Gehm B D, Rosner M R
Ben May Institute, University of Chicago, Illinois 60637.
Endocrinology. 1991 Mar;128(3):1603-10. doi: 10.1210/endo-128-3-1603.
The mechanisms by which growth factors are degraded and the role this process plays in the regulation of cell growth are not well understood. Insulin degradation is believed to be mediated by a specific metalloprotease, insulin-degrading enzyme (IDE). We have previously shown that IDE can also degrade transforming growth factor-alpha (TGF alpha), but not epidermal growth factor (EGF), in vitro. This selectivity was surprising, since TGF alpha and EGF are structurally similar and bind to the same receptor with comparable affinities. Using a spectrum of protease inhibitors, we have now analyzed the degradation of TGF alpha, EGF, and insulin by human hepatoma HepG2 cells. The results suggest that bacitracin-sensitive metalloproteases are involved in the degradation of TGF alpha and EGF as well as insulin, and that the degradation of TGF alpha, but not EGF, is mediated in part by IDE. Inhibiting the activity of these metalloproteases decreased growth factor depletion, suggesting that these enzymes play an important role in the control of extracellular growth factor levels. The existence of separate degradative pathways for EGF and TGF alpha may explain how the two factors exert differential effects in some systems, and degradation of TGF alpha by IDE would provide a possible mechanism for interaction between the insulin and TGF alpha/EGF signalling systems.
生长因子被降解的机制以及该过程在细胞生长调节中所起的作用尚未完全明确。胰岛素的降解被认为是由一种特定的金属蛋白酶——胰岛素降解酶（IDE）介导的。我们之前已经表明，IDE在体外还能降解转化生长因子-α（TGFα），但不能降解表皮生长因子（EGF）。这种选择性令人惊讶，因为TGFα和EGF在结构上相似，且以相当的亲和力结合相同的受体。我们现在使用一系列蛋白酶抑制剂，分析了人肝癌HepG2细胞对TGFα、EGF和胰岛素的降解情况。结果表明，杆菌肽敏感的金属蛋白酶参与了TGFα、EGF以及胰岛素的降解，并且TGFα的降解部分是由IDE介导的，而EGF的降解并非如此。抑制这些金属蛋白酶的活性会减少生长因子的消耗，这表明这些酶在控制细胞外生长因子水平方面发挥着重要作用。EGF和TGFα存在不同的降解途径，这或许可以解释这两种因子在某些系统中如何发挥不同的作用。此外，IDE对TGFα的降解可能为胰岛素与TGFα/EGF信号系统之间的相互作用提供一种可能的机制。
