Pak1 and Pak2 mediate tumor cell invasion through distinct signaling mechanisms
Pak1 and Pak2 mediate tumor cell invasion through distinct signaling mechanisms
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DOI：
10.1128/mcb.01532-07
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发表时间：
2008-06-01
影响因子：
5.3
通讯作者：
Symons, Marc H.
中科院分区：
文献类型：
--
作者：
Coniglio, Salvatore J.;Zavarella, Salvatore;Symons, Marc H.
Pak激酶被认为在细胞迁移和侵袭中起关键作用。在这里，我们分析的作用Pak 1和Pak 2在乳腺癌细胞侵袭使用的小干扰RNA的瞬时转染。我们发现，虽然Pak 1和Pak 2有助于乳腺癌的侵袭刺激heregulin，这些角色是由不同的信号转导机制介导的。因此，尽管Pak 1的耗尽。干扰heregulin介导的cofilin的去磷酸化，Pak 2的缺失不会。Pak 1的缺失对板状伪足突出的抑制作用也比Pak 2的缺失强。有趣的是，Pak 1和Pak 2在调节肌球蛋白轻链（MLC）的磷酸化中起相反的作用。而Pak 1的耗竭降低调蛋白刺激的细胞中的磷酸化MLC水平，Pak 2的耗竭增强MLC磷酸化。与其对MLC磷酸化的相反作用一致，Pak 1和Pak 2差异调节局灶性粘连。Pak 2-耗尽的细胞显示局灶性粘附大小的增加，而在Pak 1-耗尽的细胞中，局灶性粘附未能成熟。我们还发现，Pak 2，而不是Pak 1的耗尽，增强RhoA活性和抑制RhoA信号在Pak 2耗尽细胞减少MLC磷酸化和恢复细胞侵袭。总之，这项工作提出了第一个全面的分析Pak 1和Pak 2亚型之间的功能差异。
Pak kinases are thought to play critical roles in cell migration and invasion. Here, we analyze the roles of Pak1 and Pak2 in breast carcinoma cell invasion using the transient transfection of small interfering RNA. We find that although both Pak1 and Pak2 contribute to breast carcinoma invasion stimulated by heregulin, these roles are mediated by distinct signaling mechanisms. Thus, whereas the depletion of Pak1. interferes with the heregulin-mediated dephosphorylation of cofilin, the depletion of Pak2 does not. The depletion of Pak1 also has a stronger inhibitory effect on lamellipodial protrusion than does the depletion of Pak2. Interestingly, Pak1 and Pak2 play opposite roles in regulating the phosphorylation of the myosin light chain (MLC). Whereas the depletion of Pak1 decreases phospho-MLC levels in heregulin-stimulated cells, the depletion of Pak2 enhances MLC phosphorylation. Consistent with their opposite effects on MLC phosphorylation, Pak1 and Pak2 differentially modulate focal adhesions. Pak2-depleted cells display an increase in focal adhesion size, whereas in Pak1-depleted cells, focal adhesions fail to mature. We also found that the depletion of Pak2, but not Pak1, enhances RhoA activity and that the inhibition of RhoA signaling in Pak2-depleted cells decreases MLC phosphorylation and restores cell invasion. In summary, this work presents the first comprehensive analysis of functional differences between the Pak1 and Pak2 isoforms.