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journal article·2026-07Open access

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

Xiaolei Zhao, Shannon Erhardt, Li Tang, Xiaotong Chen, Stephen M Farmer, Zixiu Cheng, Wen Chen, Ella Ziyuan Lu, Kihan Sung, Chang‐Ru Tsai, Mingjie Zheng, Sheng Zhang, Yang Liu, Jianxin Wang, Min Li, James F Martin, Jun Wang

Advanced Science· Volume 13· Issue 37
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Source abstract

Abstract

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.
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Research context

OpenAlex topics: Hippo pathway signaling and YAP/TAZ · Developmental Biology and Gene Regulation · Zebrafish Biomedical Research Applications

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of Pediatrics McGovern Medical School University of Texas Health Science Center At Houston (UTHealth) Houston Texas USA

Department of Diagnostic and Biomedical Sciences School of Dentistry, UTHealth Houston Texas USA

MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences University of Texas Houston Texas USA

(Currently) Department of Genetics Yale School of Medicine New Haven Connecticut USA

Hunan Provincial Key Lab on Bioinformatics School of Computer Science and Engineering Central South University Changsha Hunan China

Department of Integrative Physiology Baylor College of Medicine One Baylor Plaza Houston Texas USA

The Brown Foundation Institute of Molecular Medicine McGovern Medical School At UTHealth Houston Texas USA

Department of BioSciences Rice University Houston Texas USA

(Currently) Harvard School of Dental Medicine Harvard University Boston Massachusetts USA

(Currently) Department of Cardiology The First Affiliated Hospital Zhejiang University School of Medicine Hangzhou China

Department of Neurobiology and Anatomy McGovern Medical School At UTHealth Houston Texas USA

Department of Integrative Biology and Pharmacology McGovern Medical School At UTHealth Houston Texas USA

Cardiomyocyte Renewal Laboratory Texas Heart Institute Baylor College of Medicine Houston Texas USA

Funding

National Institutes of Health

References (78)

Show source-provided references
1. 10.4103/0973-029X.16453610.4103/0973-029X.164536 ↗
2. The neural crest
3. 10.1002/dvdy.2083310.1002/dvdy.20833 ↗
4. 10.1159/00049310610.1159/000493106 ↗
5. 10.1038/ncb313910.1038/ncb3139 ↗
6. 10.1038/ncomms1052610.1038/ncomms10526 ↗
7. 10.1016/j.cell.2020.11.03710.1016/j.cell.2020.11.037 ↗
8. 10.1038/s41586-023-06526-210.1038/s41586-023-06526-2 ↗
9. 10.1038/s41467-021-24917-910.1038/s41467-021-24917-9 ↗
10. 10.1242/dev.20211610.1242/dev.202116 ↗
11. 10.1021/acsbiomaterials.0c0087810.1021/acsbiomaterials.0c00878 ↗
12. 10.1038/nature0602710.1038/nature06027 ↗
13. 10.1186/s12964-018-0307-110.1186/s12964-018-0307-1 ↗
14. 10.7554/eLife.3384510.7554/eLife.33845 ↗
15. 10.1016/j.stem.2012.01.01410.1016/j.stem.2012.01.014 ↗
16. 10.1038/ng0295-16510.1038/ng0295-165 ↗
17. 10.1007/s00223-013-9701-210.1007/s00223-013-9701-2 ↗
18. 10.1242/dev.20426410.1242/dev.204264 ↗
19. 10.1016/j.ydbio.2016.03.02610.1016/j.ydbio.2016.03.026 ↗
20. 10.1073/pnas.091220310710.1073/pnas.0912203107 ↗
21. 10.1161/CIRCULATIONAHA.121.05877710.1161/CIRCULATIONAHA.121.058777 ↗
22. 10.1161/CIRCRESAHA.121.31896610.1161/CIRCRESAHA.121.318966 ↗
23. 10.1016/j.tcb.2012.04.00610.1016/j.tcb.2012.04.006 ↗
24. 10.1038/ncb230310.1038/ncb2303 ↗
25. 10.1242/dev.04550010.1242/dev.045500 ↗
26. Hippo‐YAP Signaling Controls Lineage Differentiation of Mouse Embryonic Stem Cells Through Modulating the Formation of Super‐Enhancers
27. 10.1242/dev.17986110.1242/dev.179861 ↗
28. 10.1371/journal.pgen.100461810.1371/journal.pgen.1004618 ↗
29. 10.1073/pnas.101960310810.1073/pnas.1019603108 ↗
30. 10.1016/j.bbrc.2010.02.03410.1016/j.bbrc.2010.02.034 ↗
31. 10.3389/fcell.2021.70662310.3389/fcell.2021.706623 ↗
32. 10.1242/dev.20086010.1242/dev.200860 ↗
33. 10.1126/scisignal.abn900910.1126/scisignal.abn9009 ↗
34. 10.1016/j.devcel.2020.03.00510.1016/j.devcel.2020.03.005 ↗
35. 10.3389/fcell.2023.111289010.3389/fcell.2023.1112890 ↗
36. 10.1242/dev.0191410.1242/dev.01914 ↗
37. 10.1016/j.celrep.2020.10787110.1016/j.celrep.2020.107871 ↗
38. 10.1089/scd.2012.015510.1089/scd.2012.0155 ↗
39. 10.1038/cdd.2010.5710.1038/cdd.2010.57 ↗
40. 10.1083/jcb.20040918210.1083/jcb.200409182 ↗
41. 10.1073/pnas.12118379810.1073/pnas.121183798 ↗
42. 10.1371/journal.ppat.100036610.1371/journal.ppat.1000366 ↗
43. 10.1016/S0304-3940(00)01229-510.1016/S0304-3940(00)01229-5 ↗
44. 10.1158/0008-5472.CAN-05-415810.1158/0008-5472.CAN-05-4158 ↗
45. 10.1038/s41598-021-97133-610.1038/s41598-021-97133-6 ↗
46. 10.1016/j.cell.2011.02.03110.1016/j.cell.2011.02.031 ↗
47. 10.1073/pnas.040186610110.1073/pnas.0401866101 ↗
48. 10.1038/3500006510.1038/35000065 ↗
49. 10.1371/journal.pcbi.100090810.1371/journal.pcbi.1000908 ↗
50. 10.1038/srep1112710.1038/srep11127 ↗
51. 10.1074/jbc.M01002120010.1074/jbc.M010021200 ↗
52. 10.1242/dev.127.9.184510.1242/dev.127.9.1845 ↗
53. 10.1002/jbmr.39410.1002/jbmr.394 ↗
54. 10.1126/science.107253010.1126/science.1072530 ↗
55. 10.1038/s41580-023-00644-510.1038/s41580-023-00644-5 ↗
56. 10.1016/j.tibs.2020.08.01210.1016/j.tibs.2020.08.012 ↗
57. 10.1016/j.celrep.2013.05.02910.1016/j.celrep.2013.05.029 ↗
58. 10.7150/ijbs.2237310.7150/ijbs.22373 ↗
59. 10.1242/dev.126.24.561110.1242/dev.126.24.5611 ↗
60. 10.1097/00001665-200107000-0001910.1097/00001665-200107000-00019 ↗
61. Simultaneous Induction of Apoptosis, Collagen Type I Expression and Mineralization in the Developing Coronal Suture Following FGF4 and FGF2 Application
62. 10.1210/endo.138.9.537010.1210/endo.138.9.5370 ↗
63. Characteristics of the Infant Apert Skull and Its Subsequent Development
64. 10.1016/j.cell.2015.10.04410.1016/j.cell.2015.10.044 ↗
65. 10.1038/nm.189310.1038/nm.1893 ↗
66. 10.1016/j.bbamcr.2006.11.00110.1016/j.bbamcr.2006.11.001 ↗
67. 10.15252/embr.20164268110.15252/embr.201642681 ↗
68. 10.1128/MCB.01549-0810.1128/MCB.01549-08 ↗
69. 10.1016/j.devcel.2018.12.02110.1016/j.devcel.2018.12.021 ↗
70. 10.1038/s41368-020-00110-410.1038/s41368-020-00110-4 ↗
71. 10.1158/2159-8290.CD-24-083610.1158/2159-8290.CD-24-0836 ↗
72. 10.1073/pnas.131319211010.1073/pnas.1313192110 ↗
73. 10.1242/dev.12692010.1242/dev.126920 ↗
74. 10.1242/dev.13084910.1242/dev.130849 ↗
75. 10.1242/dev.17560410.1242/dev.175604 ↗
76. 10.1038/s41596-020-0373-x10.1038/s41596-020-0373-x ↗
77. 10.1101/06001210.1101/060012 ↗
78. 10.1371/journal.pone.001859410.1371/journal.pone.0018594 ↗