Ariga Miyako, Nedachi Taku, Katagiri Hideki, Kanzaki Makoto
21st Century COE program Comprehensive Research and Education Center for Planning of Drug Development and Clinical Evaluation, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
J Biol Chem. 2008 Apr 11;283(15):10208-20. doi: 10.1074/jbc.M710604200. Epub 2008 Feb 7.
Sortilin has been implicated in the formation of insulin-responsive GLUT4 storage vesicles in adipocytes by regulating sorting events between the trans-Golgi-network and endosomes. We herein show that sortilin serves as a potent myogenic differentiation stimulator for C2C12 myocytes by cooperatively functioning with p75NTR, which subsequently further contributes to development of the insulin-responsive glucose transport system in C2C12 myotubes. Sortilin expression was up-regulated upon C2C12 differentiation, and overexpression of sortilin in C2C12 cells significantly stimulated myogenic differentiation, a response that was completely abolished by either anti-p75NTR- or anti-nerve growth factor (NGF)-neutralizing antibodies. Importantly, small interference RNA-mediated suppression of endogenous sortilin significantly inhibited C2C12 differentiation, indicating the physiological significance of sortilin expression in the process of myogenesis. Although sortilin overexpression in C2C12 myotubes improved insulin-induced 2-deoxyglucose uptake, as previously reported, this effect apparently resulted from a decrease in the cellular content of GLUT1 and an increase in GLUT4 via differentiation-dependent alterations at both the gene transcriptional and the post-translational level. In addition, cellular contents of Ubc9 and SUMO-modified proteins appeared to be increased by sortilin overexpression. Taken together, these data demonstrate that sortilin is involved not only in development of the insulin-responsive glucose transport system in myocytes, but is also directly involved in muscle differentiation via modulation of proNGF-p75NTR.
Sortilin通过调节反式高尔基体网络和内体之间的分选事件，参与脂肪细胞中胰岛素反应性GLUT4储存囊泡的形成。我们在此表明，Sortilin通过与p75NTR协同作用，作为C2C12肌细胞的有效成肌分化刺激因子，随后进一步促进C2C12肌管中胰岛素反应性葡萄糖转运系统的发育。在C2C12分化过程中，Sortilin表达上调，并且在C2C12细胞中过表达Sortilin显著刺激成肌分化，这种反应被抗p75NTR或抗神经生长因子（NGF）中和抗体完全消除。重要的是，小干扰RNA介导的内源性Sortilin抑制显著抑制C2C12分化，表明Sortilin表达在肌生成过程中的生理意义。尽管如先前报道，在C2C12肌管中过表达Sortilin可改善胰岛素诱导的2-脱氧葡萄糖摄取，但这种作用显然是由于GLUT1细胞含量的减少和GLUT4在基因转录和翻译后水平上依赖分化的改变而增加所致。此外，Sortilin过表达似乎增加了Ubc9和SUMO修饰蛋白的细胞含量。综上所述，这些数据表明，Sortilin不仅参与肌细胞中胰岛素反应性葡萄糖转运系统的发育，而且还通过调节proNGF-p75NTR直接参与肌肉分化。
