The Evolutionary History of YAP and the Hippo/YAP Pathway
Open accessAbstract
The Hippo/YAP pathway plays an important role in animal organ size control, which it exerts by regulating tissue proliferation and apoptosis rates as a response to developmental cues, cell contact, and density. With the ever increasing advance in genome sequencing and analysis tools, our understanding of the animal world and its evolution has greatly increased in the recent years. We used bioinformatic tools to study the evolution of the Hippo/YAP pathway focusing on the transcriptional coactivator YAP, which is a pivotal effector of the pathway. The aim was to establish the origin and mode of development of YAP and its pathway in the animal world. Some pathway members can be already identified in single-celled eukaryotes like the yeast that have preceded multicellular animals. Interestingly, we can find most of the components that are present in human in the sea-anemone Nematostella, which belongs to a very basal group of metazoans, the cnidarians. All the major domains of YAP have been conserved between cnidarians and mammals, and YAP can be identified even in the more basal placozoan clade. We show a very high degree of conservation in regions such as the WW and the TEAD-binding domains, TEAD being the major DNA-binding partner of YAP. Remarkably, we found that the location of an intron in the WW1 genomic region has been invariant along an evolutionary span of over 700 My. We have followed the evolutionary changes in YAP and in other main components of the pathway from the first metazoans such as sponges, described the phylogenetic relationships between the YAP genes and indicated where YAP and other components have been secondarily lost. Evidence is provided that YAP and its binding partner TEAD demonstrate strong coevolution. This gives further support for the importance of the TEAD-YAP association. Beyond contributing to an understanding of the evolutionary history of this pathway, we have provided insights into the "birth" of this pathway, its functions and its mode of operation in animals with different body plans, development, and life styles.
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The Hippo pathway is highly conserved evolutionarily.
“The Hippo pathway is highly conserved evolutionarily (60).”
From The Hippo signal transduction network for exercise physiologists (2016) · cites this paper as [60]
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- Authors
- Hilman, D., & Gat, U.
- Affiliations
- Hebrew University of Jerusalem (IL)
- Corresponding author
- Gat, U.
- Venue
- Molecular Biology and Evolution
- Publisher
- Oxford University Press (OUP)
- Published
- 2011-03-16
- Volume
- 28
- Issue
- 8
- Pages
- 2403-2417
- ISSN
- 0737-4038 (ISSN-L)
- 1537-1719
- OpenAlex
- W2131418202
- Cited by
- 166
- References
- 88
- Citations by year
- 2026: 7 · 2025: 9 · 2024: 7 · 2023: 13 · 2022: 16 · 2021: 17 · 2020: 14 · 2019: 13 · 2018: 12 · 2017: 10 · 2016: 7 · 2015: 6 · 2014: 17 · 2013: 9 · 2012: 8
- FWCI
- 5.37
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular Biology and Evolution (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Hebrew University of Jerusalem
- Israel Science Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Physical Sciences › Earth and Planetary Sciences › Paleontology › Marine Invertebrate Physiology and Ecology
- Keywords
- YAP, Hippo signaling pathway, TEAD, organ size control, tissue proliferation, apoptosis, evolution of signaling pathways, Nematostella, Cnidaria, placozoans, sponges, WW domain, intron conservation, gene loss, coevolution, phylogenetic relationships, multicellular animals
- MeSH terms
- Amino Acid Sequence, Animals, Base Sequence, Humans, Introns, Molecular Sequence Data, Phylogeny, Protein Binding, Transcription Factors, Molecular Structure, Signal Transduction, Sequence Alignment, Evolution, Molecular, Amino Acid Motifs, Gene Order, Intracellular Signaling Peptides and Proteins
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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