Related Experiment Video
Updated: Dec 12, 2025
De Novo Generation of Somatic Stem Cells by YAP/TAZ
Published on: May 7, 2018
Alternative splicing reverses the cell-intrinsic and cell-extrinsic pro-oncogenic potentials of YAP1
Chi Ben1, Xiaojing Wu1, Atsushi Takahashi-Kanemitsu1
1Division of Microbiology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
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 YAP1-2γ) 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.
Insights
Alternative splicing of YAP1 exon 6 impacts cancer. YAP1-2γ enhances proliferation but reduces tumor growth by altering immune cells, while YAP1-2α promotes tumor growth via SHP2 nuclear localization.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Signaling
Background:
- YAP1 acts as a transcriptional co-activator and regulates SHP2 localization.
- SHP2's cytoplasmic role potentiates RAS-ERK signaling, promoting proliferation and motility.
- Nuclear SHP2 mediates gene regulation, highlighting the importance of its trafficking in cancer.
Purpose of the Study:
- To investigate how YAP1 splicing isoforms, specifically the presence or absence of the γ-segment (exon 6), affect YAP1's interaction with SHP2.
- To elucidate the distinct biological and oncogenic functions of YAP1-2α and YAP1-2γ isoforms.
- To understand the mechanistic basis for the differential regulation of cell-intrinsic and cell-extrinsic YAP1 activities by alternative splicing.
Main Methods:
- Demonstrated the binding affinity between YAP1 isoforms and SHP2.
- Assessed the impact of YAP1 isoforms on RAS-ERK signaling and cell proliferation/motility.
- Quantified the differences in in vivo tumorigenicity conferred by YAP1 isoforms.
- Investigated the regulation of CCL2 expression by YAP1 isoforms and the YAP1-2α-SHP2 complex.
- Examined the role of SRSF3 splicing factor in YAP1 exon 6 splicing and its relation to KRAS signaling.
Main Results:
- YAP1-2γ does not bind SHP2, unlike YAP1-2α.
- YAP1-2γ exhibits stronger mitogenic and motogenic activities than YAP1-2α.
- YAP1-2α-mediated nuclear SHP2 delivery weakens cytoplasmic RAS-ERK signaling.
- YAP1-2γ confers less in vivo tumorigenicity by recruiting tumor-inhibitory macrophages.
- YAP1-2γ transactivates, while the YAP1-2α-SHP2 complex transrepresses CCL2.
- Oncogenic KRAS downregulates SRSF3, favoring YAP1-2α and a "cold" immune microenvironment.
Conclusions:
- Alternative splicing of YAP1 exon 6 inversely regulates cell-intrinsic (proliferation/motility) and cell-extrinsic (tumor immunity) oncogenic activities.
- YAP1-2γ promotes proliferation but dampens tumorigenicity by modulating the immune microenvironment.
- YAP1-2α, favored by KRAS-induced SRSF3 downregulation, supports tumor growth and a "cold" immune phenotype.
Related Concept Videos
01:32RNA Splicing
02:18Alternative RNA Splicing
There are five types of alternative RNA splicing that vary in the ways the pre-mRNA segments are removed or retained in the mature mRNA. The first...
02:18Alternative RNA Splicing
01:06Induced Pluripotent Stem Cells
Somatic...
02:32Exon Recombination
Exon shuffling follows “splice frame rules.” Each exon...
01:31The Intrinsic Apoptotic Pathway