Molecule Information

General Information of the Molecule (ID: Mol01895)

• Name: Midkine (MDK) ,Homo sapiens
• Synonyms: MDK; MK1; NEGF2
• Molecule Type: Protein
• Gene Name: MDK
• Gene ID: 4192
• Location: chr11:46,380,756-46,383,837[+]
• Sequence:
  MQHRGFLLLTLLALLALTSAVAKKKDKVKKGGPGSECAEWAWGPCTPSSKDCGVGFREGT
  CGAQTQRIRCRVPCNWKKEFGADCKYKFENWGACDGGTGTKVRQGTLKKARYNAQCQETI
  RVTKPCTPKTKAKAKAKKGKGKD
• Function: Secreted protein that functions as 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.
• Uniprot ID: MK_HUMAN
• Ensembl ID: ENSG00000110492
• HGNC ID: HGNC:6972

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 1 drug(s) in total

Gemcitabine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Biliary tract cancer [1]

• Resistant Disease: Biliary tract cancer [ICD-11: 2C15.0]
• Resistant Drug: Gemcitabine
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: GBC-SD cells; Gallbladder; Homo sapiens (Human); CVCL_6903
• In Vitro Model: RBE cells; Liver; Homo sapiens (Human); CVCL_4896
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: BTC cell lines were more resistant to gemcitabine plus MDK compared with gemcitabine alone. In terms of the underlying mechanism, MDK promoted the epithelial to mesenchymal transition (EMT) of BTC cells and the enhancing effect of MDK on gemcitabine resistance was abrogated when the EMT was blocked with small interfering (si)RNA targeting Twist. In addition, MDK promoted the expression of Notch-1, while knockdown of Notch-1 by siRNA blocked the EMT process in the BTC cell lines.

References

• Ref 1: Effect of midkine on gemcitabine resistance in biliary tract cancer .Int J Mol Med. 2018 Apr;41(4):2003-2011. doi: 10.3892/ijmm.2018.3399. Epub 2018 Jan 18. 10.3892/ijmm.2018.3399