Two intracellular traffics of a growth factor

本研究探讨了生长因子中期因子(MK)的两种作用途径，即降解和核靶向。MK与癌症的发展、神经元的存活和分化以及炎症有关。低密度脂蛋白受体相关蛋白(LRP)是MK的受体之一。我们先前发现，MK通过LRP内吞，并被进一步移位到细胞核，这对MK的抗凋亡活性是重要的。在目前的研究中，我们发现MK在内吞作用后进入溶酶体和蛋白酶体的降解途径。溶酶体和蛋白酶体的抑制剂抑制内吞作用后MK的降解。MK的核内降解只被蛋白酶体抑制剂所抑制，即不被溶酶体抑制剂所抑制。MK的N-末端的一半通过蛋白酶体降解的速度比C-末端的一半快。C末端的一半负责MK的核靶向。我们的发现支持这一观点，即内吞的MK同时进入两条降解途径，至少有一部分内吞的MK从内体转移到细胞质，并进一步转移到细胞核。我们报告了其他发现，MK参与间质性肾炎、顺铂诱导的肾炎和糖尿病肾病的发病机制。

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.