A novel spatiotemporal RhoC activation pathway locally regulates cofilin activity at invadopodia.
A novel spatiotemporal RhoC activation pathway locally regulates cofilin activity at invadopodia.
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DOI：
10.1016/j.cub.2011.03.039
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发表时间：
2011-04-26
期刊：
影响因子：
9.2
通讯作者：
Condeelis, John
中科院分区：
文献类型：
--
作者：
Bravo-Cordero, Jose Javier;Oser, Matthew;Chen, Xiaoming;Eddy, Robert;Hodgson, Louis;Condeelis, John
RhoGTP酶参与了肿瘤转移的调控。浸润性癌细胞形成侵袭性、富含F-肌动蛋白的基质降解突起，这些突起被认为对肿瘤细胞的侵袭和血管内侵入很重要。肌动蛋白在内侧突起的动态调节是驱动侵袭的关键。这个过程需要粘连蛋白的切断活性才能产生无肌动蛋白的带刺末端。以前的工作表明，Cofilin的切断活性通过多种机制受到严格调控，包括Rho GTP酶对Cofilin丝氨酸磷酸化的调控。然而，目前尚不清楚哪种Rho GTP酶参与调节cofilin在不定足中的磷酸化状态。在这里，我们第一次展示了RhoC的激活是如何在无足动物体内被控制的，以及这种激活是如何调节cofilin的磷酸化来控制cofilin的无肌动蛋白带刺末端的产生的。荧光RHOC生物传感器的活细胞成像显示，RHOC的活性在空间上局限于啮齿动物周围的区域。RHOC活性的这种时空限制是由“空间上不同的调控元件”控制的，这些调控元件将RHOC的激活限制在这个隔间内。P190Rhogef定位于invadodia周围以激活RhoC，而p190RhoGAP定位于invadoodia内部以使结构内的GTPase失活。RhoC的激活增强了内侧足纲外的cofilin的磷酸化。这些结果显示了RHOC活性是如何通过p190Rhogenf和p190RhoGAP在介体上进行空间调节的。RhoC的激活使内陷内膜内的Cofilin活性局限于内膜核内，从而导致内膜外突出。这一机制可能会在转移过程中增强肿瘤细胞的侵袭能力。
RhoGTPases have been implicated in the regulation of cancer metastasis. Invasive carcinoma cells form invadopodia, F-actin-rich matrix degrading protrusions that are thought to be important for tumor cell invasion and intravasation. Regulation of actin dynamics at invadopodial protrusions is crucial to drive invasion. This process requires the severing activity of cofilin to generate actin-free barbed ends. Previous work demonstrates that cofilin’s severing activity is tightly regulated through multiple mechanisms including regulation of cofilin serine phosphorylation by Rho GTPases. However, it is not known which Rho GTPase is involved in regulating cofilin’s phosphorylation status at invadopodia. We show here, for the first time, how RhoC activation is controlled at invadopodia and how this activation regulates cofilin phosphorylation to control cofilin’s generation of actin-free barbed ends. Live-cell imaging of fluorescent RhoC biosensor reveals that RhoC activity is spatially confined to areas surrounding invadopodia. This spatiotemporal restriction of RhoC activity is controlled by “spatially distinct regulatory elements” that confines RhoC activation within this compartment. p190RhoGEF localizes around invadopodia to activate RhoC, while p190RhoGAP localizes inside invadopodia to deactivate the GTPase within the structure. RhoC activation enhances cofilin phosphorylation outside invadopodia. These results show how RhoC activity is spatially regulated at invadopodia by p190RhoGEF and p190RhoGAP. RhoC activation in areas surrounding invadopodia restricts cofilin activity to within the invadopodium core resulting in a focused invadopodial protrusion. This mechanism likely enhances tumor cell invasion during metastasis.
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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：
14.5
作者：
Price, LS;Collard, JG
通讯作者：
Collard, JG
影响因子：
9.2
作者：
Gohla, A;Bokoch, GM
通讯作者：
Bokoch, GM
影响因子：
64.8
作者：
Pertz, O;Hodgson, L;Hahn, KM
通讯作者：
Hahn, KM
影响因子：
64.8
作者：
Clark, EA;Golub, TR;Hynes, RO
通讯作者：
Hynes, RO