A novel regulator of p21-activated kinases
A novel regulator of p21-activated kinases
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DOI：
10.1074/jbc.273.37.23633
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发表时间：
1998-09-11
影响因子：
4.8
通讯作者：
Cerione, RA
中科院分区：
文献类型：
--
作者：
Bagrodia, S;Taylor, SJ;Cerione, RA
虽然CDC42和Pac GTP酶激活PAK的能力已被证实，但对PAK的调控或PAK细胞靶标的识别知之甚少，PAK家族的蛋白参与了基因表达、细胞骨架结构和细胞凋亡的调控。在这里，我们报告了两个密切相关的Pak3结合蛋白，可能来自选择性剪接，命名为p50和p85(Cool-1)(从文库中克隆出来)，这两个Cool的异构体都含有一个直接介导与Pak3和串联DBL同源结构域和Pleckstrin同源结构域相互作用的Src同源3结构域。尽管存在DBL同源-pleckstrin同源基序，这是Rho家族激活剂的特征，但Cool不能检测到CDC42或RAC的激活。相反，p50(Cool-1)而不是P85(Cool-1)与Pak3的结合抑制了其上游激活物如DBL癌蛋白的激活，表明了一种新的调节PAK信号的机制。
Proteins of the pal-activated kinase (Pak) family have been implicated in the regulation of gene expression, cytoskeletal architecture, and apoptosis, Although the ability of Cdc42 and Pac GTPases to activate Pak is well established, relatively little else is known about Pak regulation or the identity of Pak cellular targets. Here we report the identification of two closely related Pak3-binding proteins, possibly arising from alternative splicing, designated p50 and p85(Cool-1) (cloned out of library), Both isoforms of Cool contain a Src homology 3 domain that directly mediates interaction with Pak3 and tandem Dbl homology and pleckstrin homology domains. Despite the presence of the Dbl homology-pleckstrin homology motif, a characteristic of Rho family activators, activation of Cdc42 or Rac by Cool is not detectable. Instead binding of p50(Cool-1), but not p85(Cool-1), to Pak3 represses its activation by upstream activators such as the Dbl oncoprotein, indicating a novel mechanism of regulation of Pak signaling.