PAK5, a new brain-specific kinase, promotes neurite outgrowth in N1E-115 cells
PAK5, a new brain-specific kinase, promotes neurite outgrowth in N1E-115 cells
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DOI：
10.1128/mcb.22.2.567-577.2002
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发表时间：
2002-01-01
影响因子：
5.3
通讯作者：
Minden, A
中科院分区：
文献类型：
--
作者：
Dan, C;Nath, N;Minden, A
我们已经表征了哺乳动物PAK家族的丝氨酸/苏氨酸激酶PAK 5的新成员，PAK 5是Rho GTP酶Cdc 42和Rac的新靶点。PAK 5的激酶结构域和GTP酶结合结构域（GBD）在序列上与哺乳动物PAK 4的那些最密切相关。然而，在这些结构域之外，PAK 5在序列上与任何已知的哺乳动物蛋白质完全不同。PAK 5确实与果蝇MBT蛋白（“蘑菇体微小”）具有相当大的序列同源性，然而，这被认为在果蝇大脑细胞的发育中发挥作用。有趣的是，PAK 5在哺乳动物脑中高度表达，而在大多数其他组织中不表达。我们已经发现PAK 5，像Cdc 42一样，促进丝状伪足的诱导。在N1 E-115神经母细胞瘤细胞中，PAK 5的表达也触发了神经突样过程的诱导，并且显性阴性PAK 5突变体抑制神经突生长。活化的PAK 1的表达在这些细胞中没有引起明显的变化。PAK 5的活化突变体具有比野生型PAK 5更显著的作用，表明PAK 5 '诱导的形态学变化与其激酶活性直接相关。虽然PAK 5激活JNK通路，显性负性JNK不抑制神经突生长。与此相反，PAK 5的神经突起的诱导被激活的RhoA的表达废除。以前的工作表明，Cdc 42和Rac促进神经突起生长的途径是拮抗Rho。因此，我们的研究结果表明，PAK 5在Cdc 42和Rac的下游起作用，并在通路中拮抗Rho，从而导致神经突发育。
We have characterized a new member of the mammalian PAK family of serine/threonine kinases, PAK5, which is a novel target of the Rho GTPases Cdc42 and Rac. The kinase domain and GTPase-binding domain (GBD) of PAK5 are most closely related in sequence to those of mammalian PAK4. Outside of these domains, however, PAK5 is completely different in sequence from any known mammalian proteins. PAK5 does share considerable sequence homology with the Drosophila MBT protein (for "mushroom body tiny"), however, which is thought to play a role in development of cells in Drosophila brain. Interestingly, PAK5 is highly expressed in mammalian brain and is not expressed in most other tissues. We have found that PAK5, like Cdc42, promotes the induction of filopodia. In N1E-115 neuroblastoma cells, expression of PAK5 also triggered the induction of neurite-like processes, and a dominant-negative PAK5 mutant inhibited neurite outgrowth. Expression of activated PAK1 caused no noticeable changes in these cells. An activated mutant of PAK5 had an even more dramatic effect than wild-type PAK5, indicating that the morphologic changes induced by PAK5' are directly related to its kinase activity. Although PAK5 activates the JNK pathway, dominant-negative JNK did not inhibit neurite outgrowth. In contrast, the induction of neurites by PAK5 was abolished by expression of activated RhoA. Previous work has shown that Cdc42 and Rac promote neurite outgrowth by a pathway that is antagonistic to Rho. Our results suggest, therefore, that PAK5 operates downstream to Cdc42 and Rac and antagonizes Rho in the pathway, leading to neurite development.