Motility and invasion are differentially modulated by Rho family GTPases
Motility and invasion are differentially modulated by Rho family GTPases
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DOI：
10.1038/sj.onc.1203338
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发表时间：
2000-01-27
期刊：
影响因子：
8
通讯作者：
Zetter, BR
中科院分区：
文献类型：
--
作者：
Banyard, J;Anand-Apte, B;Zetter, BR
细胞在体内的迁移通常需要通过组织基质侵入。目前，关于通过三维基质调节细胞侵袭的信号通路知之甚少。小GTP酶Cdc 42、Rac和Rho是肌动蛋白细胞骨架和粘附结构的关键调节因子。我们现在表明，显性负性形式的Cdc 42，Rac或Rho的表达抑制PDGF-BB刺激的Rat 1成纤维细胞侵入3D胶原基质，表明这些GTP酶的活性是细胞所必需的。相比之下，在Boyden室中，PDGF-BB刺激的穿过平面基底的运动仅需要Rac激活。有趣的是，PDGF诱导的入侵也强烈抑制了Cdc 42或Rho的组成型活性形式的表达，并在较小程度上由组成型活性的Rac，我们还表明，组成型活性V12-Rac显着刺激基础大鼠1成纤维细胞的入侵，独立的PI-3-激酶活性，这种效果被抑制的效应突变体V12/N40-Rac。这些结果表明，细胞侵袭可能需要Cdc 42，Rho和Rac的最佳激活水平，并且迁移和侵袭由Rho家族GTP酶差异调节。
Cell migration in vivo often requires invasion through tissue matrices. Currently little is known regarding the signaling pathways that regulate cell invasion through three-dimensional matrices. The small GTPases Cdc42, Rac and Rho are key regulators of actin cytoskeletal and adhesive structures. We now show that expression of dominant negative forms of either Cdc42, Rac or Rho inhibited PDGF-BB-stimulated Rat1 fibroblast invasion into 3D collagen matrices, indicating that the activity of each of these GTPases is necessary for cell. invasion, In contrast, only Rac activation was required for PDGF-BB-stimulated locomotion across a planar substrate in the Boyden chamber. Interestingly, PDGF-induced invasion was also strongly inhibited by expression of constitutively active forms of Cdc42 or Rho, and to a lesser extent by constitutively active Rac, We also show that constitutively active V12-Rac significantly stimulated basal Rat1 fibroblast invasion, independent of PI-3-kinase activity, and that this effect was suppressed by the effector mutant V12/N40-Rac. These results suggest that cellular invasion may require an optimal level of activation of Cdc42, Rho and Rac, and that migration and invasion are differentially modulated by Rho family GTPases.