Raf-1 regulates Rho signaling and cell migration.
Raf-1 regulates Rho signaling and cell migration.
复制标题
RAF-1调节RHO信号传导和细胞迁移。
DOI：
10.1083/jcb.200409162
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发表时间：
2005-03-14
影响因子：
7.8
通讯作者：
Baccarini, Manuela
中科院分区：
文献类型：
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作者：
Ehrenreiter, Karin;Piazzolla, Daniela;Velamoor, Vanishree;Sobczak, Izabela;Small, J Victor;Takeda, Junji;Leung, Thomas;Baccarini, Manuela
Raf 激酶传递诱导增殖、分化和存活的信号。 Raf-1 同工型作为连接 Ras 激活与 MEK/ERK 模块的上游激酶已被广泛研究。然而，最近的基因实验表明，Raf-1 在对抗细胞凋亡中发挥着重要作用，并且它的作用独立于其激活 MEK 的能力。通过条件基因消融，我们现在表明 Raf-1 是体内正常伤口愈合以及体外角质形成细胞和成纤维细胞迁移所必需的。 Raf-1 缺陷的细胞表现出对称、收缩的外观，其特征是皮质肌动蛋白束和紊乱的波形蛋白细胞骨架。这些缺陷是由于 Rho 效应器 Rok-α 的过度活跃和质膜的错误定位造成的。 Raf-1 在野生型 (WT) 细胞中与 Rok-α 物理结合，在敲除的成纤维细胞中重新引入 WT 或激酶死亡的 Raf-1 可挽救其形状和迁移缺陷。因此，Raf-1 在迁移过程中作为 Rho 下游信号传导的空间调节器发挥着重要的、独立于激酶的功能。
Raf kinases relay signals inducing proliferation, differentiation, and survival. The Raf-1 isoform has been extensively studied as the upstream kinase linking Ras activation to the MEK/ERK module. Recently, however, genetic experiments have shown that Raf-1 plays an essential role in counteracting apoptosis, and that it does so independently of its ability to activate MEK. By conditional gene ablation, we now show that Raf-1 is required for normal wound healing in vivo and for the migration of keratinocytes and fibroblasts in vitro. Raf-1–deficient cells show a symmetric, contracted appearance, characterized by cortical actin bundles and by a disordered vimentin cytoskeleton. These defects are due to the hyperactivity and incorrect localization of the Rho-effector Rok-α to the plasma membrane. Raf-1 physically associates with Rok-α in wild-type (WT) cells, and reintroduction of either WT or kinase-dead Raf-1 in knockout fibroblasts rescues their defects in shape and migration. Thus, Raf-1 plays an essential, kinase-independent function as a spatial regulator of Rho downstream signaling during migration.