Two intracellular traffics of a growth factor

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This study addressed two traffics of the growth factor midkine (MK), namely degradation and nuclear targeting. MK is implicated in cancer development, neuronal survival and differentiation, and inflammation. LDL receptor-related protein (LRP) is one of the receptors for MK. We previously found that MK is endocytosed via LRP, and is further translocated to the nucleus, this being important for the anti-apoptotic activity of MK. In the present study, we found that MK goes into the lysosomal as well as proteasomal degradation pathways after endocytosis. Inhibitors for the lysosome and proteasome suppressed MK degradation after endocytosis. The intranuclear degradation of MK was only inhibited by a proteasomal inhibitor, i.e., not lysosomal inhibitors. The N-terminal half of MK is degraded via the proteasome faster than the C-terminal half. The C-terminal half was responsible for the nuclear targeting of MK. Our findings support the idea that endocytosed MK enters both the two degradation pathways, and at least a part of endocytosed MK is translocated to the cytoplasm from the endosome, and is further transferred to the nucleus. We report additional findings that MK is involved in the pathogenesis of interstitial nephritis, cisplatin-induced nephritis and diabetic nephropathy.