Revach Or-Yam, Winograd-Katz Sabina E, Samuels Yardena, Geiger Benjamin
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel.
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel.
Exp Cell Res. 2016 Apr 10;343(1):82-88. doi: 10.1016/j.yexcr.2016.02.003. Epub 2016 Feb 10.
In this article, we discuss the complex involvement of a Rho-family GTPase, Rac1, in cell migration and in invadopodia-mediated matrix degradation. We discuss the involvement of invadopodia in invasive cell migration, and their capacity to promote cancer metastasis. Considering the regulation of invadopodia formation, we describe studies that demonstrate the role of Rac1 in the metastatic process, and the suggestion that this effect is attributable to the capacity of Rac1 to promote invadopodia formation. This notion is demonstrated here by showing that knockdown of Rac1 in melanoma cells expressing a wild-type form of this GTPase, reduces invadopodia-dependent matrix degradation. Interestingly, we also show that excessive activity of Rac1, displayed by the P29S, hyperactive, "fast cycling" mutant of Rac1, which is present in 5-10% of melanoma tumors, inhibits invadopodia function. Moreover, knockdown of this hyperactive mutant enhanced matrix degradation, indicating that excessive Rac1 activity by this mutant can negatively regulate invadopodia formation and function.
在本文中，我们讨论了Rho家族GTP酶Rac1在细胞迁移和侵袭性伪足介导的基质降解中的复杂作用。我们讨论了侵袭性伪足在侵袭性细胞迁移中的作用，以及它们促进癌症转移的能力。考虑到侵袭性伪足形成的调控，我们描述了一些研究，这些研究证明了Rac1在转移过程中的作用，以及这种作用归因于Rac1促进侵袭性伪足形成的能力这一观点。通过显示在表达这种GTP酶野生型形式的黑色素瘤细胞中敲低Rac1会减少侵袭性伪足依赖性基质降解，这一观点在此得到了证实。有趣的是，我们还表明，存在于5%-10%黑色素瘤肿瘤中的Rac1的P29S高活性、“快速循环”突变体所表现出的Rac1过度活性会抑制侵袭性伪足功能。此外，敲低这种高活性突变体可增强基质降解，表明该突变体导致的Rac1过度活性可对侵袭性伪足的形成和功能产生负调控作用。
