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ERK-Mediated Phosphorylation of YAP Defines a Noncanonical FGF Signaling Mechanism in Stem Cells.

Overview

Authors: Xiaolei Zhao1,2, Shannon Erhardt1,3, Li Tang4,5,6, Xiaotong Chen1, Stephen M Farmer3,7, Zixiu Cheng1, Wen Chen1, Ella Ziyuan Lu8, Kihan Sung8,9, Chang‐Ru Tsai6, Mingjie Zheng1,10, Sheng Zhang3,7,11, Yang Liu3,12, Jianxin Wang5, Min Li5, James F Martin6,13, Jun Wang1,3
ORCID iDs: Xiaolei Zhao, Shannon Erhardt, Stephen M Farmer, Jun Wang
13 affiliations
  1. Department of Pediatrics, McGovern Medical School, University of Texas Health Science Center At Houston (UTHealth), Houston, Texas, USA
  2. Department of Diagnostic and Biomedical Sciences, School of Dentistry, UTHealth, Houston, Texas, USA
  3. MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, University of Texas, Houston, Texas, USA
  4. (Currently) Department of Genetics, Yale School of Medicine, New Haven, Connecticut, USA
  5. Hunan Provincial Key Lab on Bioinformatics, School of Computer Science and Engineering, Central South University, Changsha, Hunan, China
  6. Department of Integrative Physiology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, USA
  7. The Brown Foundation Institute of Molecular Medicine, McGovern Medical School At UTHealth, Houston, Texas, USA
  8. Department of BioSciences, Rice University, Houston, Texas, USA
  9. (Currently) Harvard School of Dental Medicine, Harvard University, Boston, Massachusetts, USA
  10. (Currently) Department of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
  11. Department of Neurobiology and Anatomy, McGovern Medical School At UTHealth, Houston, Texas, USA
  12. Department of Integrative Biology and Pharmacology, McGovern Medical School At UTHealth, Houston, Texas, USA
  13. Cardiomyocyte Renewal Laboratory, Texas Heart Institute, Baylor College of Medicine, Houston, Texas, USA
Institutions: The University of Texas Health Science Center at Houston (United States); The University of Texas MD Anderson Cancer Center (United States); Central South University (China); Baylor College of Medicine (United States); Yale University (United States); Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases (United States); Rice University (United States); Harvard University (United States); First Affiliated Hospital Zhejiang University (China); Zhejiang University (China)
Journal: Advanced science (Weinheim, Baden-Wurttemberg, Germany), volume 13, issue 37, article e11484
Dates: received 22 June 2025; accepted 1 April 2026; published online 10 April 2026; in print July 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1002/advs.202511484 · PMID 41961483 · PMCID PMC13334658 · OpenAlex W7152993026
Open access: gold, a free copy (OpenAlex)
Status: data only
Categories: human (organism), mouse (organism), cellular / molecular (subfield)
Methods: Statistics
Keywords: ERK, FGF signaling, neural crest cell, suture mesenchymal cells, YAP
MeSH: Adaptor Proteins, Signal Transducing*, Cell Cycle Proteins*, Fibroblast Growth Factors*, MAP Kinase Signaling System*, Neural Crest*, Stem Cells*, Transcription Factors*, Animals, Cell Proliferation, Humans, Mice, Osteogenesis, Phosphorylation, Signal Transduction, YAP-Signaling Proteins (* major topic)
Topic: Hippo pathway signaling and YAP/TAZ (Cell Biology, Biochemistry, Genetics and Molecular Biology), according to OpenAlex
Funding: NIH HHS (F31HL176166, K99DE033506, R01DE029014, K01DE026561, R01HL142704); National Institutes of Health (F31HL176166, R01HL142704, K01DE026561, K99DE033506, R01DE029014); NIDCR NIH HHS (K99 DE033506)
Citations: cited by 1 paper (Europe PMC); 78 references in the paper

Abstract

While Fgf and Hippo‐Yap signaling are fundamental for proper development, homeostasis, and disease, their crosstalk remains largely unknown. Here, we identified that Yap and Taz, canonical Hippo effectors, function as noncanonical effectors of Fgf signaling to maintain the proper function of neural crest (NC) lineages. NC cells are a multipotent stem cell population during vertebrate embryogenesis that contribute to numerous structures and diverse cell lineages, including craniofacial and cardiac tissues, neurons, and suture mesenchymal cells (SMCs), a specified cell population required for cranial bone growth and repair. We observed that activation of Fgf signaling in NC cells and NC‐derived SMCs inhibited osteogenesis while simultaneously enhancing stemness and proliferation. Interestingly, these effects were reversed by inhibition of either Yap/Taz or phosphorylated Erk1/2 (pErk1/2). Mechanistically, Fgf signaling promotes the interaction of Yap and pErk1/2, increasing the chromatin occupancy of Yap at genes regulating stemness, proliferation, and osteogenesis. We further show that pERK1/2 phosphorylates YAP at the noncanonical S128 site, enhancing YAP's nuclear localization. This mechanism is conserved across mouse and human cells and is active in Apert syndrome‐associated FGF gain‐of‐function models, revealing a previously unrecognized FGF‐YAP axis in stem cell regulation.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

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Data

Datasets cited

Data Availability Statement

Further information and requests for resources and reagents should be directed to and will be fulfilled by the Lead Contacts, Xiaolei Zhao, (Xiaolei.) and Jun Wang (Jun.). The CUT&Tag datasets for YAP1, H3K4me3 and IgG have been deposited to the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus under the accession number GSE287587 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE287587). Bulk RNA‐seq datasets of O9‐1 NC cells treated under various conditions at d2.5 and d5 of osteoblast differentiation have been deposited to the NCBI Gene Expression Omnibus under accession number GSE287588 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE287588). The CUT&RUN datasets for YAP1, H3K27me3 and IgG have been deposited to the NCBI Gene Expression Omnibus under the accession number GSE154332 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE154332). Bulk RNA‐seq datasets for O9‐1 NC cells under different conditions have been deposited to the NCBI Gene Expression Omnibus under accession number GSE287588 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE287588). All other data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 29 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 17 authors, 5 keywords, 15 MeSH terms, 3 funders, 78 references.

Cite

This paper

Zhao, X., Erhardt, S., Tang, L., Chen, X., Farmer, S. M., Cheng, Z., Chen, W., Lu, E. Z., Sung, K., Tsai, C., Zheng, M., Zhang, S., Liu, Y., Wang, J., Li, M., Martin, J. F., & Wang, J. (2026). ERK-Mediated Phosphorylation of YAP Defines a Noncanonical FGF Signaling Mechanism in Stem Cells. Advanced science (Weinheim, Baden-Wurttemberg, Germany), 13(37), e11484. https://doi.org/10.1002/advs.202511484

BibTeX

@article{zhao2026erk,
author = {Zhao, Xiaolei and Erhardt, Shannon and Tang, Li and Chen, Xiaotong and Farmer, Stephen M and Cheng, Zixiu and Chen, Wen and Lu, Ella Ziyuan and Sung, Kihan and Tsai, Chang‐Ru and Zheng, Mingjie and Zhang, Sheng and Liu, Yang and Wang, Jianxin and Li, Min and Martin, James F and Wang, Jun},
title = {{ERK-Mediated Phosphorylation of YAP Defines a Noncanonical FGF Signaling Mechanism in Stem Cells}},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
year = {2026},
month = apr,
volume = {13},
number = {37},
pages = {e11484},
publisher = {Wiley},
issn = {2198-3844},
doi = {10.1002/advs.202511484},
url = {https://doi.org/10.1002/advs.202511484},
pmid = {41961483},
pmcid = {PMC13334658}
}

RIS

TY - JOUR
AU - Zhao, Xiaolei
AU - Erhardt, Shannon
AU - Tang, Li
AU - Chen, Xiaotong
AU - Farmer, Stephen M
AU - Cheng, Zixiu
AU - Chen, Wen
AU - Lu, Ella Ziyuan
AU - Sung, Kihan
AU - Tsai, Chang‐Ru
AU - Zheng, Mingjie
AU - Zhang, Sheng
AU - Liu, Yang
AU - Wang, Jianxin
AU - Li, Min
AU - Martin, James F
AU - Wang, Jun
TI - ERK-Mediated Phosphorylation of YAP Defines a Noncanonical FGF Signaling Mechanism in Stem Cells
T2 - Advanced science (Weinheim, Baden-Wurttemberg, Germany)
J2 - Adv Sci (Weinh)
PY - 2026
DA - 2026/04/10
VL - 13
IS - 37
SP - e11484
SN - 2198-3844
PB - Wiley
DO - 10.1002/advs.202511484
UR - https://doi.org/10.1002/advs.202511484
LA - en
ER -

CSL-JSON

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