Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTO4M459)

• DOT Name: Low-density lipoprotein receptor-related protein 4 (LRP4)
• Synonyms: LRP-4; Multiple epidermal growth factor-like domains 7
• Gene Name: LRP4
• Related Disease:
  Cenani-Lenz syndactyly syndrome
  Autoimmune disease
  Bone disease
  Congenital deformities of limbs
  Congenital myasthenic syndrome
  Congenital myasthenic syndrome 17
  Hyperalphalipoproteinemia
  Neuromuscular disease
  Osteoporosis
  Thyroid gland papillary carcinoma
  Venous thromboembolism
  Amyotrophic lateral sclerosis
  Richter syndrome
  Small lymphocytic lymphoma
  Postsynaptic congenital myasthenic syndrome
  Sclerosteosis
  Advanced cancer
  Coffin-Lowry syndrome
  Microphthalmia
  Schizophrenia
  Sclerosteosis 2
  Stroke
  Thyroid cancer
  Thyroid gland carcinoma
  Thyroid tumor
• UniProt ID: LRP4_HUMAN
• PDB ID: 8S9P
• Pfam ID: PF12662 ; PF14670 ; PF00057 ; PF00058
• Sequence:
  MRRQWGALLLGALLCAHGLASSPECACGRSHFTCAVSALGECTCIPAQWQCDGDNDCGDH
  SDEDGCILPTCSPLDFHCDNGKCIRRSWVCDGDNDCEDDSDEQDCPPRECEEDEFPCQNG
  YCIRSLWHCDGDNDCGDNSDEQCDMRKCSDKEFRCSDGSCIAEHWYCDGDTDCKDGSDEE
  NCPSAVPAPPCNLEEFQCAYGRCILDIYHCDGDDDCGDWSDESDCSSHQPCRSGEFMCDS
  GLCINAGWRCDGDADCDDQSDERNCTTSMCTAEQFRCHSGRCVRLSWRCDGEDDCADNSD
  EENCENTGSPQCALDQFLCWNGRCIGQRKLCNGVNDCGDNSDESPQQNCRPRTGEENCNV
  NNGGCAQKCQMVRGAVQCTCHTGYRLTEDGHTCQDVNECAEEGYCSQGCTNSEGAFQCWC
  ETGYELRPDRRSCKALGPEPVLLFANRIDIRQVLPHRSEYTLLLNNLENAIALDFHHRRE
  LVFWSDVTLDRILRANLNGSNVEEVVSTGLESPGGLAVDWVHDKLYWTDSGTSRIEVANL
  DGAHRKVLLWQNLEKPRAIALHPMEGTIYWTDWGNTPRIEASSMDGSGRRIIADTHLFWP
  NGLTIDYAGRRMYWVDAKHHVIERANLDGSHRKAVISQGLPHPFAITVFEDSLYWTDWHT
  KSINSANKFTGKNQEIIRNKLHFPMDIHTLHPQRQPAGKNRCGDNNGGCTHLCLPSGQNY
  TCACPTGFRKISSHACAQSLDKFLLFARRMDIRRISFDTEDLSDDVIPLADVRSAVALDW
  DSRDDHVYWTDVSTDTISRAKWDGTGQEVVVDTSLESPAGLAIDWVTNKLYWTDAGTDRI
  EVANTDGSMRTVLIWENLDRPRDIVVEPMGGYMYWTDWGASPKIERAGMDASGRQVIISS
  NLTWPNGLAIDYGSQRLYWADAGMKTIEFAGLDGSKRKVLIGSQLPHPFGLTLYGERIYW
  TDWQTKSIQSADRLTGLDRETLQENLENLMDIHVFHRRRPPVSTPCAMENGGCSHLCLRS
  PNPSGFSCTCPTGINLLSDGKTCSPGMNSFLIFARRIDIRMVSLDIPYFADVVVPINITM
  KNTIAIGVDPQEGKVYWSDSTLHRISRANLDGSQHEDIITTGLQTTDGLAVDAIGRKVYW
  TDTGTNRIEVGNLDGSMRKVLVWQNLDSPRAIVLYHEMGFMYWTDWGENAKLERSGMDGS
  DRAVLINNNLGWPNGLTVDKASSQLLWADAHTERIEAADLNGANRHTLVSPVQHPYGLTL
  LDSYIYWTDWQTRSIHRADKGTGSNVILVRSNLPGLMDMQAVDRAQPLGFNKCGSRNGGC
  SHLCLPRPSGFSCACPTGIQLKGDGKTCDPSPETYLLFSSRGSIRRISLDTSDHTDVHVP
  VPELNNVISLDYDSVDGKVYYTDVFLDVIRRADLNGSNMETVIGRGLKTTDGLAVDWVAR
  NLYWTDTGRNTIEASRLDGSCRKVLINNSLDEPRAIAVFPRKGYLFWTDWGHIAKIERAN
  LDGSERKVLINTDLGWPNGLTLDYDTRRIYWVDAHLDRIESADLNGKLRQVLVSHVSHPF
  ALTQQDRWIYWTDWQTKSIQRVDKYSGRNKETVLANVEGLMDIIVVSPQRQTGTNACGVN
  NGGCTHLCFARASDFVCACPDEPDSRPCSLVPGLVPPAPRATGMSEKSPVLPNTPPTTLY
  SSTTRTRTSLEEVEGRCSERDARLGLCARSNDAVPAAPGEGLHISYAIGGLLSILLILVV
  IAALMLYRHKKSKFTDPGMGNLTYSNPSYRTSTQEVKIEAIPKPAMYNQLCYKKEGGPDH
  NYTKEKIKIVEGICLLSGDDAEWDDLKQLRSSRGGLLRDHVCMKTDTVSIQASSGSLDDT
  ETEQLLQEEQSECSSVHTAATPERRGSLPDTGWKHERKLSSESQV
• Function: Mediates SOST-dependent inhibition of bone formation. Functions as a specific facilitator of SOST-mediated inhibition of Wnt signaling. Plays a key role in the formation and the maintenance of the neuromuscular junction (NMJ), the synapse between motor neuron and skeletal muscle. Directly binds AGRIN and recruits it to the MUSK signaling complex. Mediates the AGRIN-induced phosphorylation of MUSK, the kinase of the complex. The activation of MUSK in myotubes induces the formation of NMJ by regulating different processes including the transcription of specific genes and the clustering of AChR in the postsynaptic membrane. Alternatively, may be involved in the negative regulation of the canonical Wnt signaling pathway, being able to antagonize the LRP6-mediated activation of this pathway. More generally, has been proposed to function as a cell surface endocytic receptor binding and internalizing extracellular ligands for degradation by lysosomes. May play an essential role in the process of digit differentiation.
• Tissue Specificity: Expressed in bone; present in osteoblasts and osteocytes. No expression is observed in osteoclast. Expressed in several regions of the brain.
• Reactome Pathway: ECM proteoglycans (R-HSA-3000178)

Molecular Interaction Atlas (MIA) of This DOT

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cenani-Lenz syndactyly syndrome	DISHZEW1	Definitive	Autosomal recessive	[1]
Autoimmune disease	DISORMTM	Strong	Biomarker	[2]
Bone disease	DISE1F82	Strong	Biomarker	[3]
Congenital deformities of limbs	DISP4N1Q	Strong	Genetic Variation	[4]
Congenital myasthenic syndrome	DISJLG2T	Strong	Biomarker	[5]
Congenital myasthenic syndrome 17	DISY2TGK	Strong	Autosomal recessive	[6]
Hyperalphalipoproteinemia	DISPUX00	Strong	Biomarker	[7]
Neuromuscular disease	DISQTIJZ	Strong	Biomarker	[8]
Osteoporosis	DISF2JE0	Strong	Genetic Variation	[9]
Thyroid gland papillary carcinoma	DIS48YMM	Strong	Biomarker	[10]
Venous thromboembolism	DISUR7CR	Strong	Genetic Variation	[11]
Amyotrophic lateral sclerosis	DISF7HVM	moderate	Biomarker	[12]
Richter syndrome	DISBX2TK	moderate	Genetic Variation	[13]
Small lymphocytic lymphoma	DIS30POX	moderate	Biomarker	[13]
Postsynaptic congenital myasthenic syndrome	DIS92VN2	Supportive	Autosomal recessive	[14]
Sclerosteosis	DISB8RTM	Supportive	Autosomal recessive	[15]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[16]
Coffin-Lowry syndrome	DISMTBDA	Limited	Genetic Variation	[17]
Microphthalmia	DISGEBES	Limited	Altered Expression	[18]
Schizophrenia	DISSRV2N	Limited	Genetic Variation	[19]
Sclerosteosis 2	DISVECXQ	Limited	Semidominant	[20]
Stroke	DISX6UHX	Limited	Altered Expression	[21]
Thyroid cancer	DIS3VLDH	Limited	Altered Expression	[22]
Thyroid gland carcinoma	DISMNGZ0	Limited	Altered Expression	[22]
Thyroid tumor	DISLVKMD	Limited	Altered Expression	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Low-density lipoprotein receptor-related protein 4 (LRP4).	[23]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Low-density lipoprotein receptor-related protein 4 (LRP4).	[24]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Low-density lipoprotein receptor-related protein 4 (LRP4).	[25]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Low-density lipoprotein receptor-related protein 4 (LRP4).	[26]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Low-density lipoprotein receptor-related protein 4 (LRP4).	[27]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Low-density lipoprotein receptor-related protein 4 (LRP4).	[28]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Low-density lipoprotein receptor-related protein 4 (LRP4).	[30]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Low-density lipoprotein receptor-related protein 4 (LRP4).	[31]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Low-density lipoprotein receptor-related protein 4 (LRP4).	[32]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Low-density lipoprotein receptor-related protein 4 (LRP4).	[33]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Low-density lipoprotein receptor-related protein 4 (LRP4).	[34]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Low-density lipoprotein receptor-related protein 4 (LRP4).	[35]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Low-density lipoprotein receptor-related protein 4 (LRP4).	[37]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Low-density lipoprotein receptor-related protein 4 (LRP4).	[39]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Low-density lipoprotein receptor-related protein 4 (LRP4).	[40]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Low-density lipoprotein receptor-related protein 4 (LRP4).	[41]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Low-density lipoprotein receptor-related protein 4 (LRP4).	[42]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Low-density lipoprotein receptor-related protein 4 (LRP4).	[43]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Low-density lipoprotein receptor-related protein 4 (LRP4).	[29]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Low-density lipoprotein receptor-related protein 4 (LRP4).	[36]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Low-density lipoprotein receptor-related protein 4 (LRP4).	[38]

References

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