Critical role of transient activity of MT1-MMP for ECM degradation in invadopodia.
Critical role of transient activity of MT1-MMP for ECM degradation in invadopodia.
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DOI：
10.1371/journal.pcbi.1003086
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发表时间：
2013
影响因子：
4.3
通讯作者：
Ichikawa K
中科院分区：
文献类型：
--
作者：
Watanabe A;Hoshino D;Koshikawa N;Seiki M;Suzuki T;Ichikawa K
细胞外基质（ECM）的局部降解是癌细胞侵袭的第一步。MT1-MMP是侵袭性癌细胞使用的一种有效的膜蛋白酶。在我们之前的研究中，我们报道了MT1-MMP优先位于称为invadopodia的膜突起，在那里MT1-MMP进行快速周转。我们的计算机模拟和实验表明，这种快速的转换对于入侵虫体内ECM的降解是必不可少的(Hoshino， D.等，（2012）PLoS Comp. Biol。科学通报，8:e1002479)。本文报道了MT1-MMP降解ECM活性的表征和分析，旨在阐明其在ECM降解中重复插入的可能原因。首先，在我们的计算模型中，我们发现MT1-MMP的活性有一个非常窄的瞬态峰值，然后是稳态活性。这种短暂的活性是由于TIMP-2的抑制，在较高的TIMP-2浓度下，MT1-MMP的稳态活性急剧下降。其次，我们评估了窄瞬态活性在ECM降解中的作用。在计算机模拟中，当瞬态活动被强制抑制时，ECM退化被严重抑制，表明该瞬态峰值在ECM退化中起重要作用。第三，我们比较了在入侵植物ECM降解过程中MT1-MMP的连续和脉动转换。脉冲插入与连续插入在ECM降解中的结果基本一致，两种模型的ECM降解效果在很大程度上取决于MT1-MMP的瞬时活性。然而，出乎意料的是，即使插入MT1-MMP的时间平均量相同，低频/高浓度插入MT1-MMP比高频/低浓度脉冲插入更有效地降解ECM。本文对MT1-MMP对ECM降解的分析和表征，以及我们之前的报告表明，MT1-MMP在入侵时具有动态性质，以及其瞬时峰值在ECM降解中的重要性。转移是癌症患者死亡的主要原因。如果转移被阻断，生存率将大大提高。癌细胞被ECM（细胞外基质）包围，这阻碍了它们的自由运动。MT1-MMP是一种有效的膜蛋白酶，可降解ECM，这是癌细胞侵袭的第一步。因此，控制MT1-MMP活性是预防转移的关键。通过计算机模拟，我们发现MT1-MMP在ECM降解活性中存在一个急剧的瞬态峰值，计算消除该峰值大大延长了ECM降解时间。MT1-MMP在细胞内运输到癌细胞膜表面，其插入被认为是以脉动的方式发生的。因此，我们想知道低频/高浓度和高频/低浓度插入MT1-MMP对ecm的降解效果是否相同。出乎意料的是，即使MT1-MMP插入的时间平均量相同，低频/高浓度方案也会导致更快的ECM降解。因此，降低MT1-MMP的瞬时活性和囊泡含量是重要的治疗靶点。
Focal degradation of extracellular matrix (ECM) is the first step in the invasion of cancer cells. MT1-MMP is a potent membrane proteinase employed by aggressive cancer cells. In our previous study, we reported that MT1-MMP was preferentially located at membrane protrusions called invadopodia, where MT1-MMP underwent quick turnover. Our computer simulation and experiments showed that this quick turnover was essential for the degradation of ECM at invadopodia (Hoshino, D., et al., (2012) PLoS Comp. Biol., 8: e1002479). Here we report on characterization and analysis of the ECM-degrading activity of MT1-MMP, aiming at elucidating a possible reason for its repetitive insertion in the ECM degradation. First, in our computational model, we found a very narrow transient peak in the activity of MT1-MMP followed by steady state activity. This transient activity was due to the inhibition by TIMP-2, and the steady state activity of MT1-MMP decreased dramatically at higher TIMP-2 concentrations. Second, we evaluated the role of the narrow transient activity in the ECM degradation. When the transient activity was forcibly suppressed in computer simulations, the ECM degradation was heavily suppressed, indicating the essential role of this transient peak in the ECM degradation. Third, we compared continuous and pulsatile turnover of MT1-MMP in the ECM degradation at invadopodia. The pulsatile insertion showed basically consistent results with the continuous insertion in the ECM degradation, and the ECM degrading efficacy depended heavily on the transient activity of MT1-MMP in both models. Unexpectedly, however, low-frequency/high-concentration insertion of MT1-MMP was more effective in ECM degradation than high-frequency/low-concentration pulsatile insertion even if the time-averaged amount of inserted MT1-MMP was the same. The present analysis and characterization of ECM degradation by MT1-MMP together with our previous report indicate a dynamic nature of MT1-MMP at invadopodia and the importance of its transient peak in the degradation of the ECM. Metastasis is the major cause of death in cancer patients. If metastasis is blocked, the survival rate will be greatly increased. Cancer cells are surrounded by ECM (extracellular matrix), which prevents their free movement. MT1-MMP is a potent membrane proteinase that degrades ECM, which is the first step of cancer cell invasion. Thus, the control of MT1-MMP activity is a key to the prevention of metastasis. Here we found a sharp transient peak in the ECM-degrading activity of MT1-MMP by computer simulations, and computational elimination of this peak greatly prolonged the ECM degradation. MT1-MMP is transported intracellularly to the surface of the membrane of cancer cells, and its insertion into the membrane is thought to occur in a pulsatile manner. Therefore, we asked whether the ECM-degrading efficacy was the same in low-frequency/high-concentration and high-frequency/low-concentration insertions of MT1-MMP. Unexpectedly, the low-frequency/high-concentration regimen resulted in much faster ECM degradation even if the time-averaged amount of MT1-MMP insertion was the same. Thus, reduction of the sharp transient activity and vesicular content of MT1-MMP are important therapeutic targets.
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DOI：
10.1083/jcb.200709076
发表时间：
2008-06-16
期刊：
The Journal of cell biology
影响因子：
--
作者：
Sakurai-Yageta M;Recchi C;Le Dez G;Sibarita JB;Daviet L;Camonis J;D'Souza-Schorey C;Chavrier P
通讯作者：
Chavrier P
影响因子：
4.3
作者：
Hoshino D;Koshikawa N;Suzuki T;Quaranta V;Weaver AM;Seiki M;Ichikawa K
通讯作者：
Ichikawa K
影响因子：
11.4
作者：
Bravo-Cordero, Jose J.;Marrero-Diaz, Raquel;Montoya, Maria C.
通讯作者：
Montoya, Maria C.
影响因子：
4.8
作者：
Hoshino, Daisuke;Tomari, Taizo;Seiki, Motoharu
通讯作者：
Seiki, Motoharu
影响因子：
4.8
作者：
Kinoshita, T;Sato, H;Seiki, M
通讯作者：
Seiki, M