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Updated: Nov 13, 2025
Identification of Alternative Splicing and Polyadenylation in RNA-seq Data
Published on: June 24, 2021
Evidence for discrete modes of YAP1 signaling via mRNA splice isoforms in development and diseases
Jan Vrbský1, Vladimir Vinarský2, Ana Rubina Perestrelo1
1International Clinical Research Center (ICRC), St Anne's University Hospital, CZ-65691 Brno, Czech Republic.
Abstract:
Yes-associated protein 1 (YAP1) is a transcriptional co-activator downstream of Hippo pathway. The pathway exerts crucial roles in organogenesis and its dysregulation is associated with the spreading of different cancer types. YAP1 gene encodes for multiple protein isoforms, whose specific functions are not well defined. We demonstrate the splicing of isoform-specific mRNAs is controlled in a stage- and tissue-specific fashion. We designed expression vectors encoding for the most-represented isoforms of YAP1 with either one or two WW domains and studied their specific signaling activities in YAP1 knock-out cell lines. YAP1 isoforms display both common and unique functions and activate distinct transcriptional programs, as the result of their unique protein interactomes. By generating TEAD-based transcriptional reporter cell lines, we demonstrate individual YAP1 isoforms display unique effects on cell proliferation and differentiation. Finally, we illustrate the complexity of the regulation of Hippo-YAP1 effector in physiological and in pathological conditions of the heart.
Insights
Yes-associated protein 1 (YAP1) isoforms have distinct functions and signaling activities. Their stage- and tissue-specific splicing impacts organogenesis and cancer, highlighting complex Hippo-YAP1 pathway regulation.
Area of Science:
- Molecular Biology
- Cell Biology
- Developmental Biology
Background:
- Yes-associated protein 1 (YAP1) is a key transcriptional co-activator in the Hippo pathway.
- Hippo pathway dysregulation is linked to cancer progression.
- The specific functions of YAP1 protein isoforms are not well understood.
Purpose of the Study:
- To investigate the isoform-specific functions of YAP1.
- To explore the regulation of YAP1 splicing.
- To understand YAP1's role in cell proliferation, differentiation, and heart conditions.
Main Methods:
- Designed expression vectors for YAP1 isoforms.
- Studied isoform signaling in YAP1 knock-out cell lines.
- Utilized TEAD-based transcriptional reporter cell lines.
Main Results:
- YAP1 mRNA splicing is stage- and tissue-specific.
- YAP1 isoforms exhibit both shared and unique functions and protein interactomes.
- Individual YAP1 isoforms differentially affect cell proliferation and differentiation.
- The regulation of Hippo-YAP1 effectors in the heart is complex.
Conclusions:
- YAP1 isoforms possess distinct functional properties.
- Isoform-specific functions contribute to diverse biological processes.
- Understanding YAP1 isoform complexity is crucial for studying organogenesis and cancer, particularly in the heart.
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