVDIPNLPS
  SSSSSFSVSPTYSMTVIISIMSSFAIFVLLTITTLYCCRRRKQWKNKKRESAAVTLTTLP
  SELLLDRLHPNPMYQRMPLLLNPKLLSLEYPRNNIEYVRDIGEGAFGRVFQARAPGLLPY
  EPFTMVAVKMLKEEASADMQADFQREAALMAEFDNPNIVKLLGVCAVGKPMCLLFEYMAY
  GDLNEFLRSMSPHTVCSLSHSDLSMRAQVSSPGPPPLSCAEQLCIARQVAAGMAYLSERK
  FVHRDLATRNCLVGENMVVKIADFGLSRNIYSADYYKANENDAIPIRWMPPESIFYNRYT
  TESDVWAYGVVLWEIFSYGLQPYYGMAHEEVIYYVRDGNILSCPENCPVELYNLMRLCWS
  KLPADRPSFTSIHRILERMCERAEGTVSV
• 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. 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.
• Reactome Pathway: ECM proteoglycans (R-HSA-3000178)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Congenital myasthenic syndrome 9	DISMVPNU	Strong	Autosomal recessive	[1]
Fetal akinesia deformation sequence 1	DISKDI9L	Strong	Autosomal recessive	[2]
Postsynaptic congenital myasthenic syndrome	DIS92VN2	Supportive	Autosomal recessive	[3]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Muscle, skeletal receptor tyrosine-protein kinase (MUSK).	[4]

2 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Muscle, skeletal receptor tyrosine-protein kinase (MUSK).	[5]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Muscle, skeletal receptor tyrosine-protein kinase (MUSK).	[6]

References

• [1] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [2] Identification of a Dutch founder mutation in MUSK causing fetal akinesia deformation sequence. Eur J Hum Genet. 2015 Sep;23(9):1151-7. doi: 10.1038/ejhg.2014.273. Epub 2014 Dec 24.
• [3] Congenital Myasthenic Syndromes Overview. 2003 May 9 [updated 2021 Dec 23]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [4] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [5] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [6] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.