Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT78QB4A)

• DOT Name: Myosin light chain kinase, smooth muscle (MYLK)
• Synonyms: MLCK; smMLCK; EC 2.7.11.18; Kinase-related protein; KRP; Telokin
• Gene Name: MYLK
• Related Disease:
  Aortic aneurysm, familial thoracic 7
  Familial thoracic aortic aneurysm and aortic dissection
  Connective tissue disorder
  Obsolete megacystis-microcolon-intestinal hypoperistalsis syndrome
• UniProt ID: MYLK_HUMAN
• PDB ID: 2CQV; 2K0F; 2YR3; 5JQA; 5JTH; 6C6M
• EC Number: 2.7.11.18
• Pfam ID: PF16620 ; PF00041 ; PF07679 ; PF00069
• Sequence:
  MGDVKLVASSHISKTSLSVDPSRVDSMPLTEAPAFILPPRNLCIKEGATAKFEGRVRGYP
  EPQVTWHRNGQPITSGGRFLLDCGIRGTFSLVIHAVHEEDRGKYTCEATNGSGARQVTVE
  LTVEGSFAKQLGQPVVSKTLGDRFSAPAVETRPSIWGECPPKFATKLGRVVVKEGQMGRF
  SCKITGRPQPQVTWLKGNVPLQPSARVSVSEKNGMQVLEIHGVNQDDVGVYTCLVVNGSG
  KASMSAELSIQGLDSANRSFVRETKATNSDVRKEVTNVISKESKLDSLEAAAKSKNCSSP
  QRGGSPPWAANSQPQPPRESKLESCKDSPRTAPQTPVLQKTSSSITLQAARVQPEPRAPG
  LGVLSPSGEERKRPAPPRPATFPTRQPGLGSQDVVSKAANRRIPMEGQRDSAFPKFESKP
  QSQEVKENQTVKFRCEVSGIPKPEVAWFLEGTPVRRQEGSIEVYEDAGSHYLCLLKARTR
  DSGTYSCTASNAQGQLSCSWTLQVERLAVMEVAPSFSSVLKDCAVIEGQDFVLQCSVRGT
  PVPRITWLLNGQPIQYARSTCEAGVAELHIQDALPEDHGTYTCLAENALGQVSCSAWVTV
  HEKKSSRKSEYLLPVAPSKPTAPIFLQGLSDLKVMDGSQVTMTVQVSGNPPPEVIWLHNG
  NEIQESEDFHFEQRGTQHSLCIQEVFPEDTGTYTCEAWNSAGEVRTQAVLTVQEPHDGTQ
  PWFISKPRSVTASLGQSVLISCAIAGDPFPTVHWLRDGKALCKDTGHFEVLQNEDVFTLV
  LKKVQPWHAGQYEILLKNRVGECSCQVSLMLQNSSARALPRGREPASCEDLCGGGVGADG
  GGSDRYGSLRPGWPARGQGWLEEEDGEDVRGVLKRRVETRQHTEEAIRQQEVEQLDFRDL
  LGKKVSTKTLSEDDLKEIPAEQMDFRANLQRQVKPKTVSEEERKVHSPQQVDFRSVLAKK
  GTSKTPVPEKVPPPKPATPDFRSVLGGKKKLPAENGSSSAETLNAKAVESSKPLSNAQPS
  GPLKPVGNAKPAETLKPMGNAKPAETLKPMGNAKPDENLKSASKEELKKDVKNDVNCKRG
  HAGTTDNEKRSESQGTAPAFKQKLQDVHVAEGKKLLLQCQVSSDPPATIIWTLNGKTLKT
  TKFIILSQEGSLCSVSIEKALPEDRGLYKCVAKNDAGQAECSCQVTVDDAPASENTKAPE
  MKSRRPKSSLPPVLGTESDATVKKKPAPKTPPKAAMPPQIIQFPEDQKVRAGESVELFGK
  VTGTQPITCTWMKFRKQIQESEHMKVENSENGSKLTILAARQEHCGCYTLLVENKLGSRQ
  AQVNLTVVDKPDPPAGTPCASDIRSSSLTLSWYGSSYDGGSAVQSYSIEIWDSANKTWKE
  LATCRSTSFNVQDLLPDHEYKFRVRAINVYGTSEPSQESELTTVGEKPEEPKDEVEVSDD
  DEKEPEVDYRTVTINTEQKVSDFYDIEERLGSGKFGQVFRLVEKKTRKVWAGKFFKAYSA
  KEKENIRQEISIMNCLHHPKLVQCVDAFEEKANIVMVLEIVSGGELFERIIDEDFELTER
  ECIKYMRQISEGVEYIHKQGIVHLDLKPENIMCVNKTGTRIKLIDFGLARRLENAGSLKV
  LFGTPEFVAPEVINYEPIGYATDMWSIGVICYILVSGLSPFMGDNDNETLANVTSATWDF
  DDEAFDEISDDAKDFISNLLKKDMKNRLDCTQCLQHPWLMKDTKNMEAKKLSKDRMKKYM
  ARRKWQKTGNAVRAIGRLSSMAMISGLSGRKSSTGSPTSPLNAEKLESEEDVSQAFLEAV
  AEEKPHVKPYFSKTIRDLEVVEGSAARFDCKIEGYPDPEVVWFKDDQSIRESRHFQIDYD
  EDGNCSLIISDVCGDDDAKYTCKAVNSLGEATCTAELIVETMEEGEGEGEEEEE
• Function: Calcium/calmodulin-dependent myosin light chain kinase implicated in smooth muscle contraction via phosphorylation of myosin light chains (MLC). Also regulates actin-myosin interaction through a non-kinase activity. Phosphorylates PTK2B/PYK2 and myosin light-chains. Involved in the inflammatory response (e.g. apoptosis, vascular permeability, leukocyte diapedesis), cell motility and morphology, airway hyperreactivity and other activities relevant to asthma. Required for tonic airway smooth muscle contraction that is necessary for physiological and asthmatic airway resistance. Necessary for gastrointestinal motility. Implicated in the regulation of endothelial as well as vascular permeability, probably via the regulation of cytoskeletal rearrangements. In the nervous system it has been shown to control the growth initiation of astrocytic processes in culture and to participate in transmitter release at synapses formed between cultured sympathetic ganglion cells. Critical participant in signaling sequences that result in fibroblast apoptosis. Plays a role in the regulation of epithelial cell survival. Required for epithelial wound healing, especially during actomyosin ring contraction during purse-string wound closure. Mediates RhoA-dependent membrane blebbing. Triggers TRPC5 channel activity in a calcium-dependent signaling, by inducing its subcellular localization at the plasma membrane. Promotes cell migration (including tumor cells) and tumor metastasis. PTK2B/PYK2 activation by phosphorylation mediates ITGB2 activation and is thus essential to trigger neutrophil transmigration during acute lung injury (ALI). May regulate optic nerve head astrocyte migration. Probably involved in mitotic cytoskeletal regulation. Regulates tight junction probably by modulating ZO-1 exchange in the perijunctional actomyosin ring. Mediates burn-induced microvascular barrier injury; triggers endothelial contraction in the development of microvascular hyperpermeability by phosphorylating MLC. Essential for intestinal barrier dysfunction. Mediates Giardia spp.-mediated reduced epithelial barrier function during giardiasis intestinal infection via reorganization of cytoskeletal F-actin and tight junctional ZO-1. Necessary for hypotonicity-induced Ca(2+) entry and subsequent activation of volume-sensitive organic osmolyte/anion channels (VSOAC) in cervical cancer cells. Responsible for high proliferative ability of breast cancer cells through anti-apoptosis.
• Tissue Specificity: Smooth muscle and non-muscle isozymes are expressed in a wide variety of adult and fetal tissues and in cultured endothelium with qualitative expression appearing to be neither tissue- nor development-specific. Non-muscle isoform 2 is the dominant splice variant expressed in various tissues. Telokin has been found in a wide variety of adult and fetal tissues. Accumulates in well differentiated enterocytes of the intestinal epithelium in response to tumor necrosis factor (TNF).
• KEGG Pathway:
  Calcium sig.ling pathway (hsa04020)
  cGMP-PKG sig.ling pathway (hsa04022)
  Vascular smooth muscle contraction (hsa04270)
  Apelin sig.ling pathway (hsa04371)
  Focal adhesion (hsa04510)
  Platelet activation (hsa04611)
  Regulation of actin cytoskeleton (hsa04810)
  Oxytocin sig.ling pathway (hsa04921)
  Gastric acid secretion (hsa04971)
• Reactome Pathway:
  RHO GTPases activate PAKs (R-HSA-5627123)
  Smooth Muscle Contraction (R-HSA-445355)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Aortic aneurysm, familial thoracic 7	DISEZ71K	Strong	Autosomal dominant	[1]
Familial thoracic aortic aneurysm and aortic dissection	DIS069FB	Strong	Autosomal dominant	[2]
Connective tissue disorder	DISKXBS3	Moderate	Autosomal dominant	[3]
Obsolete megacystis-microcolon-intestinal hypoperistalsis syndrome	DISP6WWH	Supportive	Autosomal dominant	[4]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
LPA	DMI5XR1	Investigative	Myosin light chain kinase, smooth muscle (MYLK) affects the response to substance of LPA.	[38]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Myosin light chain kinase, smooth muscle (MYLK).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Myosin light chain kinase, smooth muscle (MYLK).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Myosin light chain kinase, smooth muscle (MYLK).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Myosin light chain kinase, smooth muscle (MYLK).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Myosin light chain kinase, smooth muscle (MYLK).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Myosin light chain kinase, smooth muscle (MYLK).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Myosin light chain kinase, smooth muscle (MYLK).	[11]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Myosin light chain kinase, smooth muscle (MYLK).	[12]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Myosin light chain kinase, smooth muscle (MYLK).	[13]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Myosin light chain kinase, smooth muscle (MYLK).	[14]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Myosin light chain kinase, smooth muscle (MYLK).	[15]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Myosin light chain kinase, smooth muscle (MYLK).	[16]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Myosin light chain kinase, smooth muscle (MYLK).	[14]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Myosin light chain kinase, smooth muscle (MYLK).	[16]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Myosin light chain kinase, smooth muscle (MYLK).	[17]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Myosin light chain kinase, smooth muscle (MYLK).	[18]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Myosin light chain kinase, smooth muscle (MYLK).	[15]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Myosin light chain kinase, smooth muscle (MYLK).	[19]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Myosin light chain kinase, smooth muscle (MYLK).	[20]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Myosin light chain kinase, smooth muscle (MYLK).	[21]
Dasatinib	DMJV2EK	Approved	Dasatinib increases the expression of Myosin light chain kinase, smooth muscle (MYLK).	[22]
Indomethacin	DMSC4A7	Approved	Indomethacin increases the expression of Myosin light chain kinase, smooth muscle (MYLK).	[23]
Fenofibrate	DMFKXDY	Approved	Fenofibrate decreases the expression of Myosin light chain kinase, smooth muscle (MYLK).	[24]
Acocantherin	DM7JT24	Approved	Acocantherin decreases the expression of Myosin light chain kinase, smooth muscle (MYLK).	[25]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Myosin light chain kinase, smooth muscle (MYLK).	[26]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Myosin light chain kinase, smooth muscle (MYLK).	[19]
Curcumin	DMQPH29	Phase 3	Curcumin increases the expression of Myosin light chain kinase, smooth muscle (MYLK).	[27]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Myosin light chain kinase, smooth muscle (MYLK).	[28]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Myosin light chain kinase, smooth muscle (MYLK).	[19]
ACYLINE	DM9GRTK	Phase 2	ACYLINE decreases the expression of Myosin light chain kinase, smooth muscle (MYLK).	[29]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Myosin light chain kinase, smooth muscle (MYLK).	[6]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Myosin light chain kinase, smooth muscle (MYLK).	[30]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Myosin light chain kinase, smooth muscle (MYLK).	[33]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Myosin light chain kinase, smooth muscle (MYLK).	[34]
D-glucose	DMMG2TO	Investigative	D-glucose increases the expression of Myosin light chain kinase, smooth muscle (MYLK).	[35]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal decreases the expression of Myosin light chain kinase, smooth muscle (MYLK).	[36]
PD98059	DMZC90M	Investigative	PD98059 decreases the activity of Myosin light chain kinase, smooth muscle (MYLK).	[37]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Myosin light chain kinase, smooth muscle (MYLK).	[31]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Myosin light chain kinase, smooth muscle (MYLK).	[32]

References

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