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MDK


Official Full Name
midkine
Organism
Homo sapiens
Gene ID
4192
Background
This gene encodes a member of a small family of secreted growth factors that binds heparin and responds to retinoic acid. The encoded protein promotes cell growth, migration, and angiogenesis, in particular during tumorigenesis. This gene has been targeted as a therapeutic for a variety of different disorders. Alternatively spliced transcript variants encoding multiple isoforms have been observed. [provided by RefSeq, Jul 2012]
Synonyms
MK; ARAP; NEGF2
Protein Sequence
MQHRGFLLLTLLALLALTSAVAKKKDKVKKGGPGSECAEWAWGPCTPSSKDCGVGFREGTCGAQTQRIRCRVPCNWKKEFGADCKYKFENWGACDGGTGTKVRQGTLKKARYNAQCQETIRVTKPCTPKTKAKAKAKKGKGKD
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Cat.No. Product Name Price
SHH182567 shRNA set against Mouse Mdk(NM_010784.4) Inquiry
SHH182549 shRNA set against Rat Mdk(NM_030859.2) Inquiry
SHH182603 shRNA set against Mouse Mdk(NM_001012336.1) Inquiry
SHH182621 shRNA set against Mouse Mdk(NM_001012335.1) Inquiry
SHH339651 shRNA set against Human MDK (NM_002391.4) Inquiry
SHH339655 shRNA set against Mouse MDK (NM_010784.4) Inquiry
SHH339659 shRNA set against Rat MDK (NM_030859.2) Inquiry
SHW002742 shRNA set against Chicken MDK (NM_001113289) Inquiry
SHW015123 shRNA set against Danio rerio MDKB (NM_131716) Inquiry
Cat.No. Product Name Price
CDCB180435 Rabbit MDK ORF clone (NM_001082167.1) Inquiry
CDCR249629 Mouse Mdk ORF Clone(NM_010784.4) Inquiry
CDFR012391 Rat Mdk cDNA Clone(NM_030859.2) Inquiry
MiUTR1M-07022 MDK miRNA 3'UTR clone Inquiry
MiUTR1M-07023 MDK miRNA 3'UTR clone Inquiry
MiUTR1M-07024 MDK miRNA 3'UTR clone Inquiry
MiUTR1R-03744 MDK miRNA 3'UTR clone Inquiry
MiUTR3H-01522 MDK miRNA 3'UTR clone Inquiry
MiUTR3H-01523 MDK miRNA 3'UTR clone Inquiry
MiUTR3H-01524 MDK miRNA 3'UTR clone Inquiry
CDCB164217 Chicken MDK ORF Clone (NM_001113289) Inquiry
CDCB176598 Danio rerio MDKB ORF Clone (NM_131716) Inquiry
CDCB196035 Rabbit LOC103351245 ORF clone (XM_008269615.1) Inquiry
CDCL131521 Human Mdk ORF clone (NM_001012335.1) Inquiry
CDCR379428 Rat Mdk ORF Clone(NM_030859.2) Inquiry
CDCS406487 Human MDK ORF Clone (BC011704) Inquiry

Detailed Information

The MDK (Midkine) gene is located on chromosome 11q11.2 and encodes a heparin-binding growth factor that, together with pleiotrophin (PTN), constitutes the midkine family. The protein structure includes two highly positively charged domains (N-cluster and C-cluster) and highly conserved cysteine residues. MDK binds to multiple receptors via heparin chains:

  • Transmembrane receptors: LRP1 (low-density lipoprotein receptor-related protein 1), ALK (anaplastic lymphoma kinase), and PTPRZ (receptor-type tyrosine-protein phosphatase zeta) mediate downstream signaling.
  • Cell surface proteoglycans: Chondroitin sulfate proteoglycan (CSPG5) and heparan sulfate proteoglycans (SDC3, GPC2) enhance ligand–receptor affinity.

MDK expression exhibits spatiotemporal specificity. It is highly expressed during embryonic development, especially in the kidney and nervous system, but significantly downregulated in adulthood. It is reactivated in response to tissue injury or pathological conditions. Single-cell sequencing data reveal that MDK expression in infiltrative basal cell carcinoma (iBCC) is 4.7 times higher than in nodular subtypes and is positively correlated with tumor invasion depth (r = 0.83, P < 0.001).

Biological Functions and Disease Mechanisms

MDK regulates development, repair, and malignant transformation through a complex receptor network:

Neurodevelopment and Injury Repair: MDK binds to PTPRZ1 to promote neuronal migration and activates the PI3K/AKT pathway via LRP1 to support neuronal survival. In brain injury models, MDK overexpression increases neural progenitor proliferation by 2.1-fold and improves functional recovery by 40%. However, in Alzheimer's disease, aberrant MDK deposition accelerates Aβ oligomerization and neurotoxic plaque formation.

Tumor Microenvironment Remodeling: The oncogenic roles of MDK involve three key pathways:

  • Angiogenesis: Induces VEGF expression and promotes neovascularization through binding to endothelial integrin α6β1 and activating the FAK/ERK signaling pathway (microvessel density increases 1.9-fold).
  • Immune Evasion: Single-cell analysis of iBCC reveals that tumor-secreted MDK recruits SPP1+ macrophages, which activate immunosuppressive plasma cells via BAFF signaling and secrete CXCL9/10 to inhibit CD8+ T cell cytotoxicity.
  • Metastatic Initiation: MDK activates the ALK/PI3K pathway, inducing epithelial-mesenchymal transition (EMT) and upregulating SNAIL and MMP9. In lung cancer tissues, MDK levels positively correlate with clinical stage (3.4-fold higher in stage III than in stage I).

Tissue Regeneration vs. Fibrosis: After cardiac injury, MDK promotes repair via macrophage-dependent angiogenesis (infarct area reduced by 35%). However, in renal fibrosis, sustained MDK expression activates fibroblasts through NOTCH2 signaling, increasing collagen deposition by 2.3-fold.

Figure 1. MDK receptor candidates and signaling pathways. (Neumaier EE, et al., 2023)

Clinical Applications and Translational Potential

Early Diagnosis of Lung Cancer: MDK shows a high diagnostic value in lung cancer with an AUC of 0.878, outperforming traditional markers such as CEA. When combined with AI-assisted immunohistochemical analysis, the early detection rate (stage I) increases to 89%.

Targeted Cancer Therapy:

  • Antibody Drugs: The humanized anti-MDK monoclonal antibody (iMDK) reduces tumor volume by 68% in iBCC models by blocking MDK–LRP1 interaction and restoring CD8+ T cell infiltration.
  • Small-Molecule Inhibitors: TPX-013, a dual ALK/MDK inhibitor, overcomes crizotinib resistance in ALK-positive lung cancer.

Neural Repair and Regeneration: MDK siRNA encapsulated in chitosan nanoparticles (80 nm diameter, +35 mV zeta potential) effectively penetrates the blood–spinal cord barrier in spinal cord injury models, reducing MDK expression by 73% and glial scar formation by 50%.

Challenges and Future Directions

The multifunctionality of MDK presents a therapeutic paradox: complete inhibition may impair tissue repair, while partial blockade may be insufficient for tumor control. Proposed solutions include:

Microenvironment-responsive prodrugs, such as MDK inhibitors conjugated with MMP–9–cleavable linkers.

Personalized therapeutics based on receptor expression profiles, such as using antibodies for LRP1-high patients or small molecules for ALK-mutant tumors.

Advances in single-cell spatial transcriptomics will help elucidate the dynamic regulation of MDK in tumor heterogeneity, enabling more precise and adaptive intervention strategies.

References:

  1. Saikia M, Cheung N, Singh AK, et al. Role of Midkine in Cancer Drug Resistance: Regulators of Its Expression and Its Molecular Targeting. Int J Mol Sci. 2023 May 14;24(10):8739.
  2. Neumaier EE, Rothhammer V, et al. The role of midkine in health and disease. Front Immunol. 2023 Nov 30;14:1310094.
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