Cell migration is an essential physiological process, and aberrant migration of epithelial cells underlies many pathological conditions. However, the molecular mechanisms governing cell migration are not fully understood. We report here that growth factor-induced epithelial cell migration is critically dependent on the crosstalk of two molecular switches, namely phosphorylation switch (P-switch) and transcriptional switch (T-switch). P-switch refers to dynamic interactions of deleted in liver cancer 1 (DLC1) and PI3K with tensin-3 (TNS3), phosphatase and tensin homolog (PTEN), C-terminal tension, and vav guanine nucleotide exchange factor 2 (VAV2) that are dictated by mitogen-activated protein kinase kinase 1/2-extracellular signal-regulated protein kinase 1/2-dependent phosphorylation of TNS3, PTEN, and VAV2. Phosphorylation of TNS3 and PTEN on specific Thr residues led to the switch of DLC1-TNS3 and PI3K-PTEN complexes to DLC1-PTEN and PI3K-TNS3 complexes, whereas Ser phosphorylation of VAV2 promotes the transition of the PI3K-TNS3/PTEN complexes to PI3K-VAV2 complex. T-switch denotes an increase in C-terminal tension transcription/expression regulated by both extracellular signal-regulated protein kinase 1/2 and signal transducer and activator of transcription 3 (STAT3) via interleukin-6-Janus kinase-STAT3 signaling pathway. We have found that, the P-switch is indispensable for both the initiation and continuation of cell migration induced by growth factors, whereas the T-switch is only required to sustain cell migration. The interplay of the two switches facilitated by the interleukin-6-Janus kinase-STAT3 pathway governs a sequence of dynamic protein-protein interactions for sustained cell migration. That a similar mechanism is employed by both normal and tumorigenic epithelial cells to drive their respective migration suggests that the P-switch and T-switch are general regulators of epithelial cell migration and potential therapeutic targets.

中文翻译：

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由 MEK1/2-ERK1/2 和 IL-6-STAT3 信号轴启用的两个分子开关的动态相互作用控制响应生长因子的上皮细胞迁移。

细胞迁移是一个重要的生理过程，上皮细胞的异常迁移是许多病理条件的基础。然而，控制细胞迁移的分子机制尚不完全清楚。我们在此报告生长因子诱导的上皮细胞迁移严重依赖于两个分子开关的串扰，即磷酸化开关 (P-switch) 和转录开关 (T-switch)。P 开关是指肝癌 1 (DLC1) 和 PI3K 中缺失的与张力蛋白 3 (TNS3)、磷酸酶和张力蛋白同源物 (PTEN)、C 端张力和 vav 鸟嘌呤核苷酸交换因子 2 (VAV2) 的动态相互作用由丝裂原活化蛋白激酶激酶 1/2-细胞外信号调节蛋白激酶 1/2 依赖的 TNS3、PTEN 和 VAV2 磷酸化决定。TNS3 和 PTEN 在特定 Thr 残基上的磷酸化导致 DLC1-TNS3 和 PI3K-PTEN 复合物转变为 DLC1-PTEN 和 PI3K-TNS3 复合物，而 VAV2 的 Ser 磷酸化促进 PI3K-TNS3/PTEN 复合物向 PI3K 的转变-VAV2 复合体。T-switch 表示 C 端张力转录/表达增加，受细胞外信号调节蛋白激酶 1/2 和信号转导和转录激活因子 3 (STAT3) 通过白细胞介素 6-Janus 激酶-STAT3 信号通路调节。我们发现，P-开关对于生长因子诱导的细胞迁移的启动和持续都是必不可少的，而T-开关只需要维持细胞迁移。由白细胞介素-6-Janus 激酶-STAT3 通路促进的两个开关的相互作用控制着一系列动态蛋白质-蛋白质相互作用，以实现持续的细胞迁移。正常和致瘤上皮细胞都采用类似的机制来驱动它们各自的迁移，这表明 P 开关和 T 开关是上皮细胞迁移的一般调节器和潜在的治疗靶点。