Matrix metalloproteinase-7 triggers the matricrine action of insulin-like growth factor-II via proteinase activity on insulin-like growth factor binding protein 2 in the extracellular matrix
Matrix metalloproteinase-7 triggers the matricrine action of insulin-like growth factor-II via proteinase activity on insulin-like growth factor binding protein 2 in the extracellular matrix
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DOI：
10.1111/j.1349-7006.2007.00448.x
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发表时间：
2007-05-01
期刊：
影响因子：
5.7
通讯作者：
Ochiai, Atsushi
中科院分区：
文献类型：
--
作者：
Miyamoto, Shin'ichi;Nakamura, Michio;Ochiai, Atsushi
许多生长因子和细胞因子通过与糖胺聚糖结合而固定在细胞外基质(ECM)上，并以非活性形式储存在细胞微环境中。然而，ECM结合的生长因子或细胞因子激活的机制还没有很好的文献报道。我们发现，在血清缺乏的人结肠癌细胞系(HT29)中加入基质金属蛋白酶-7后，胰岛素样生长因子-1受体(IGF-1R)迅速被磷酸化，并且这种磷酸化被IGF-II中和抗体完全抑制。在该细胞系的ECM中，IGF-II和IGF结合蛋白(BP)-2共存，但经MMP-7或肝素酶III处理的ECM组分中IGFBP-2消失。另一方面，在IGF-1R过表达的细胞系中，IGF-1R被MMP7处理的HT29 ECM组分的上清所磷酸化，而不被肝素酶III处理的ECM组分的上清液磷酸化。我们还证明了基质金属蛋白酶-7在体外降解IGFBP-2的三个位置(肽键E-151-L-152，G(175)-L-176和K-181-L-182)，这是以前没有文献报道的。综上所述，这些结果表明，MMP-7通过降解细胞外基质中与硫酸乙酰肝素蛋白多糖结合的IGF-II/IGFBP-2复合体而产生生物活性的IGF-II，从而导致IGF-II诱导的信号转导。这一证据表明，一些ECM相关的生长因子通过肿瘤微环境中的一些蛋白酶增强了它们与受体结合的能力。这种作用机制(‘蛋白酶触发的苦参碱’)是理解ECM-肿瘤相互作用的一个有吸引力的模型。
Many growth factors and cytokines are immobilized on the extracellular matrix (ECM) by binding to glycosaminoglycans and are stored in an inactive form in the cellular microenvironment. However, the mechanisms of ECM-bound growth factor or cytokine activation have not been well documented. We showed that the insulin-like growth factor type-1 receptor (IGF-1R) was rapidly phosphorylated after the addition of matrix metalloproteinase (MMP)-7 to a serum-starved human colon cancer cell line (HT29) and that phosphorylation was completely inhibited by an IGF-II neutralizing antibody. In the ECM of this cell line, IGF-II and IGF binding protein (BP)-2 coexisted, but IGFBP-2 disappeared from the ECM fraction after treatment with MMP-7 or heparinase III. On the other hand, in a cell line in which IGF-1R was overexpressed, IGF-1R was phosphorylated by supernatant from the MMP-7-treated ECM fraction of HT29 but not by that from a heparinase-III-treated ECM fraction. We also demonstrated that MMP-7 degrades IGFBP-2 in vitro at three cleavage sites (peptide bonds E-151-L-152, G(175)-L-176 and K-181-L-182), which have not been documented previously. Taken together, these results demonstrate that MMP-7 generates bioactive IGF-II by degrading the IGF-II/IGFBP-2 complex binding to heparan sulfate proteoglycan in the ECM, resulting in IGF-II-induced signal transduction. This evidence indicates that some ECM-associated growth factors enhance their ability to bind to their receptors by some proteases in the tumor microenvironment. This mechanism of action ('protease-triggered matricrine') represents an attractive model for understanding ECM-tumor interactions.