Alternative splicing reverses the cell-intrinsic and cell-extrinsic pro-oncogenic potentials of YAP1
Alternative splicing reverses the cell-intrinsic and cell-extrinsic pro-oncogenic potentials of YAP1
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DOI：
10.1074/jbc.ra120.013820
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发表时间：
2020-10-09
影响因子：
4.8
通讯作者：
Hatakeyama, Masanori
中科院分区：
文献类型：
--
作者：
Ben, Chi;Wu, Xiaojing;Hatakeyama, Masanori
除了作为转录共激活因子外，YAP1还直接介导致癌磷酸酶SHP2从细胞质到细胞核的转位。在细胞质中，SHP2增强Ras-ERK信号，促进细胞增殖和运动；在细胞核中，SHP2介导基因调控。因此，阐明SHP2转运的细节对于理解其生物学作用非常重要，包括在癌症中的作用。YAP1包括多种剪接异构体，部分由由外显子6编码的伽马片段的存在(如在YAP1-2α中)或缺失(如在YAP1-2α中)所定义，该外显子6破坏了关键的亮氨酸拉链。虽然已知干扰片段会降低共激活因子的功能，但目前还不清楚该元件如何影响YAP1和SHP2之间的物理和功能关系。为了探索这个问题，我们首先证明了YAP1-2伽马不能与SHP2结合。然而，YAP1-2γ比YAP1-2α表现出更强的有丝分裂和运动生成活性，因为YAP1-2α介导的SHP2到细胞核的传递减弱了细胞质Ras-ERK信号。然而，YAP1-2伽马通过招募肿瘤抑制巨噬细胞，比YA1-2α更能赋予Lessin活体致瘤性。从机制上讲，YAP1-2伽马反式激活，YAP1-2α-SHP2复合体反转抑制单核/巨噬细胞趋化因子CCL2。因此，细胞内和细胞外的致癌前YAP1活性被外显子6的选择性剪接反向调节。值得注意的是，致癌KRAS下调了SRSF3剪接因子，防止外显子6跳过，从而创造了YAP1-2α占优势的局面，支持“冷”的免疫微环境。
In addition to acting as a transcriptional co-activator, YAP1 directly mediates translocalization of the pro-oncogenic phosphatase SHP2 from the cytoplasm to nucleus. In the cytoplasm, SHP2 potentiates RAS-ERK signaling, which promotes cell proliferation and cell motility, whereas in the nucleus, it mediates gene regulation. As a result, elucidating the details of SHP2 trafficking is important for understanding its biological roles, including in cancer. YAP1 comprises multiple splicing isoforms defined in part by the presence (as in YAP1-2 gamma) or absence (as in YAP1-2 alpha) of a gamma-segment encoded by exon 6 that disrupts a critical leucine zipper. Although the disruptive segment is known to reduce co-activator function, it is unclear how this element impacts the physical and functional relationships between YAP1 and SHP2. To explore this question, we first demonstrated that YAP1-2 gamma cannot bind SHP2. Nevertheless, YAP1-2 gamma exhibits stronger mitogenic and motogenic activities than does YAP1-2 alpha because the YAP1-2 alpha-mediated delivery of SHP2 to the nucleus weakens cytoplasmic RAS-ERK signaling. However, YAP1-2 gamma confers lessin vivotumorigenicity than does YA1-2 alpha by recruiting tumor-inhibitory macrophages. Mechanistically, YAP1-2 gamma transactivates and the YAP1-2 alpha-SHP2 complex transrepresses the monocyte/macrophage chemoattractantCCL2. Thus, cell-intrinsic and cell-extrinsic pro-oncogenic YAP1 activities are inversely regulated by alternative splicing of exon 6. Notably, oncogenic KRAS down-regulates the SRSF3 splicing factor that prevents exon 6 skipping, thereby creating a YAP1-2 alpha-dominant situation that supports a "cold" immune microenvironment.