The cool-2/α-Pix protein mediates a Cdc42-Rac signaling cascade
The cool-2/α-Pix protein mediates a Cdc42-Rac signaling cascade
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DOI：
10.1016/j.cub.2004.12.040
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发表时间：
2005-01-11
期刊：
影响因子：
9.2
通讯作者：
Cerione, RA
中科院分区：
文献类型：
--
作者：
Baird, D;Feng, QY;Cerione, RA
背景资料：克隆出的库-2（Cool-2）/PAK相互作用交换因子（alpha-Pix）通过其结合Cdc 42/Rac靶点p21激活激酶（PAK）的能力被鉴定，并且已经涉及某些形式的X-连锁精神发育迟滞以及生长因子和趋化因子偶联的信号传导途径。我们最近发现，二聚体形式的Cool-2是一个特定的鸟嘌呤核苷酸交换因子（GEF）的Rac，而单体Cool-2是一个GEF的Cdc 42以及Rac。然而，与许多GEF不同的是，Cool-2与Cdc 42和Rac的活化形式结合。因此，我们已经调查了这些interaction.Results的功能后果：我们表明，激活Cdc 42的Cool-2二聚体的结合显着增强其与GDP结合Rac 1的能力，导致在一个显着的激活Rac-GEF活动。虽然Cool-2的Rac特异性GEF活性通过来自一个单体的Dbl同源（DH）结构域和来自另一个单体的Pleckstrin同源结构域介导，但活化的Cdc 42与DH结构域相互作用，最可能与GDP结合的Rac的DH结构域结合位点相对。激活的Rac也与Cool-2结合，但它强烈抑制Cool-2二聚体的GEF活性。结论：我们为Cool-2二聚体的Rac-GEF活性的变构调节提供了新的证据，涉及Cdc 42的刺激作用和Rac的反馈抑制作用。这些发现表明，通过充当GTP结合Cdc 42的靶标和Rac的GEF，Cool-2介导了GTdR级联反应，其中Cdc 42的活化被翻译成Rac的活化。
Background: Cloned-out of library-2 (Cool-2)/PAK-interactive exchange factor (alpha-Pix) was identified through its ability to bind the Cdc42/Rac target p21-activated kinase (PAK) and has been implicated in certain forms of X-linked mental retardation as well as in growth factor- and chemoattractant-coupled signaling pathways. We recently found that the dimeric form of Cool-2 is a specific guanine nucleotide exchange factor (GEF) for Rac, whereas monomeric Cool-2 is a GEF for Cdc42 as well as Rac. However, unlike many GEFs, Cool-2 binds to activated forms of Cdc42 and Rac. Thus, we have investigated the functional consequences of these interactions.Results: We show that the binding of activated Cdc42 to the Cool-2 dimer markedly enhances its ability to associate with GDP bound Rac1, resulting in a significant activation of Rac-GEF activity. While the Rac-specific GEF activity of Cool-2 is mediated through the Dbl homology (DH) domain from one monomer and the Pleckstrin homology domain from the other, activated Cdc42 interacts with the DH domain, most likely opposite the DH domain binding site for GDP bound Rac. Activated Rac also binds to Cool-2; however, it strongly inhibits the GEF activity of dimeric Cool-2.Conclusions: We provide evidence for novel mechanisms of allosteric regulation of the Rac-GEF activity of the Cool-2 dimer, involving stimulatory effects by Cdc42 and feedback inhibition by Rac. These findings demonstrate that by serving as a target for GTP bound Cdc42 and a GEF for Rac, Cool-2 mediates a GTPase cascade where the activation of Cdc42 is translated into the activation of Rac.