Encoded by the MDK gene, Midkine is a basic heparin-binding growth factor. Also known as neurite growth-promoting factor 2, or NEGF2, Midkine is classified as a protein and is found in humans. Associated with cell migration and proliferation, Midkine is believed to play a significant role in the replication of cells.
In particular, Midkine has been seen in higher levels when cancers are present. Relevant during mid-gestation, it is believed that retinoic acid-responsive gene, which is important in terms of cell development.
Known to bind to various receptors, studies have shown that Midkine does bind to Receptor Protein Tyrosine Phosphatase (RPTP), syndecan-3, anaplastic lymphoma kinase (ALK) and other proteoglycans, such as Neuroglycan C. In addition to this, some studies have shown that Midkine also binds to low-density lipoprotein receptor-related protein (LRP). It is believed that by binding to various receptors, Midkine helps to trigger signaling pathways associated with neuroinflammation. Whilst studies to establish further information about Midkine’s mechanism of action are underway, it has been suggested that the protein triggers these signaling pathways in order to modulate neuroinflammation.
Comprised of two domains, Midkine has a more N-terminally located N-domain and a more C-terminally located C-domain. Both of these domains are believed to be composed of three antiparallel β-sheets, and both the N-terminal and C-terminal sides have short tails, with a hinge connecting both domains. Created with 121 amino acids, Midkine has a molecular mass of 13 kDa after cleaving off the signal sequence and an isoform with two extended amino acids at the N-terminal has been noted in Midkine preparations from varying species.
As a heparin-binding growth factor, Midkine plays a significant role in the regulation of numerous pathological processes and cellular activities. Routinely, Midkine is involved in the reproduction, development, and restoration of damaged cells, and is thought to have a role in the cause of malignant and inflammatory diseases.
However, by binding to cell-surface nucleolin as a low-affinity receptor, it is also thought that Midkine could act as an inhibitor to HIV infection. With studies suggesting that Midkine does inhibit HIV infection as a result of binding with cell-surface nucleolin, the functions of Midkine can have varying effects across different conditions and diseases.
It has been suggested that Midkine, or MK, could play a role in epithelial-mesenchymal interactions, although further studies are required in order to verify this finding. Studies have also shown the Midkine may promote tetraspanin-integrin interaction and subsequently induces the FAK-Stat1alpha pathway. Established following studies of the impact of Midkine on head and neck squamous cell carcinoma, it is also suggested that it is this interaction which links Midkine to the invasiveness and/or migration of head and neck squamous cell carcinoma. Furthermore, alternative studies have also suggested that the interactions associated with Midkine could be associated with more aggressive types of tumors.
Although researchers are learning more about Midkine and its functions, further studies are required in order to verify the data which has been obtained thus far.