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

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.