Positive regulation of Rho GTPase activity by RhoGDIs as a result of their direct interaction with GAPs.
Positive regulation of Rho GTPase activity by RhoGDIs as a result of their direct interaction with GAPs.
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RHOGDIS与间隙的直接相互作用对Rho GTPase活性的正调控。
DOI：
10.1186/s12918-015-0143-5
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发表时间：
2015-01-28
影响因子：
--
通讯作者：
Tatsuka M
中科院分区：
文献类型：
--
作者：
Ota T;Maeda M;Okamoto M;Tatsuka M
Rho GTP酶在许多不同的信号通路中发挥分子开关的作用，控制着广泛的细胞过程。Rho GDP解离抑制物(RhoGDIs)调节Rho GTP酶信号转导，具有正负调节作用。RhoGDIs作为Rho GTPase信号的负调节因子的作用已经被广泛研究，然而，关于RhoGDIs如何作为正调节因子的研究很少。此外，GDIs的这种相反作用如何影响Rho GTP酶循环尚不清楚。我们构建了Rho GTP酶循环的常微分方程式模型，在该模型中，RhoGDIs通过直接与鸟嘌呤核苷酸交换因子(GEF)和GTP酶激活蛋白(GAP)相互作用以及隔离Rho GTP酶来抑制它们的调节活性。利用该模型，我们分析了RhoGDis在Rho GTP酶信号转导中的作用。在本研究中构建的模型表明，GEF和GAP的功能通过这些调节因子与GDIs的相互作用整合到Rho GTP酶信号中，GDIs的负面作用是通过抑制GEF来抑制Rho的整体活性。此外，GDIs的积极作用是在一定条件下通过抑制GAP来维持Rho的激活。瞬时和持续的Rho激活之间的相互转化主要是通过改变GDI与GAP的亲和力和GAP的浓度来实现的。RhoGDIs主要通过与GAP相互作用对Rho GTP酶信号进行正向调节，并可能参与Rho GTP酶瞬时信号与持续信号之间的切换。这些发现加深了我们对RhoGDIs和Rho GTPase信号的生理作用的理解。本文的在线版本(doi：10.1186/s12918-0150143-5)包含补充材料，授权用户可以使用。
Rho GTPases function as molecular switches in many different signaling pathways and control a wide range of cellular processes. Rho GDP-dissociation inhibitors (RhoGDIs) regulate Rho GTPase signaling and can function as both negative and positive regulators. The role of RhoGDIs as negative regulators of Rho GTPase signaling has been extensively investigated; however, little is known about how RhoGDIs act as positive regulators. Furthermore, it is unclear how this opposing role of GDIs influences the Rho GTPase cycle. We constructed ordinary differential equation models of the Rho GTPase cycle in which RhoGDIs inhibit the regulatory activities of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) by interacting with them directly as well as by sequestering the Rho GTPases. Using this model, we analyzed the role of RhoGDIs in Rho GTPase signaling. The model constructed in this study showed that the functions of GEFs and GAPs are integrated into Rho GTPase signaling through the interactions of these regulators with GDIs, and that the negative role of GDIs is to suppress the overall Rho activity by inhibiting GEFs. Furthermore, the positive role of GDIs is to sustain Rho activation by inhibiting GAPs under certain conditions. The interconversion between transient and sustained Rho activation occurs mainly through changes in the affinities of GDIs to GAPs and the concentrations of GAPs. RhoGDIs positively regulate Rho GTPase signaling primarily by interacting with GAPs and may participate in the switching between transient and sustained signals of the Rho GTPases. These findings enhance our understanding of the physiological roles of RhoGDIs and Rho GTPase signaling. The online version of this article (doi:10.1186/s12918-015-0143-5) contains supplementary material, which is available to authorized users.
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影响因子：
4
作者：
Behar, Marcelo;Hoffmann, Alexander
通讯作者：
Hoffmann, Alexander
影响因子：
5.7
作者：
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通讯作者：
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影响因子：
7.8
作者：
Elfenbein, Arye;Rhodes, John M.;Simons, Michael
通讯作者：
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影响因子：
46.9
作者：
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通讯作者：
Oda, K
DOI：
10.1074/jbc.m109.098129
发表时间：
2010-07-23
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Dovas A;Choi Y;Yoneda A;Multhaupt HA;Kwon SH;Kang D;Oh ES;Couchman JR
通讯作者：
Couchman JR