Alternative splicing reverses the cell-intrinsic and cell-extrinsic prooncogenic potentials of YAP1.

Ben, Chi; Wu, Xiaojing; Takahashi-Kanemitsu, Atsushi; Knight, Christopher Takaya; Hayashi, Takeru; Hatakeyama, Masanori

In addition to acting as a transcriptional coactivator, 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, while 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 YAP1-2γ) or absence (as in YAP1-2α) of a γ-segment encoded by exon 6 that disrupts a critical leucine zipper. While the disruptive segment is known to reduce coactivator 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 YAP1-2γ cannot bind SHP2. Nevertheless, YAP1-2γ exhibits stronger mitogenic and motogenic activities than does YAP1-2α because the YAP1-2α-mediated delivery of SHP2 to the nucleus weakens cytoplasmic RAS-ERK signaling. However, YAP1-2γ confers less in vivo tumorigenicity than does YA1-2α by recruiting tumor-inhibitory macrophages. Mechanistically, YAP1-2γ transactivates and the YAP1-2α-SHP2 complex transrepresses the monocyte/macrophage chemoattractant CCL2. Thus, cell-intrinsic and cell-extrinsic pro-oncogenic YAP1 activities are inversely regulated by alternative splicing of exon 6. Notably, oncogenic KRAS downregulates the SRSF3 splicing factor that prevents exon 6 skipping, thereby creating a YAP1-2α-dominant situation that supports a "cold" immune microenvironment.