Control of the G-protein cascade dynamics by GDP dissociation inhibitors
Control of the G-protein cascade dynamics by GDP dissociation inhibitors
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DOI：
10.1039/c3mb70152b
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发表时间：
2013-01-01
影响因子：
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通讯作者：
Kholodenko, Boris N.
中科院分区：
文献类型：
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作者：
Nikonova, Elena;Tsyganov, Mikhail A.;Kholodenko, Boris N.
Rho家族gtp酶的网络，在无活性的gtp结合状态和活跃的gtp结合状态之间循环，控制关键的细胞过程，包括增殖和迁移。GTPase的激活和失活是由鸟嘌呤核苷酸交换因子（GEFs）、GTPase激活蛋白（GAPs）和GDP解离抑制剂（gdi）控制的，GTPase将GTPase从细胞膜隔离到细胞质。在这里，我们展示了两个Rho家族gtpase， RhoA和Rac1，由RhoGDI1调节的级联，表现出不同的动态行为模式，包括突然，双稳态开关，可激过调转换和振荡。RhoGDI1的丰度和信号诱导的对GTPase亲和力的变化控制着这些不同的动力学，使GTPase活性从单一稳定的稳态过渡到双稳态，到可激发的脉冲和持续的振荡。这些rhogdi1控制的RhoA和Rac1活性的动态模式构成了细胞迁移行为的基础，包括迁移细胞前沿的伸出-收缩周期。
A network of the Rho family GTPases, which cycle between inactive GDP-bound and active GTP-bound states, controls key cellular processes, including proliferation and migration. Activating and deactivating GTPase transitions are controlled by guanine nucleotide exchange factors (GEFs), GTPase activating proteins (GAPs) and GDP dissociation inhibitors (GDIs) that sequester GTPases from the membrane to the cytoplasm. Here we show that a cascade of two Rho family GTPases, RhoA and Rac1, regulated by RhoGDI1, exhibits distinct modes of the dynamic behavior, including abrupt, bistable switches, excitable overshoot transitions and oscillations. The RhoGDI1 abundance and signal-induced changes in the RhoGDI1 affinity for GTPases control these different dynamics, enabling transitions from a single stable steady state to bistability, to excitable pulses and to sustained oscillations of GTPase activities. These RhoGDI1-controlled dynamic modes of RhoA and Rac1 activities form the basis of cell migration behaviors, including protrusion-retraction cycles at the leading edge of migrating cells.