A βPIX-PAK2 complex confers protection against Scrib-dependent and cadherin-mediated apoptosis.
A βPIX-PAK2 complex confers protection against Scrib-dependent and cadherin-mediated apoptosis.
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DOI：
10.1016/j.cub.2012.07.011
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发表时间：
2012-10-09
期刊：
影响因子：
9.2
通讯作者：
Hansen, Steen H.
中科院分区：
文献类型：
--
作者：
Frank, Scott R.;Bell, Jennifer H.;Frodin, Morten;Hansen, Steen H.
在上皮形态发生期间，由βPIX（PAK相互作用交换因子β）和I类PAK（p21激活激酶）组成的复合物被募集到粘附连接处。Scribb是果蝇极性决定簇和肿瘤抑制因子Scribble的哺乳动物直向同源物，直接结合βPIX。Scrib还通过E-钙粘蛋白靶向粘附连接，其中Scrib加强钙粘蛋白介导的细胞-细胞粘附。虽然已经阐明了Scrib-βPIX-PAK信号传导复合物在促进伤口边缘处的膜突出中的作用，但是该复合物在粘附连接处的功能仍然未知。在这里，我们确定Scrib将βPIX和PAK 2靶向粘附连接，其中β PIX-PAK 2复合物平衡Scrib转导的凋亡刺激和钙粘蛋白介导的细胞-细胞粘附。此外，我们表明，这一信号通路调节细胞的生存响应渗透胁迫。最后，我们确定在悬浮培养中，Scrib-β PIX-PAK 2复合物的功能是调节由钙粘蛋白接合引起的失巢凋亡，Scrib促进失巢凋亡，β PIX-PAK 2复合物抑制失巢凋亡。我们的研究结果表明，Scrib-β PIX-PAK 2信号传导复合物在定位于极化上皮的粘附连接时作为细胞存活的重要调节剂发挥作用。因此，这种复合物在粘附连接处的活性对于正常上皮形态发生和生理应激耐受性是必不可少的。此外，当定位于粘附连接时，Scrib-β PIX-PAK 2信号传导复合物充当失巢凋亡敏感性的关键决定因素，失巢凋亡敏感性是肿瘤抑制的关键机制。因此，这项工作也揭示了需要扩大失巢凋亡的定义，包括粘附连接的核心作用。
During epithelial morphogenesis, a complex comprised of the βPIX (PAK-interacting exchange factor β) and class I PAKs (p21-activated kinases) is recruited to adherens junctions. Scrib, the mammalian orthologue of the Drosophila polarity determinant and tumor suppressor Scribble, binds βPIX directly. Scrib is also targeted to adherens junctions by E-cadherin, where Scrib strengthens cadherin-mediated cell-cell adhesion. While a role for the Scrib-βPIX-PAK signaling complex in promoting membrane protrusion at wound edges has been elucidated, a function for this complex at adherens junctions remains unknown. Here, we establish that Scrib targets βPIX and PAK2 to adherens junctions where a βPIX-PAK2 complex counterbalances apoptotic stimuli transduced by Scrib and elicited by cadherin-mediated cell-cell adhesion. Moreover, we show that this signaling pathway regulates cell survival in response to osmotic stress. Finally, we determine that in suspension cultures, the Scrib-βPIX-PAK2 complex functions to regulate anoikis elicited by cadherin engagement, with Scrib promoting and the βPIX-PAK2 complex suppressing anoikis, respectively. Our findings demonstrate that the Scrib-βPIX-PAK2 signaling complex functions as an essential modulator of cell survival when localized to adherens junctions of polarized epithelia. The activity of this complex at adherens junctions is thereby essential for normal epithelial morphogenesis and tolerance of physiological stress. Furthermore, when localized to adherens junctions, the Scrib-βPIX-PAK2 signaling complex serves as a key determinant of anoikis sensitivity, a pivotal mechanism in tumor suppression. Thus, this work also reveals the need to expand the definition of anoikis to include a central role for adherens junctions.
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