APC and Smad7 link TGFβ type I receptors to the microtubule system to promote cell migration.
APC and Smad7 link TGFβ type I receptors to the microtubule system to promote cell migration.
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DOI：
10.1091/mbc.e10-12-1000
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发表时间：
2012-06
影响因子：
3.3
通讯作者：
Landström M
中科院分区：
文献类型：
--
作者：
Ekman M;Mu Y;Lee SY;Edlund S;Kozakai T;Thakur N;Tran H;Qian J;Groeden J;Heldin CH;Landström M
Smad 7的一个新功能是在某些细胞类型的细胞迁移过程中建立细胞极性。TGFβ I型受体、Smad 7、活性p38和APC定位于极化迁移细胞的前缘。细胞迁移是通过激活复杂的调控途径发生的，这些途径在空间和时间上整合以响应细胞外信号。结肠腺瘤性息肉病（APC）与极化细胞中微管正末端的结合受糖原合成酶激酶3β（GSK-3β）的调节。这一事件对于定向迁移过程中细胞极性的建立至关重要。然而，APC在细胞外信号应答中的细胞延伸作用尚不清楚。Smad 7是转化生长因子-β（TGFβ）的直接靶基因，并且已知其抑制各种TGFβ诱导的反应。在这里，我们报告了Smad 7的一个新功能。我们发现Smad 7和p38丝裂原活化蛋白激酶共同调节前列腺癌细胞对TGFβ刺激的APC表达和细胞迁移。此外，Smad 7与APC形成复合物，并作为p38和GSK-3β激酶的接头蛋白，以促进GSK-3β的局部TGFβ/p38依赖性失活、β-连环蛋白的积累以及APC向微管的募集，以及在迁移的前列腺癌细胞的前缘中的末端。此外，Smad 7-APC复合物将TGFβ I型受体连接到微管系统以调节由TGFβ诱发的定向细胞延伸和迁移反应。
A novel function for Smad7 is demonstrated in the establishment of cell polarity during cell migration in certain cell types. TGFβ type I receptors, Smad7, active p38, and APC are localized in the leading edge of polarized, migrating cells. Cell migration occurs by activation of complex regulatory pathways that are spatially and temporally integrated in response to extracellular cues. Binding of adenomatous polyposis coli (APC) to the microtubule plus ends in polarized cells is regulated by glycogen synthase kinase 3β (GSK-3β). This event is crucial for establishment of cell polarity during directional migration. However, the role of APC for cellular extension in response to extracellular signals is less clear. Smad7 is a direct target gene for transforming growth factor-β (TGFβ) and is known to inhibit various TGFβ-induced responses. Here we report a new function for Smad7. We show that Smad7 and p38 mitogen–activated protein kinase together regulate the expression of APC and cell migration in prostate cancer cells in response to TGFβ stimulation. In addition, Smad7 forms a complex with APC and acts as an adaptor protein for p38 and GSK-3β kinases to facilitate local TGFβ/p38–dependent inactivation of GSK-3β, accumulation of β-catenin, and recruitment of APC to the microtubule plus end in the leading edge of migrating prostate cancer cells. Moreover, the Smad7–APC complex links the TGFβ type I receptor to the microtubule system to regulate directed cellular extension and migratory responses evoked by TGFβ.