LIM kinases are required for invasive path generation by tumor and tumor-associated stromal cells.
LIM kinases are required for invasive path generation by tumor and tumor-associated stromal cells.
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DOI：
10.1083/jcb.201002041
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发表时间：
2010-10-04
期刊：
影响因子：
--
通讯作者：
Olson MF
中科院分区：
文献类型：
--
作者：
Scott RW;Hooper S;Crighton D;Li A;König I;Munro J;Trivier E;Wickman G;Morin P;Croft DR;Dawson J;Machesky L;Anderson KI;Sahai EA;Olson MF
在集体细胞迁移过程中，引导细胞需要LIMK来降解基质和形成侵袭伪足。LIM激酶1和2（LIMK 1/2）是位于中央的肌动蛋白细胞骨架动力学的调节剂。使用siRNA介导的敲除或一种新的小分子抑制剂，我们表明LIMK是所需的路径生成的领导肿瘤细胞和非肿瘤间质细胞在集体肿瘤细胞入侵。LIMK抑制降低了cofilin磷酸化、F-肌动蛋白水平、血清应答因子转录活性和胶原收缩，并减少了三维侵袭测定中的侵袭。尽管运动性不受影响，但LIMK抑制损害基质蛋白降解和侵袭伪足形成，这与FRAP测定中显著更快的恢复时间相关，表明F-肌动蛋白稳定性降低。当LIMK在MDA-MB-231细胞中被敲低时，它们失去了引导集体入侵细胞链的能力。类似地，当LIMK活性在癌症相关成纤维细胞中被阻断时，它们不能在器官型皮肤模型中导致鳞状癌细胞的集体侵袭。这些结果表明，LIMK是所需的基质重塑活动的路径产生的领导细胞在集体入侵。
Leading cells require LIMK for matrix degradation and invadopodia formation during collective cell migration. LIM kinases 1 and 2 (LIMK1/2) are centrally positioned regulators of actin cytoskeleton dynamics. Using siRNA-mediated knockdown or a novel small molecule inhibitor, we show LIMK is required for path generation by leading tumor cells and nontumor stromal cells during collective tumor cell invasion. LIMK inhibition lowers cofilin phosphorylation, F-actin levels, serum response factor transcriptional activity and collagen contraction, and reduces invasion in three-dimensional invasion assays. Although motility was unaffected, LIMK inhibition impairs matrix protein degradation and invadopodia formation associated with significantly faster recovery times in FRAP assays indicative of reduced F-actin stability. When LIMK is knocked down in MDA-MB-231 cells, they lose the ability to lead strands of collectively invading cells. Similarly, when LIMK activity is blocked in cancer-associated fibroblasts, they are unable to lead the collective invasion of squamous carcinoma cells in an organotypic skin model. These results show that LIMK is required for matrix remodeling activities for path generation by leading cells in collective invasion.
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影响因子：
56.9
作者：
Cukierman, E;Pankov, R;Yamada, KM
通讯作者：
Yamada, KM
DOI：
10.1083/jcb.200810041
发表时间：
2009-02-23
期刊：
The Journal of cell biology
影响因子：
--
作者：
Doyle AD;Wang FW;Matsumoto K;Yamada KM
通讯作者：
Yamada KM
影响因子：
6.4
作者：
Kunigal, Sateesh;Lakka, Sajani S.;Rao, Jasti S.
通讯作者：
Rao, Jasti S.
影响因子：
5.3
作者：
Ding, Yuemin;Milosavljevic, Tanja;Alahari, Suresh K.
通讯作者：
Alahari, Suresh K.
DOI：
10.1083/jcb.115.3.677
发表时间：
1991-11
期刊：
The Journal of cell biology
影响因子：
--
作者：
Cano ML;Lauffenburger DA;Zigmond SH
通讯作者：
Zigmond SH