Disease relevance of Mdk

• Differential expression of pleiotrophin and midkine in advanced neuroblastomas [1].
• Nuclear localization of MK was shown in hemangioma cells by immunohistochemical staining [2].
• Immunohistochemistry revealed expression of MK in S-100 positive Schwann cells of dermal and plexiform neurofibromas, and in endothelial cells of tumor blood vessels, but not in normal blood vessels [3].
• The data support a possible central role for MK as a mediator of angiogenesis and neurofibroma growth in NF1 [3].
• Female infertility in mice deficient in midkine and pleiotrophin, which form a distinct family of growth factors [4].

High impact information on Mdk

• To find a new target to suppress neointima formation, we investigated the possible role of midkine (MK), a heparin-binding growth factor with neurotrophic and chemotactic activities, in neointima formation [5].
• Soluble MK as well as that bound to the substratum induced migration of macrophages in vitro [5].
• Leukocyte recruitment to the vascular walls after injury was markedly decreased in MK-deficient mice [5].
• MK expression increased during neointima formation caused by intraluminal balloon injury of the rat carotid artery [5].
• These findings establish the Mek/Erk pathway as the dominant pathway involved in conferring the cytoskeletal and junctional manifestations of the Ras-induced transformed phenotype [6].

Chemical compound and disease context of Mdk

• Midkine expression was induced in the glomerular mesangium of Mdk+/+ mice with diabetic nephropathy and in primary cultured mesangial cells exposed to high glucose [7].
• Using the Streptozotocin-induced model of diabetes, we report that mice deficient in the growth factor midkine (Mdk-/-) exhibited strikingly milder nephropathy than Mdk+/+ mice, even though both mice showed similar extents of hyperglycemia after Streptozotocin injection [7].
• A retinoic acid responsive gene MK found in the teratocarcinoma system is expressed in spatially and temporally controlled manner during mouse embryogenesis [8].
• Midkine (MK), a heparin-binding growth factor, is overexpressed in a wide range of human carcinomas and is believed to contribute to tumorigenesis and tumor progression [9].
• MK mRNA was found in retinoid acid-induced teratocarcinoma cells and during early development of the mouse embryo, but no biological activity for MK is yet known [10].

Biological context of Mdk

• Mdk maps to mouse Chromosome (Chr) 2, linked to the Hoxd gene cluster [11].
• We used affinity-purified antibodies against MK and HB-GAM to analyze their distribution during mouse embryonic development [12].
• Taken together these results indicate that MK and HB-GAM may play regulatory roles in differentiation and morphogenesis of the vertebrate embryo, particularly in epithelio-mesenchymal organs, and suggest molecular interactions with syndecan-1 [12].
• Neither MK nor HB-GAM stimulated mesenchymal cell proliferation or induced syndecan-1 expression [12].
• To investigate the potential role of MK in tumor growth, we expressed MK in human SW-13 cells and studied receptor binding, signal transduction, and activity of MK [13].

Anatomical context of Mdk

• RESULTS: Migration of neutrophils and macrophages to the liver 1-5 days after partial hepatectomy was suppressed in Mdk (-/-) mice [14].
• PTN also transforms NIH 3T3 cells, and MK is mitogenic to certain cell lines [1].
• The biological effects of MK and HB-GAM on limb and facial mesenchyme were studied in vitro by application of beads preloaded with the proteins [12].
• MK and HB-GAM were often localized on the surface of differentiating cells and in basement membranes of organs undergoing epithelial-mesenchymal interactions [12].
• The MK protein stimulates soft agar colony formation in vitro and tumor growth of SW-13 cells in athymic nude mice, as well as proliferation of human endothelial cells from brain microvasculature and umbilical vein (HUVEC) in the low ng/ml range [13].

Associations of Mdk with chemical compounds

• Both MK and HB-GAM bound syndecan-1 in solid-phase assays in a heparan sulfate-dependent manner [12].
• Midkine (MK) is a 13-kDa heparin-binding growth factor that is thought to mediate developmental processes, including vasculogenesis, cell migration, and proliferation in various organs [15].
• These results suggest that midkine binds to a polysulfated domain in the chondroitin sulfate chain with a region of dermatan sulfate structure [16].
• Midkine, a newly discovered regulator of the renin-angiotensin pathway in mouse aorta: significance of the pleiotrophin/midkine developmental gene family in angiotensin II signaling [17].
• Phenylethanolamine-N-methyltransferase, the enzyme catalyzing the conversion of norepinephrine into epinephrine, was not detected in either Mk -/- and WT (+/+) mouse aorta [18].

Physical interactions of Mdk

• PG-M/versican isolated from day 13 mouse embryos bound midkine with a Kd of 1.0 nM [16].
• Sequence determination of N-terminal 23 amino acid residues revealed that the MK-binding protein was nucleolin, a major nucleolar protein, which functions as a shuttle protein between the nucleus and cytoplasm and is located also on the cell surface [2].
• Midkine is a 13-kDa heparin-binding growth factor with 45% sequence identity to pleiotrophin [19].
• These results suggested that Arg78 in midkine plays an essential role in high affinity binding to PTPzeta by interacting with the chondroitin sulfate portion of this receptor [19].
• Prp8 was shown to bind to midkine (MK), a heparin-binding growth factor [20].

Regulatory relationships of Mdk

• TTF-1 regulates expression of MK in the lung [15].
• Midkine activated both PI3-kinase and MAP kinases, the latter activation was blocked by a PI3-kinase inhibitor [21].
• Recombinant mouse MK (10 ng/ml) induced the increased expression of macrophage inflammatory protein 2 (MIP-2) mRNA in TEpiCs [22].
• A newly identified gene MK is transiently expressed in early stages of retinoic acid-induced differentiation of embryonal carcinoma cells (Kadomatsu, K., M. Tomomura, and T. Muramatsu, 1988. Biochem. Biophys. Res. Commun. 151:1312-1318) [8].

Other interactions of Mdk

• The level of MK protein decreased considerably in the 16.5 dpc embryo, whereas HB-GAM staining persisted in many tissues [12].
• Furthermore, MK expression was not detected in lungs of TTF-1 null mice [15].
• In limb buds and facial processes, MK, HB-GAM, and syndecan-1 were localized to the apical epithelium and the adjacent proliferating mesenchyme [12].
• A heparin-binding growth factor, midkine, binds to a chondroitin sulfate proteoglycan, PG-M/versican [16].
• These findings supported the hypothesis that parts of the MK and HB-GAM are translocated to the nucleus after binding with nucleolin [2].

Analytical, diagnostic and therapeutic context of Mdk

• The weight of the liver 7 and 14 days after partial hepatectomy was significantly less in Mdk (-/-) mice than wild-type mice [14].
• Our in situ hybridization results revealed a widespread expression of MK transcripts that was not always consistent with the distribution of MK protein in developing tissues [12].
• Western blot analysis revealed the presence of MK in amniotic fluid and cerebrospinal fluid, in amounts of more than 1 microgram/ml, raising the possibility that MK delivered by these fluids participates in the regulation of organogenesis [23].
• This MK-binding protein was purified by affinity chromatography on an MK-agarose column followed by SDS polyacrylamide gel electrophoresis [2].
• MK cDNA probe reacts with two bands, a 4 kb one and a 3 kb one, upon Southern blot analysis of Hin dIII fragments of mouse genomic DNA: the midkine gene (Mdk) is on the 4 kb fragment [24].

References