GI Cell Biology Research Laboratory, Children's Hospital Boston and Harvard Medical School, Boston, MA 02115, USA.
Curr Biol. 2012 Oct 9;22(19):1747-54. doi: 10.1016/j.cub.2012.07.011. Epub 2012 Aug 2.
During epithelial morphogenesis, a complex comprising the βPIX (PAK-interacting exchange factor β) and class I PAKs (p21-activated kinases) is recruited to adherens junctions. Scrib, the mammalian ortholog 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. Although 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.
在上皮形态发生过程中，包含βPIX（PAK 相互作用交换因子β）和 I 类 PAK（p21 激活激酶）的复合物被招募到黏着连接。哺乳动物 Scrib 的同源物 Scribble 是果蝇极性决定因子和肿瘤抑制因子，它直接与βPIX 结合。Scrib 也通过 E-钙黏蛋白靶向黏着连接，在那里 Scrib 增强了钙黏蛋白介导的细胞-细胞黏附。虽然 Scrib-βPIX-PAK 信号复合物在促进伤口边缘的膜突形成中的作用已经阐明，但该复合物在黏着连接中的功能仍然未知。
在这里，我们确定 Scrib 将βPIX 和 PAK2 靶向到黏着连接，在那里，βPIX-PAK2 复合物平衡由 Scrib 和由钙黏蛋白介导的细胞-细胞黏附引起的凋亡刺激。此外，我们表明，这种信号通路调节细胞对渗透压应激的存活。最后，我们确定在悬浮培养中，Scrib-βPIX-PAK2 复合物通过调节钙黏蛋白结合引发的细胞凋亡来发挥作用，其中 Scrib 促进，而βPIX-PAK2 复合物抑制细胞凋亡。
我们的研究结果表明，当定位于极化上皮的黏着连接时，Scrib-βPIX-PAK2 信号复合物作为细胞存活的重要调节剂。该复合物在黏着连接处的活性对于正常的上皮形态发生和对生理应激的耐受至关重要。此外，当定位于黏着连接时，Scrib-βPIX-PAK2 信号复合物作为细胞凋亡敏感性的关键决定因素，这是肿瘤抑制的一个重要机制。因此，这项工作还揭示了需要将细胞凋亡的定义扩展到包括黏着连接的核心作用。
