Mutant B-RAF regulates a Rac-dependent cadherin switch in melanoma.
Mutant B-RAF regulates a Rac-dependent cadherin switch in melanoma.
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DOI：
10.1038/onc.2012.492
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发表时间：
2013-10
期刊：
影响因子：
8
通讯作者：
Burridge, K.
中科院分区：
文献类型：
--
作者：
Monaghan-Benson, E.;Burridge, K.
细胞侵入真皮的能力是皮肤黑色素瘤发展的关键事件，也是预后不良的最终指标。然而，围绕获得这种侵入性表型的分子事件仍不完全清楚。 B-RAF 突变在黑色素瘤中很常见，并且已知可调节侵袭性表型。在这项研究中，我们试图确定控制黑色素瘤侵袭的分子机制。我们发现突变的 B-RAF 信号传导可调节钙粘蛋白开关。在表达突变 B-RAF 的黑色素瘤细胞中，我们观察到高水平的 N-钙粘蛋白和低水平的 E-钙粘蛋白。通过 siRNA 消除突变体 B-RAF，导致 N-钙粘蛋白水平下降，而 E-钙粘蛋白水平增加。从机制上讲，我们发现这种钙粘蛋白开关需要 Rac1 及其 GEF、Tiam1 的活性，这两者在突变 B-RAF 存在的情况下均表现出抑制的活性。与其他人的工作一致，我们发现突变体 B-RAF 的消耗降低了黑色素瘤细胞的侵袭能力。然而，同时去除 B-RAF 和 Rac 或 Tiam1 会导致与对照细胞相似的侵袭能力。综上所述，我们的结果表明突变的 B-RAF 信号传导下调 Tiam1/Rac 活性，导致 N-钙粘蛋白水平增加和 E-钙粘蛋白水平降低，最终增强侵袭。
The ability of cells to invade into the dermis is a critical event in the development of cutaneous melanoma and ultimately an indicator of poor prognosis. However, the molecular events surrounding the acquisition of this invasive phenotype remain incompletely understood. Mutations in B-RAF are frequent in melanoma and are known to regulate the invasive phenotype. In this study, we sought to determine the molecular mechanisms controlling melanoma invasion. We found that mutant B-RAF signaling regulates a cadherin switch. In melanoma cells expressing mutant B-RAF we observed high levels of N-cadherin and low levels of E-cadherin. Depletion of mutant B-RAF, by siRNA, caused a decrease in the levels of N-cadherin and an increase in the levels of E-cadherin. Mechanistically, we found that this cadherin switch required the activity of Rac1 and its GEF, Tiam1, both of which show suppressed activity in the presence of mutant B-RAF. Consistent with the work of others, we found that depletion of mutant B-RAF decreased the invasive capacity of the melanoma cells. However, simultaneous depletion of B-RAF and Rac or Tiam1 resulted in invasive capacity similar to that of control cells. Taken together, our results suggest that mutant B-RAF signaling downregulates Tiam1/Rac activity resulting in an increase in N-cadherin levels and a decrease in E-cadherin levels and ultimately enhanced invasion.
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DOI：
10.1084/jem.20082044
发表时间：
2009-01-16
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Massoumi R;Kuphal S;Hellerbrand C;Haas B;Wild P;Spruss T;Pfeifer A;Fässler R;Bosserhoff AK
通讯作者：
Bosserhoff AK
影响因子：
30.8
作者：
Pollock, PM;Cohen-Solal, K;Chen, S
通讯作者：
Chen, S
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
64.5
作者：
HABETS, GGM;SCHOLTES, EHM;COLLARD, JG
通讯作者：
COLLARD, JG
影响因子：
11.2
作者：
Klein RM;Aplin AE
通讯作者：
Aplin AE