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

ABSTRACT: 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?) or absence (as in YAP1-2?) of a ?-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? cannot bind SHP2. Nevertheless, YAP1-2? exhibits stronger mitogenic and motogenic activities than does YAP1-2? because the YAP1-2?-mediated delivery of SHP2 to the nucleus weakens cytoplasmic RAS-ERK signaling. However, YAP1-2? confers less in vivo tumorigenicity than does YA1-2? by recruiting tumor-inhibitory macrophages. Mechanistically, YAP1-2? transactivates and the YAP1-2?-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 YAP1-2?-dominant situation that supports a "cold" immune microenvironment.

SUBMITTER: Ben C 

PROVIDER: S-EPMC7549027 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature