Binding of GEF-H1 to the tight junction-associated adaptor cingulin results in inhibition of Rho signaling and G1/S phase transition
Binding of GEF-H1 to the tight junction-associated adaptor cingulin results in inhibition of Rho signaling and G1/S phase transition
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DOI：
10.1016/j.devcel.2005.03.003
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发表时间：
2005-05-01
影响因子：
11.8
通讯作者：
Matter, K
中科院分区：
文献类型：
--
作者：
Aijaz, S;D'Atri, F;Matter, K
Rho GTP酶的活性被仔细定时以控制上皮细胞增殖和分化。当上皮细胞达到汇合时，RhoA下调，导致刺激增殖的信号通路的抑制。在这里，我们表明，GEFH 1/LFC，鸟嘌呤核苷酸交换因子RhoA，直接与扣带蛋白，连接接头相互作用。扣带蛋白结合抑制RhoA活化和信号传导，表明汇合细胞中扣带蛋白表达的增加通过抑制GEF-H1/Lfc引起RhoA下调。一致的是，GEF-H1的RNA干扰或转染GEF-H1结合扣带蛋白突变体抑制MDCK细胞的G1/S相变，并且通过调节RNA干扰导致扣带蛋白的耗尽导致不规则单层和RhoA激活。这些结果表明，形成上皮紧密连接有助于下调RhoA在上皮细胞中通过灭活GEF-H1扣带蛋白依赖性的方式，提供了一种分子机制，其中紧密连接的形成与抑制RhoA信号转导。
The activity of Rho GTPases is carefully timed to control epithelial proliferation and differentiation. RhoA is downregulated when epithelial cells reach confluence, resulting in inhibition of signaling pathways that stimulate proliferation. Here we show that GEFH1/Lfc, a guanine nucleotide exchange factor for RhoA, directly interacts with cingulin, a junctional adaptor. Cingulin binding inhibits RhoA activation and signaling, suggesting that the increase in cingulin expression in confluent cells causes downregulation of RhoA by inhibiting GEF-H1/Lfc. In agreement, RNA interference of GEF-H1 or transfection of GEF-H1 binding cingulin mutants inhibit G1/S phase transition of MDCK cells, and depletion of cingulin by regulated RNA interference results in irregular monolayers and RhoA activation. These results indicate that forming epithelial tight junctions contribute to the downregulation of RhoA in epithelia by inactivating GEF-H1 in a cingulin-dependent manner, providing a molecular mechanism whereby tight junction formation is linked to inhibition of RhoA signaling.