Symmetry-breaking polarization driven by a Cdc42p GEF-PAK complex.
Symmetry-breaking polarization driven by a Cdc42p GEF-PAK complex.
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DOI：
10.1016/j.cub.2008.09.060
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发表时间：
2008-11-25
期刊：
影响因子：
9.2
通讯作者：
Lew, Daniel J.
中科院分区：
文献类型：
--
作者：
Kozubowski, Lukasz;Saito, Koji;Johnson, Jayme M.;Howell, Audrey S.;Zyla, Trevin R.;Lew, Daniel J.
1952年，阿兰·图灵提出，空间模式可以通过随机波动的反馈放大从均匀的起始条件中产生。这种自我组织的一个例子，称为对称性破缺，涉及在缺乏空间线索的情况下自发的细胞极化。保守的GTdR Cdc 42 p是必不可少的指导和自发极化，并在芽殖酵母细胞Cdc 42 p集中在一个单一的网站（推定的芽网站）在皮层。Cdc 42 p集中在一个随机的皮质网站在对称性破缺的方式，需要的支架蛋白Bem 1 p。Bem 1 p促进这种极化的机制尚不清楚。在这里，我们表明，Bem 1 p促进对称性破缺组装一个复杂的Cdc 42 p导向的鸟嘌呤核苷酸交换因子（GEF）和Cdc 42 p效应p21激活激酶（PAK）与Bem 1 p。对Bem 1 p突变体的分析表明，GEF和PAK必须与Bem 1 p的相同分子结合，并且连接酵母GEF和PAK的蛋白融合体绕过了对Bem 1 p的需要。虽然哺乳动物细胞缺乏Bem 1 p的直系同源物，但它们含有更复杂的多结构域GEF，在某些情况下可以直接与PAK相互作用，我们表明，即使没有Bem 1 p，含有具有类似结构的人工GEF的酵母也可以打破对称性。酵母破胶极化涉及GEF-PAK复合物，其通过PAK结合GTP-Cdc 42 p并通过GEF促进局部Cdc 42 p GTP负载。通过在预先存在的GTP-Cdc 42 p附近产生新鲜的GTP-Cdc 42 p，该复合物扩增了皮质处的GTP-Cdc 42 p簇。我们的研究结果提供了一个进化保守的模式形成的正反馈途径的机制的见解。
In 1952, Alan Turing suggested that spatial patterns could arise from homogeneous starting conditions by feedback amplification of stochastic fluctuations. One example of such self-organization, called symmetry breaking, involves spontaneous cell polarization in the absence of spatial cues. The conserved GTPase Cdc42p is essential for both guided and spontaneous polarization, and in budding yeast cells Cdc42p concentrates at a single site (the presumptive bud site) at the cortex. Cdc42p concentrates at a random cortical site during symmetry breaking in a manner that requires the scaffold protein Bem1p. The mechanism whereby Bem1p promotes this polarization was unknown. Here we show that Bem1p promotes symmetry breaking by assembling a complex in which both a Cdc42p-directed guanine nucleotide exchange factor (GEF) and a Cdc42p effector p21-activated kinase (PAK) associate with Bem1p. Analysis of Bem1p mutants indicates that both GEF and PAK must bind to the same molecule of Bem1p, and a protein fusion linking the yeast GEF and PAK bypasses the need for Bem1p. Although mammalian cells lack a Bem1p ortholog, they contain more complex multidomain GEFs that in some cases can directly interact with PAKs, and we show that yeast containing an artificial GEF with similar architecture can break symmetry even without Bem1p. Yeast symmetry-breaking polarization involves a GEF-PAK complex that binds GTP-Cdc42p via the PAK and promotes local Cdc42p GTP-loading via the GEF. By generating fresh GTP-Cdc42p near pre-existing GTP-Cdc42p, the complex amplifies clusters of GTP-Cdc42p at the cortex. Our findings provide mechanistic insight into an evolutionarily conserved pattern-forming positive-feedback pathway.
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