Affinage

MDK

Midkine · UniProt P21741

Length
143 aa
Mass
15.6 kDa
Annotated
2026-06-10
55 papers in source corpus 35 papers cited in narrative 35 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MDK (Midkine) is a secreted growth factor that signals through cell-surface receptors to activate pro-survival and pro-proliferative cascades, functioning as a context-dependent factor in tissue regeneration, neuronal development, and tumor progression (PMID:23976985, PMID:39040052). Its dominant downstream output is the PI3K/AKT survival axis: PI3K activation underlies MDK-driven cell survival in lung cancer (PMID:23976985), endothelial angiogenesis (PMID:30001734), cervical carcinoma proliferation and lymphangiogenesis (PMID:39040052), and colorectal EMT via AP2A1 (PMID:42073635), with additional engagement of MAPK/p38, JAK/STAT, Notch1/p-JNK, and NF-κB outputs in different contexts (PMID:31972179, PMID:36381313, PMID:39040052, PMID:41674663). MDK exerts these effects through several receptors—LRP1, syndecan-1 (SDC1), syndecan-4 (SDC4), nucleolin (NCL), and ALK—engaged in distinct settings [PMID:34171432, PMID:39040052, PMID:38614865, PMID:42031197, PMID:bio_10.1101_2025.05.27.656365]. A recurrent role is reprogramming the tumor microenvironment: MDK secreted by tumor cells engages LRP1 on macrophages to drive immunosuppressive M2 polarization across gallbladder, renal, glioma, and liver cancers (PMID:34171432, PMID:39107475, PMID:40527884, PMID:41525571), and engages NCL to promote mast cell activation (PMID:42031197). Beyond ligand–receptor signaling, MDK binds c-Myc directly and stabilizes it against ubiquitination to activate Wnt/β-catenin signaling and confer temozolomide resistance in glioma (PMID:40468625). MDK expression is induced by SP1 (PMID:25428991), IFN-γ/STAT1 (PMID:35747815, PMID:36672515), p53/DDR (PMID:30773478), Wnt/β-catenin (PMID:39900120), and CDK7 (PMID:39004275), and repressed by microRNAs including miR-9, miR-326, miR-1275, and miR-1275 (PMID:30001734, PMID:31972179, PMID:36594100). In non-malignant tissue, MDK is required for postnatal hippocampal development (PMID:10096022) and peripheral nerve degeneration/regeneration (PMID:19437545), drives LRP1-dependent neurotrophic signaling and BDNF upregulation after spinal cord injury (PMID:42257999), and attenuates Aβ fibril formation, protecting against amyloid pathology [PMID:bio_10.1101_2025.03.20.644383].

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1993 Medium

    Establishing the chromosomal location of MDK provided the genomic anchor needed for subsequent functional and comparative studies.

    Evidence FISH mapping to chromosome 11p11.2, refined by somatic cell hybrid and interspecific backcross analysis to mouse synteny

    PMID:7835084 PMID:8406506

    Open questions at the time
    • Mapping alone gives no functional or mechanistic information
    • Does not address regulation or protein activity
  2. 1998 High

    Loss-of-function in mice answered whether MDK has a physiological developmental role, revealing it is required for postnatal hippocampal development and normal behavior.

    Evidence Mdk knockout mouse with immunohistochemistry and behavioral testing (Y-maze, elevated plus-maze)

    PMID:10096022

    Open questions at the time
    • Receptor and signaling pathway mediating the hippocampal phenotype not identified
    • Cell-autonomous versus secreted action not resolved
  3. 2009 High

    A second knockout phenotype established MDK as a required factor for peripheral nerve degeneration and regeneration, extending its physiological role beyond development.

    Evidence Mdk knockout mice subjected to sciatic nerve injury with histomorphometry, EMG, and functional recovery readouts

    PMID:19437545

    Open questions at the time
    • Molecular mediators of the regeneration defect not defined
    • Receptor involvement not tested
  4. 2006 Medium

    Reciprocal gain- and loss-of-function tied MDK to drug resistance, a phenotype later recurring across many cancers.

    Evidence Overexpression and siRNA knockdown with IC50 drug cytotoxicity assays in cancer cell lines

    PMID:16644108

    Open questions at the time
    • Mechanism linking MDK to multidrug resistance not defined at this stage
    • No receptor or signaling pathway identified
  5. 2013 High

    Small-molecule inhibition with specificity controls established the PI3K survival pathway as a core mediator of MDK's pro-tumor function.

    Evidence iMDK inhibitor with PI3K western blotting, viability assays, and xenografts using MDK-negative controls

    PMID:23976985

    Open questions at the time
    • Receptor coupling MDK to PI3K not identified
    • iMDK acts by suppressing MDK expression rather than blocking ligand binding
  6. 2014 High

    ChIP-based identification of SP1 as a direct transcriptional activator, with rescue, began defining the regulatory inputs controlling MDK levels.

    Evidence ChIP, siRNA silencing, MDK overexpression rescue, and xenografts in glioma

    PMID:25428991

    Open questions at the time
    • Other transcriptional regulators not addressed here
    • Downstream MDK signaling in glioma not dissected
  7. 2018 Medium

    MicroRNA targeting and reporter validation showed MDK is post-transcriptionally repressed and functions in endothelial angiogenesis via PI3K/AKT.

    Evidence Luciferase 3'UTR reporter (miR-9), tube formation, migration, matrigel plug, and phosphorylation array assays

    PMID:30001734

    Open questions at the time
    • Endothelial receptor for MDK not identified
    • Direct versus paracrine angiogenic action not separated
  8. 2019 Medium

    Linking MDK to p53/DDR and showing it drives microglial M2 polarization introduced its role in shaping the immunosuppressive tumor microenvironment.

    Evidence In vitro/in vivo M2 polarization assays, western blotting, and transcriptomics in glioblastoma

    PMID:30773478

    Open questions at the time
    • Receptor on microglia not identified in this study
    • Mechanism of p53-mediated MDK induction not detailed
  9. 2021 Medium

    Identification of LRP1 as the macrophage receptor mediating MDK-driven M2 polarization assigned a molecular basis to MDK's immunomodulatory role.

    Evidence scRNA-seq, bulk RNA-seq, immunostaining, and macrophage polarization functional assays in gallbladder cancer

    PMID:34171432

    Open questions at the time
    • Direct biochemical MDK-LRP1 binding affinity not measured
    • Downstream macrophage signaling from LRP1 not fully mapped
  10. 2022 Medium

    Multiple studies placed MDK downstream of IFN-γ/STAT1 and Notch1/p-JNK, establishing it as a driver of EMT, metastasis, stemness, and therapy resistance across cancer types.

    Evidence Knockdown/overexpression, iMDK inhibition, EMT/stem-cell markers, combination index analysis, and xenografts in lung, ovarian, and glioblastoma models

    PMID:31972179 PMID:35747815 PMID:36381313 PMID:36672515

    Open questions at the time
    • Receptor coupling IFN-γ-induced MDK to EMT not defined
    • Convergence of multiple pathways onto common effectors unresolved
  11. 2024 Medium

    A series of studies expanded MDK's receptor repertoire (SDC1, SDC4, LRP1) and upstream regulators (GPC2, CDK7), consolidating PI3K/AKT as the convergent output across tumor and regenerative contexts.

    Evidence Co-IP (SDC1), rescue assays (GPC2), CDK7 inhibition (THZ1), spatial/single-cell transcriptomics (SDC4-Treg), and macrophage polarization assays across cervical, prostate, colorectal, and renal cancers

    PMID:38255198 PMID:38614865 PMID:39004275 PMID:39014225 PMID:39040052 PMID:39107475

    Open questions at the time
    • Receptor selection in different tissues not mechanistically explained
    • Some receptor assignments rely on transcriptomic inference without binding validation
  12. 2025 High

    Direct demonstration that MDK binds and stabilizes c-Myc revealed an intracellular, receptor-independent mechanism activating Wnt/β-catenin and conferring temozolomide resistance.

    Evidence Microthermometry and co-IP for binding, proteomics, ubiquitination/degradation assays, ACT001 disruptor, and glioma models

    PMID:40468625

    Open questions at the time
    • How secreted MDK accesses intracellular c-Myc not resolved
    • Structural basis of the MDK-c-Myc interaction not determined
  13. 2025 Medium

    Functional dissection in non-malignant and immune contexts established LRP1-, NCL-, SDC4-, and ALK-dependent MDK signaling in wound healing, neural repair, mast cell activation, beta-cell dysfunction, and dormancy escape.

    Evidence LRP1 silencing/efferocytosis assays, NCL neutralization, scRNA-seq receptor-ligand inference, ALK-mediated p38/ERK ratio analysis, and in vivo regeneration and metastasis models

    PMID:30001734 PMID:39900120 PMID:40441854 PMID:40468625 PMID:40527884 PMID:40709672 PMID:42031197 PMID:42073635 PMID:42257999

    Open questions at the time
    • Receptor specificity determinants across tissues unresolved
    • Some receptor-ligand links rest on computational inference
  14. 2025 High

    Biophysical and genetic evidence established a protective role for MDK in suppressing amyloid pathology, contrasting its pro-tumor functions.

    Evidence Thioflavin T, circular dichroism, electron microscopy, NMR on Aβ fibrils, and Mdk/5xFAD double-knockout mice (preprint)

    PMID:bio_10.1101_2025.03.20.644383

    Open questions at the time
    • Whether the anti-amyloid effect is receptor-dependent not determined
    • Preprint not yet peer-reviewed

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved what determines MDK's choice among its multiple receptors in a given tissue and how secreted MDK reaches intracellular targets such as c-Myc.
  • No unified model of receptor selection across LRP1/SDC1/SDC4/NCL/ALK
  • Mechanism of intracellular access for secreted MDK unknown
  • Structural basis of receptor and c-Myc binding undetermined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 4 GO:0008289 lipid binding 1 GO:0098772 molecular function regulator activity 1
Localization
GO:0005576 extracellular region 4
Pathway
R-HSA-168256 Immune System 5 R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3
Partners
ALKGPC2LRP1MYCNCLSDC1SDC4

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 MDK gene maps to chromosome 11p11.2 by fluorescence in situ hybridization, establishing its chromosomal location. Fluorescence in situ hybridization (FISH) Genomics Medium 8406506
1995 Human MDK was mapped to chromosome 11p13→p11, and mouse Mdk was mapped to a syntenic region of mouse chromosome 2; a pseudogene of Mdk was mapped to mouse chromosome 11. Somatic cell hybrid analysis and interspecific backcross analysis Cytogenetics and cell genetics Medium 7835084
1998 Mdk knockout mice show altered calretinin expression in hippocampal dentate gyrus granule cell layer and deficits in working memory and increased anxiety, establishing MDK's role in postnatal hippocampal development. Gene knockout mouse model, immunohistochemistry, Y-maze and elevated plus-maze behavioral tests Genes to cells High 10096022
2006 MDK overexpression in HeLa cells confers resistance to 5-FU, doxorubicin, and cisplatin; siRNA-mediated MDK knockdown in SNU-638 gastric cancer cells decreases IC50 for all three drugs by 18–44%, establishing MDK as a modulator of multi-drug resistance. Stable transfection (overexpression), siRNA knockdown, drug cytotoxicity assays (IC50 measurement) Cancer letters Medium 16644108
2009 MDK-deficient (Mdk−/−) mice show delayed Wallerian degeneration and delayed axonal regeneration after sciatic nerve freeze injury, with impaired recovery of motor function, establishing MDK as a required factor for peripheral nerve degeneration and regeneration. Mdk knockout mouse model, histomorphometry, electromyography, muscle wet weight analysis Journal of neuroscience research High 19437545
2013 A small molecule inhibitor iMDK suppresses endogenous MDK expression, inhibits PI3K pathway activation, and induces apoptosis in MDK-positive lung cancer cells, but not in MDK-negative cells; systemic iMDK inhibits tumor growth in xenograft models, establishing MDK's role in activating the PI3K survival pathway in lung cancer. Small molecule inhibition (iMDK), cell viability assays, PI3K pathway western blotting, xenograft mouse model, specificity controls with MDK-negative cells PloS one High 23976985
2014 SP1 binds to the promoter of the MDK gene (confirmed by chromatin immunoprecipitation) and directly transcriptionally upregulates MDK expression; overexpression of MDK in SP1-silenced glioma cells partially rescues SP1 inhibition effects on proliferation in vitro and tumor growth in vivo. Chromatin immunoprecipitation (ChIP), gene silencing (siRNA), MDK overexpression rescue assays, xenograft mouse model Molecular biology of the cell High 25428991
2014 MDK promotes cell migration and proliferation in lacrimal gland cells; recombinant MDK was found in iPSC-conditioned medium and suppresses the p38/JNK pathway and Akt phosphorylation in irradiated lacrimal gland tissue, establishing a role for MDK in radiation injury repair. iPSC-conditioned medium treatment, western blotting for p38/JNK and Akt phosphorylation, cell migration and proliferation assays, in vivo murine model International journal of molecular sciences Low 25314301
2018 Exosomal miR-9 secreted by NPC cells directly suppresses MDK expression in endothelial cells (confirmed by luciferase reporter assay targeting MDK 3'UTR), and MDK knockdown inhibits endothelial tube formation and migration via PDK/AKT signaling, establishing MDK as a downstream mediator of PI3K/AKT-driven angiogenesis in endothelial cells. Luciferase 3'UTR reporter assay, western blotting, tube formation assay, migration assay, matrigel plug assay, Phosphorylation Array Journal of experimental & clinical cancer research Medium 30001734
2019 p53 (a key DDR transcription factor) mediates overexpression of MDK, and MDK promotes M2 polarization of microglia to remodel the glioblastoma immunosuppressive microenvironment, establishing MDK as a downstream effector of p53/DDR signaling in shaping the tumor microenvironment. In vitro and in vivo experiments, western blotting, functional M2 polarization assays, transcriptomic analysis EBioMedicine Medium 30773478
2020 miR-326 targets and inhibits MDK expression, thereby negatively regulating JAK/STAT and MAPK signaling pathways; rescue assays confirmed that MDK re-expression reverses miR-326-mediated attenuation of cardiac hypertrophy in Ang II-treated H9c2 cells and TAC mice. Luciferase reporter assay (implied target validation), miR-326 overexpression, MDK rescue assays, western blotting for JAK/STAT and MAPK pathways, in vivo TAC model European journal of pharmacology Medium 31972179
2021 MDK secreted from ErbB pathway-mutated gallbladder cancer epithelial cells interacts with its receptor LRP1 expressed on tumor-infiltrating macrophages to promote immunosuppressive M2 macrophage differentiation. Single-cell RNA sequencing, bulk RNA-seq, immunohistochemistry, immunofluorescence, functional experiments (macrophage polarization assays) Journal of hepatology Medium 34171432
2022 IFN-γ upregulates MDK via STAT1 signaling in cancer cell lines; MDK drives EMT activation and cancer metastasis; pharmacological MDK inhibition (iMDK) reverses IFN-γ-activated EMT and abrogates IFN-γ-triggered metastasis across multiple cancer types. Cell line knockdown/overexpression, western blotting, migration/invasion assays, iMDK inhibitor treatment Frontiers in oncology Medium 35747815
2022 MDK enhances glioblastoma stem-like properties by activating Notch1/p-JNK signaling, leading to increased CD133 and Nanog expression, thereby promoting temozolomide resistance; MDK knockdown inhibits tumor growth in xenograft models. MDK overexpression/knockdown, western blotting for Notch1/p-JNK/CD133/Nanog, xenograft mouse model, in vitro stem cell assays American journal of cancer research Medium 36381313
2022 MDK is a downstream target of IFN-γ/STAT1 in ovarian cancer cells; MDK overexpression promotes proliferation and EMT/metastasis; MDK inhibition (iMDK) reverses IFN-γ-driven EMT and synergistically enhances IFN-γ growth inhibition (combination index <0.1). Gain-of-function MDK overexpression, iMDK inhibitor, combination index analysis, EMT western blotting, migration/invasion assays Biomedicines Medium 36672515
2023 miR-1275 directly targets MDK as a downstream protein, and MDK initiates PI3K/Akt signaling in breast cancer cells; CRISPR/Cas9 knockout of miR-1275 promotes chemoresistance by increasing cancer stem cell properties via the MDK/AKT axis. CRISPR/Cas9 gene editing, RT-qPCR, western blotting for PI3K/Akt, cancer stem cell assays International journal of biological sciences Medium 36594100
2024 MDK interacts with Syndecan-1 (SDC1) receptor and activates PI3K/AKT and p38 MAPK pathways to promote proliferation, migration, invasion, lymphangiogenesis, and lymph node metastasis of cervical squamous cell carcinoma. MDK overexpression/knockdown, co-immunoprecipitation (implied interaction with SDC1), western blotting for PI3K/AKT and p38, invasion/migration assays, in vivo lymphangiogenesis assays iScience Medium 39040052
2024 MDK promotes M2 macrophage polarization via MDK-LRP1 interaction; MDK inhibition suppresses M2 polarization in clear cell renal cell carcinoma. Multiomics analysis, functional M2 polarization assays, MDK inhibition experiments Scientific reports Medium 39107475
2024 GPC2 promotes prostate cancer cell proliferation, migration, and invasion via MDK-mediated activation of the PI3K/AKT signaling pathway; MDK overexpression rescues the inhibitory effects of GPC2 knockdown on PI3K/AKT signaling and cell behavior. siRNA knockdown, MDK overexpression rescue assay, western blotting for PI3K/AKT, proliferation/migration/invasion assays Functional & integrative genomics Medium 39014225
2024 CDK7 promotes MDK expression in irinotecan-resistant colorectal cancer cells; suppression of CDK7 by siRNA or the inhibitor THZ1 significantly reduces MDK expression and re-sensitizes resistant cells to irinotecan, placing MDK downstream of CDK7 in a drug resistance pathway. Bulk RNA sequencing, siRNA knockdown, CDK7 inhibitor (THZ1), in vivo xenograft experiments, patient tissue analysis Life sciences Medium 39004275
2024 Syndecan-4 (SDC4) is identified as a receptor for MDK associated with regulatory T cell (Treg) colocalisation in colorectal cancer; MDK-high CRC cells interact with SPP1+ macrophages and stromal cells to establish immunosuppression in the tumor microenvironment. Spatial transcriptomics, single-cell transcriptome, deep generative model colocalisation analysis, clinical CRC dataset analysis EBioMedicine Low 38614865
2024 Angelica sinensis polysaccharide (ASP) upregulates MDK expression in adipose-derived stem cells; MDK knockdown abolishes ASP-induced elevation of chondrogenic differentiation markers and PI3K/AKT pathway activity, placing MDK upstream of PI3K/AKT in ASP-induced chondrogenesis. Transcriptome sequencing, siRNA knockdown, western blotting for PI3K/AKT, chondrogenic differentiation assays (Alcian blue, qRT-PCR) Biomedicine & pharmacotherapy Medium 39191028
2024 MDK inhibition (iMDK) suppresses the proliferation, migration, and EMT of glioblastoma cells induced by hypoxia; in vivo, hypoxia promotes MDK expression and MDK knockdown reduces these hypoxia-driven malignant behaviors. MDK knockdown, iMDK inhibitor, CCK8, EdU proliferation assay, wound healing, transwell assay, western blotting for EMT markers Biomedicines Medium 38255198
2025 EGFRvIII-positive GBM secretes high levels of MDK via the ERK-c-Fos signaling pathway; secreted MDK drives M2 macrophage polarization and CXCL1 secretion via LRP1 receptor on macrophages; blocking MDK signaling in an intracranial glioma model inhibits M2 macrophage polarization and tumor progression. Western blotting, functional macrophage polarization assays, intracranial glioma mouse model, MDK pathway blockade Cell death & disease Medium 40527884
2025 MDK interacts directly with c-Myc (demonstrated by microthermometry and co-immunoprecipitation); MDK interaction with c-Myc influences c-Myc ubiquitination and stabilizes it, activating Wnt/β-catenin signaling and EMT, contributing to temozolomide resistance; small molecule ACT001 disrupts the MDK/c-Myc complex, promotes c-Myc degradation, and sensitizes resistant glioma cells to TMZ. Microthermometry, co-immunoprecipitation, proteomics, western blotting, xenograft and in situ glioma models Clinical and translational medicine High 40468625
2025 Wnt/β-catenin signaling drives MDK upregulation in hepatoblastoma cells; MDK modifies macrophage phenotype toward immunosuppression; MDK inhibition partially reverses macrophage phenotype change, establishing MDK as a Wnt-responsive immunomodulator. Western blotting, RNA-seq of hepatoblastoma and macrophage cell lines, MDK inhibition experiments, single-cell and spatial transcriptomics Journal of hepatology Medium 39900120
2025 MDK binds the SDC4 receptor on beta cells to downregulate Ras signaling, impairing insulin production and secretion, establishing a mechanism for pancreatic cancer-associated new-onset diabetes. Single-cell RNA sequencing, receptor-ligand interaction analysis, functional beta cell assays (insulin production/secretion) Advanced science Low 40709672
2025 Remote neuromuscular electrical stimulation (rNMES) upregulates MDK expression in skeletal muscle via the AMPK-ERK axis; circulating MDK reaches wounds and promotes macrophage efferocytosis in a LRP1-dependent manner, accelerating wound healing. GEO database analysis, in vivo rNMES model, MDK-LRP1 functional assays, macrophage efferocytosis assay Journal of biomedical research Medium 40441854
2025 MDK facilitates M2-like macrophage polarization via interaction with LRP1 receptor on macrophages in MASH-HCC; silencing LRP1 in macrophages abolishes MDK-driven M2 polarization and increases cytotoxic cytokine secretion; LRP1-positive macrophages contribute to T cell exhaustion via CXCL16-CXCR6 axis; combining Resmetirom with iMDK synergistically suppresses tumorigenesis in vivo. scRNA-seq, LRP1 silencing in macrophages, cytokine measurement, in vivo combination therapy model Hepatology Medium 41525571
2025 MDK promotes M2 macrophage polarization and mast cell activation via interaction with the nucleolin (NCL) receptor; MDK knockdown in pancreatic stellate cells reduces PSC activation/fibrosis and suppresses mast cell proliferation and degranulation in chronic pancreatitis; these effects are reversed by recombinant MDK and blocked by NCL neutralization. scRNA-seq analysis, MDK knockdown in PSCs, co-culture experiments, recombinant MDK rescue, NCL neutralization, in vivo MDK/NCL knockdown, flow cytometry Experimental cell research Medium 42031197
2025 Recombinant MDK protein dose-dependently inhibits osteogenic differentiation via the PI3K/AKT signaling pathway and increases expression of inflammatory cytokines (IL-6, TNF-α, IL-1β) via NF-κB signaling; iMDK inhibitor mitigates estrogen deficiency-induced bone loss in ovariectomized mice. Recombinant MDK protein treatment, transcriptome analysis, western blotting for PI3K/AKT and NF-κB, in vitro osteogenic differentiation assays, ovariectomy mouse model Genes & diseases Medium 41674663
2025 MDK activates the PI3K/AKT pathway in colorectal cancer cells, leading to upregulated AP2A1 expression and promotion of EMT; PI3K inhibitor LY294002 reduces AP2A1 levels and reverses MDK-induced malignant behaviors. MDK overexpression/knockdown, western blotting for PI3K/AKT/AP2A1/EMT markers, PI3K inhibitor (LY294002), invasion/migration/proliferation assays, xenograft and metastasis mouse models Cancers Medium 42073635
2025 MDK treadmill training upregulates MDK expression and promotes neuronal MDK localization (confirmed by NeuN co-staining); MDK signals through LRP1 receptor to activate PI3K/Akt and upregulate BDNF in neurons; LRP1 siRNA blocks exercise-induced Akt activation, BDNF upregulation, and motor recovery after spinal cord injury. LRP1 siRNA knockdown in vivo, immunofluorescence co-staining, western blotting for PI3K/Akt/BDNF, in vitro MDK treatment with LRP1 inhibitor (RAP), behavioral analysis (BBB score, gait analysis) Neurochemical research Medium 42257999
2025 MDK attenuates Aβ40 and Aβ42 fibril formation in vitro as demonstrated by Thioflavin T fluorescence assay, circular dichroism, negative stain electron microscopy, and NMR; Mdk knockout in 5xFAD mice increases amyloid plaque formation and microglial activation, establishing MDK as a protective factor counteracting amyloid pathology. Thioflavin T fluorescence assay, circular dichroism, negative stain electron microscopy, NMR, Mdk/5xFAD double-knockout mouse model, mass spectrometry-based proteomics bioRxiv (preprint)preprint High bio_10.1101_2025.03.20.644383
2025 MDK disrupts melanoma disseminated cancer cell dormancy through an autocrine signal that suppresses the dormancy inducer NR2F1 and alters the p-p38/p-ERK ratio via ALK signaling; dual targeting of MDK (genetic blockade) and NR2F1 (activation) markedly limits metastatic outgrowth and extends survival in mouse models. MDK genetic blockade, NR2F1 agonist treatment, p-p38/p-ERK ratio analysis, dormancy assays in lymph nodes and visceral tissues, in vivo mouse survival experiments bioRxiv (preprint)preprint Medium bio_10.1101_2025.05.27.656365

Source papers

Stage 0 corpus · 55 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 Midkine (MDK) growth factor: a key player in cancer progression and a promising therapeutic target. Oncogene 258 31801970
2018 Exosomal miR-9 inhibits angiogenesis by targeting MDK and regulating PDK/AKT pathway in nasopharyngeal carcinoma. Journal of experimental & clinical cancer research : CR 189 30001734
2021 Single-cell RNA-sequencing atlas reveals an MDK-dependent immunosuppressive environment in ErbB pathway-mutated gallbladder cancer. Journal of hepatology 159 34171432
1998 Disruption of the midkine gene (Mdk) resulted in altered expression of a calcium binding protein in the hippocampus of infant mice and their abnormal behaviour. Genes to cells : devoted to molecular & cellular mechanisms 125 10096022
2019 DNA damage repair alterations modulate M2 polarization of microglia to remodel the tumor microenvironment via the p53-mediated MDK expression in glioma. EBioMedicine 86 30773478
2023 Integrating single-cell RNA-seq and spatial transcriptomics reveals MDK-NCL dependent immunosuppressive environment in endometrial carcinoma. Frontiers in immunology 75 37081869
2014 Transcriptional factor specificity protein 1 (SP1) promotes the proliferation of glioma cells by up-regulating midkine (MDK). Molecular biology of the cell 62 25428991
2013 Inhibition of the growth factor MDK/midkine by a novel small molecule compound to treat non-small cell lung cancer. PloS one 62 23976985
1993 Midkine gene (MDK), a gene for prenatal differentiation and neuroregulation, maps to band 11p11.2 by fluorescence in situ hybridization. Genomics 46 8406506
2024 Spatial and single-cell colocalisation analysis reveals MDK-mediated immunosuppressive environment with regulatory T cells in colorectal carcinogenesis. EBioMedicine 44 38614865
2006 Regulation of MDK expression in human cancer cells modulates sensitivities to various anticancer drugs: MDK overexpression confers to a multi-drug resistance. Cancer letters 33 16644108
2020 The Long Noncoding RNA ZFAS1 Potentiates the Development of Hepatocellular Carcinoma via the microRNA-624/MDK/ERK/JNK/P38 Signaling Pathway. OncoTargets and therapy 29 32547074
2023 miR-1275 targets MDK/AKT signaling to inhibit breast cancer chemoresistance by lessening the properties of cancer stem cells. International journal of biological sciences 27 36594100
2009 Disruption of the midkine gene (Mdk) delays degeneration and regeneration in injured peripheral nerve. Journal of neuroscience research 27 19437545
2020 MiR-326 targets MDK to regulate the progression of cardiac hypertrophy through blocking JAK/STAT and MAPK signaling pathways. European journal of pharmacology 26 31972179
2022 Targeting MDK Abrogates IFN-γ-Elicited Metastasis inCancers of Various Origins. Frontiers in oncology 25 35747815
2024 Midkine (MDK) in Hepatocellular Carcinoma: More than a Biomarker. Cells 24 38247828
2023 Secreted proteins MDK, WFDC2, and CXCL14 as candidate biomarkers for early diagnosis of lung adenocarcinoma. BMC cancer 23 36721112
2024 MDK promotes M2 macrophage polarization to remodel the tumour microenvironment in clear cell renal cell carcinoma. Scientific reports 21 39107475
2014 Improvement of radiotherapy-induced lacrimal gland injury by induced pluripotent stem cell-derived conditioned medium via MDK and inhibition of the p38/JNK pathway. International journal of molecular sciences 20 25314301
2022 MDK induces temozolomide resistance in glioblastoma by promoting cancer stem-like properties. American journal of cancer research 18 36381313
2025 Multiomic analysis uncovers a continuous spectrum of differentiation and Wnt-MDK-driven immune evasion in hepatoblastoma. Journal of hepatology 14 39900120
2022 Combined Usage of MDK Inhibitor Augments Interferon-γ Anti-Tumor Activity in the SKOV3 Human Ovarian Cancer Cell Line. Biomedicines 14 36672515
2020 MicroRNA-188 inhibits biological activity of lung cancer stem cells through targeting MDK and mediating the Hippo pathway. Experimental physiology 14 32592428
2025 EGFRvIII-positive glioblastoma contributes to immune escape and malignant progression via the c-Fos-MDK-LRP1 axis. Cell death & disease 12 40527884
2025 Integrative single-cell and spatial transcriptomics analysis reveals MDK-NCL pathway's role in shaping the immunosuppressive environment of lung adenocarcinoma. Frontiers in immunology 11 40396179
2024 Identification of MDK as a Hypoxia- and Epithelial-Mesenchymal Transition-Related Gene Biomarker of Glioblastoma Based on a Novel Risk Model and In Vitro Experiments. Biomedicines 11 38255198
2025 Midkine (MDK) in cancer and drug resistance: from inflammation to therapy. Discover oncology 10 40500394
2024 GPC2 promotes prostate cancer progression via MDK-mediated activation of PI3K/AKT signaling pathway. Functional & integrative genomics 8 39014225
1995 Chromosomal assignment of the heparin-binding cytokine genes MDK and PTN in mouse and man. Cytogenetics and cell genetics 7 7835084
2024 Autocrine and paracrine effects of MDK promote lymph node metastasis of cervical squamous cell carcinoma. iScience 6 39040052
2025 Ugonin P mitigates osteolytic bone metastasis by suppressing MDK via upregulating miR-223-3p expression. International journal of biological sciences 4 40520001
2025 Unraveling the Role of MDK-SDC4 Interaction in Pancreatic Cancer-Associated New-Onset Diabetes by Single-Cell Transcriptomic Analysis. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 4 40709672
2025 Metabolic reprogramming of arachidonic acid in clear cell renal carcinoma promotes an immunosuppressive microenvironment by activating MDK signaling pathway. Clinical and experimental medicine 4 40802073
2024 Targeting the CDK7-MDK axis to suppresses irinotecan resistance in colorectal cancer. Life sciences 4 39004275
2024 Over-expression of KRT17 and MDK genes at mRNA levels in urine-exfoliated cells is associated with early non-invasive diagnosis of non-muscle-invasive bladder cancer. Clinical biochemistry 4 39069115
2024 Angelica sinensis polysaccharide facilitates chondrogenic differentiation of adipose-derived stem cells via MDK-PI3K/AKT signaling cascade. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 4 39191028
2026 Midkine (MDK) as a central regulator of the tumor microenvironment: From developmental cytokine to therapeutic target. Cancer letters 3 41570933
2025 RGS16-driven cancer-associated fibroblasts promote esophageal squamous cell carcinoma progression via the MDK-SDC1 axis-mediated intercellular crosstalk. Biology direct 3 41094576
2026 Remote neuromuscular electrical stimulation upregulates MDK to enhance macrophage efferocytosis via LRP1 in wound healing. Journal of biomedical research 2 40441854
2026 Repurposing Resmetirom suppresses MASH-associated hepatocellular carcinoma, with mechanistic implications of MDK/LRP1-mediated metabolic reprogramming and immunosuppression. Hepatology (Baltimore, Md.) 1 41525571
2025 Targeting the MDK/c-Myc complex to overcome temozolomide resistance in glioma. Clinical and translational medicine 1 40468625
2025 Deciphering the Acetabular Labrum's Cellular Atlas: MDK Inhibition as a Novel Therapeutic Method for Developmental Dysplasia of the Hip. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 1 40605494
2024 BAG2, MAD2L1, and MDK are cancer-driver genes and candidate targets for novel therapies in malignant pleural mesothelioma. Cancer gene therapy 1 39300217
2024 The significance of MDK growth factor in the antler development of sika deer (Cervus nippon): An in-depth analysis. Gene expression patterns : GEP 1 39733918
1976 [Adenylat-kinase-Systeme, ein Beitrag zum manisch-depressiven Kranksein (MDK)]. Arzneimittel-Forschung 1 183795
2026 Pharmacological Targeting of Midkine (MDK) Reveals Stiffness-Dependent Control of Hepatocellular Carcinoma Invasiveness. International journal of molecular sciences 0 41751909
2026 BGN/MDK Axis in the Melanoma Tumor Microenvironment Strengthens Tumor Malignancy by Modulating Cancer Cells and Cancer-Associated Fibroblasts Crosstalk. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 0 41833003
2026 MDK promotes the mast cell activation and pancreatic fibrosis in mice with chronic pancreatitis via MDK-NCL signaling pathway. Experimental cell research 0 42031197
2026 MDK Activates the PI3K/AKT Axis to Induce AP2A1 Expression and Epithelial-Mesenchymal Transition in Colorectal Cancer. Cancers 0 42073635
2026 Body weight-supported treadmill training enhances motor recovery and ameliorates neuron injury through the MDK/LRP-1 signaling pathway in T10 incomplete spinal cord-injured rats. Neurochemical research 0 42257999
2025 LBX2-AS1 in acceleration of glycolysis and cancer angiogenesis via miR-491-5p/MDK signaling axis in colorectal cancer: an experimental study. Annals of medicine 0 41388614
2025 Targeting MDK alleviates bone loss via dual regulation of osteogenic differentiation and inflammatory cytokine expression. Genes & diseases 0 41674663
2024 Correction: Inhibition of the Growth Factor MDK/Midkine by a Novel Small Molecule Compound to Treat Non-Small Cell Lung Cancer. PloS one 0 38980851
2023 Heterologous expression of the cryptic mdk gene cluster and structural revision of maduralactomycin A. RSC advances 0 38019997

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