Correlation Engine 2.0
Clear Search sequence regions

  • CCL2 (1)
  • cell cycle (2)
  • cytoplasm (2)
  • down regulates (1)
  • exon (3)
  • factor (3)
  • humans (1)
  • isoforms (3)
  • macrophages (2)
  • mice (1)
  • monocyte (1)
  • protein human (2)
  • ptpn11 protein, human (1)
  • segment (2)
  • SHP2 (8)
  • signal (3)
  • YAP1 (17)
  • Sizes of these terms reflect their relevance to your search.

    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 YAP1-2γ) or absence (as in YAP1-2α) of a γ-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 YAP1-2γ 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 down-regulates the SRSF3 splicing factor that prevents exon 6 skipping, thereby creating a YAP1-2α-dominant situation that supports a "cold" immune microenvironment. © 2020 Ben et al.


    Chi Ben, Xiaojing Wu, Atsushi Takahashi-Kanemitsu, Christopher Takaya Knight, Takeru Hayashi, Masanori Hatakeyama. Alternative splicing reverses the cell-intrinsic and cell-extrinsic pro-oncogenic potentials of YAP1. The Journal of biological chemistry. 2020 Oct 09;295(41):13965-13980

    Expand section icon Mesh Tags

    Expand section icon Substances

    PMID: 32763976

    View Full Text