Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTF24HKC)

• DOT Name: Midkine (MDK)
• Synonyms: MK; Amphiregulin-associated protein; ARAP; Midgestation and kidney protein; Neurite outgrowth-promoting factor 2; Neurite outgrowth-promoting protein
• Gene Name: MDK
• UniProt ID: MK_HUMAN
• PDB ID: 1MKC; 1MKN
• Pfam ID: PF01091 ; PF05196
• Sequence:
  MQHRGFLLLTLLALLALTSAVAKKKDKVKKGGPGSECAEWAWGPCTPSSKDCGVGFREGT
  CGAQTQRIRCRVPCNWKKEFGADCKYKFENWGACDGGTGTKVRQGTLKKARYNAQCQETI
  RVTKPCTPKTKAKAKAKKGKGKD
• Function: Secreted protein that functions as a cytokine and growth factor and mediates its signal through cell-surface proteoglycan and non-proteoglycan receptors. Binds cell-surface proteoglycan receptors via their chondroitin sulfate (CS) groups. Thereby regulates many processes like inflammatory response, cell proliferation, cell adhesion, cell growth, cell survival, tissue regeneration, cell differentiation and cell migration. Participates in inflammatory processes by exerting two different activities. Firstly, mediates neutrophils and macrophages recruitment to the sites of inflammation both by direct action by cooperating namely with ITGB2 via LRP1 and by inducing chemokine expression. This inflammation can be accompanied by epithelial cell survival and smooth muscle cell migration after renal and vessel damage, respectively. Secondly, suppresses the development of tolerogenic dendric cells thereby inhibiting the differentiation of regulatory T cells and also promote T cell expansion through NFAT signaling and Th1 cell differentiation. Promotes tissue regeneration after injury or trauma. After heart damage negatively regulates the recruitment of inflammatory cells and mediates cell survival through activation of anti-apoptotic signaling pathways via MAPKs and AKT pathways through the activation of angiogenesis. Also facilitates liver regeneration as well as bone repair by recruiting macrophage at trauma site and by promoting cartilage development by facilitating chondrocyte differentiation. Plays a role in brain by promoting neural precursor cells survival and growth through interaction with heparan sulfate proteoglycans. Binds PTPRZ1 and promotes neuronal migration and embryonic neurons survival. Binds SDC3 or GPC2 and mediates neurite outgrowth and cell adhesion. Binds chondroitin sulfate E and heparin leading to inhibition of neuronal cell adhesion induced by binding with GPC2. Binds CSPG5 and promotes elongation of oligodendroglial precursor-like cells. Also binds ITGA6:ITGB1 complex; this interaction mediates MDK-induced neurite outgrowth. Binds LRP1; promotes neuronal survival. Binds ITGA4:ITGB1 complex; this interaction mediates MDK-induced osteoblast cells migration through PXN phosphorylation. Binds anaplastic lymphoma kinase (ALK) which induces ALK activation and subsequent phosphorylation of the insulin receptor substrate (IRS1), followed by the activation of mitogen-activated protein kinase (MAPK) and PI3-kinase, and the induction of cell proliferation. Promotes epithelial to mesenchymal transition through interaction with NOTCH2. During arteriogenesis, plays a role in vascular endothelial cell proliferation by inducing VEGFA expression and release which in turn induces nitric oxide synthase expression. Moreover activates vasodilation through nitric oxide synthase activation. Negatively regulates bone formation in response to mechanical load by inhibiting Wnt/beta-catenin signaling in osteoblasts. In addition plays a role in hippocampal development, working memory, auditory response, early fetal adrenal gland development and the female reproductive system.
• Tissue Specificity: Expressed in various tumor cell lines. In insulinoma tissue predominantly expressed in precancerous lesions.
• Reactome Pathway:
  NOTCH2 Activation and Transmission of Signal to the Nucleus (R-HSA-2979096)
  Signaling by ALK (R-HSA-201556)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Marinol	DM70IK5	Approved	Midkine (MDK) decreases the response to substance of Marinol.	[27]
Mitomycin	DMH0ZJE	Approved	Midkine (MDK) affects the response to substance of Mitomycin.	[28]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Midkine (MDK).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Midkine (MDK).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Midkine (MDK).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Midkine (MDK).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Midkine (MDK).	[4]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Midkine (MDK).	[5]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Midkine (MDK).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Midkine (MDK).	[7]
Selenium	DM25CGV	Approved	Selenium increases the expression of Midkine (MDK).	[8]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Midkine (MDK).	[9]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Midkine (MDK).	[10]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Midkine (MDK).	[11]
Piroxicam	DMTK234	Approved	Piroxicam increases the expression of Midkine (MDK).	[12]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of Midkine (MDK).	[13]
Bicalutamide	DMZMSPF	Approved	Bicalutamide increases the expression of Midkine (MDK).	[14]
Phenytoin	DMNOKBV	Approved	Phenytoin increases the expression of Midkine (MDK).	[15]
Enzalutamide	DMGL19D	Approved	Enzalutamide affects the expression of Midkine (MDK).	[16]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of Midkine (MDK).	[18]
Fenretinide	DMRD5SP	Phase 3	Fenretinide increases the expression of Midkine (MDK).	[19]
Seocalcitol	DMKL9QO	Phase 3	Seocalcitol decreases the expression of Midkine (MDK).	[20]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Midkine (MDK).	[21]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Midkine (MDK).	[8]
Gossypol	DMJWE3I	Phase 2	Gossypol decreases the expression of Midkine (MDK).	[22]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Midkine (MDK).	[24]
SB-431542	DM0YOXQ	Preclinical	SB-431542 increases the expression of Midkine (MDK).	[25]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Midkine (MDK).	[26]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Chondroitin sulfate	DM0N19Y	Phase 4	Chondroitin sulfate affects the binding of Midkine (MDK).	[17]

References

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