| First Author | Ben C | Year | 2020 |
| Journal | J Biol Chem | Volume | 295 |
| Issue | 41 | Pages | 13965-13980 |
| PubMed ID | 32763976 | Mgi Jnum | J:298036 |
| Mgi Id | MGI:6477800 | Doi | 10.1074/jbc.RA120.013820 |
| Citation | Ben C, et al. (2020) Alternative splicing reverses the cell-intrinsic and cell-extrinsic pro-oncogenic potentials of YAP1. J Biol Chem 295(41):13965-13980 |
| abstractText | 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 YAP1-2gamma) or absence (as in YAP1-2alpha) 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 YAP1-2gamma cannot bind SHP2. Nevertheless, YAP1-2gamma exhibits stronger mitogenic and motogenic activities than does YAP1-2alpha because the YAP1-2alpha-mediated delivery of SHP2 to the nucleus weakens cytoplasmic RAS-ERK signaling. However, YAP1-2gamma confers less in vivo tumorigenicity than does YA1-2alpha by recruiting tumor-inhibitory macrophages. Mechanistically, YAP1-2gamma transactivates and the YAP1-2alpha-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 down-regulates the SRSF3 splicing factor that prevents exon 6 skipping, thereby creating a YAP1-2alpha-dominant situation that supports a "cold" immune microenvironment. |
