Lens differentiation is controlled by the balance between PDGF and FGF signaling
| Autor: | Honglian Yu, Gen-Sheng Feng, Fen Wang, Hongge Li, Xin Zhang, Carrie J. Shawber, Michael Bouaziz, Yingyu Mao, Xiuxia Qu |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Embryology Receptor Platelet-Derived Growth Factor alpha Fibroblast Growth Factor Physiology Cellular differentiation ERK signaling cascade Fibroblast growth factor Ligands Receptor tyrosine kinase Epithelium Mice Phosphatidylinositol 3-Kinases 0302 clinical medicine Endocrinology Cell Signaling Animal Cells Medicine and Health Sciences Biology (General) Protein-tyrosine kinase bcl-2-Associated X Protein Notch Signaling Platelet-Derived Growth Factor Receptors Notch Protein Stability General Neuroscience Signaling cascades Cell Differentiation Cell biology bcl-2 Homologous Antagonist-Killer Protein Fibroblast growth factor receptor Signal transduction Anatomy Cellular Types General Agricultural and Biological Sciences Platelet-derived growth factor receptor Research Article Signal Transduction MAPK signaling cascades QH301-705.5 Cell Survival MAP Kinase Signaling System Fibroblast Growth Factor Receptor Substrate 2 Notch signaling pathway Biology Microbiology General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Protein Domains Growth Factors Lens Crystalline Animals General Immunology and Microbiology Endocrine Physiology Embryos Biology and Life Sciences Epithelial Cells Cell Biology Fibroblast Growth Factors 030104 developmental biology Biological Tissue FOS: Biological sciences Mutation biology.protein Proto-Oncogene Proteins c-akt 030217 neurology & neurosurgery Developmental Biology |
| Zdroj: | PLoS Biology PLoS Biology, Vol 17, Iss 2, p e3000133 (2019) |
| ISSN: | 1545-7885 1544-9173 |
| Popis: | How multiple receptor tyrosine kinases coordinate cell fate determination is yet to be elucidated. We show here that the receptor for platelet-derived growth factor (PDGF) signaling recruits the p85 subunit of Phosphoinositide 3-kinase (PI3K) to regulate mammalian lens development. Activation of PI3K signaling not only prevents B-cell lymphoma 2 (BCL2)-Associated X (Bax)- and BCL2 Antagonist/Killer (Bak)-mediated apoptosis but also promotes Notch signaling to prevent premature cell differentiation. Reducing PI3K activity destabilizes the Notch intracellular domain, while the constitutive activation of Notch reverses the PI3K deficiency phenotype. In contrast, fibroblast growth factor receptors (FGFRs) recruit Fibroblast Growth Factor Receptor Substrate 2 (Frs2) and Rous sarcoma oncogene (Src) Homology Phosphatase 2 (Shp2) to activate Mitogen-Activated Protein Kinase (MAPK) signaling, which induces the Notch ligand Jagged 1 (Jag1) and promotes cell differentiation. Inactivation of Shp2 restored the proper timing of differentiation in the p85 mutant lens, demonstrating the antagonistic interaction between FGF-induced MAPK and PDGF-induced PI3K signaling. By selective activation of PI3K and MAPK, PDGF and FGF cooperate with and oppose each other to balance progenitor cell maintenance and differentiation. Author summary A central aim in understanding cell signaling is to decode the cellular logic that underlies the functional specificity of growth factors. Although these factors are known to activate a common set of intracellular pathways, they nevertheless play specific roles in development and physiology. Using lens development in mice as a model, we show that fibroblast growth factor (FGF) and platelet-derived growth factor (PDGF) antagonize each other through their intrinsic biases toward distinct downstream targets. While FGF primarily induces the Ras–Mitogen-Activated Protein Kinase (MAPK) axis to promote lens cell differentiation, PDGF preferentially stimulates Phosphoinositide 3-kinase (PI3K) to enhance Notch signaling, which is necessary for maintaining the lens progenitor cell pool. By revealing the intricate interactions between PDGF, FGF, and Notch, we present a paradigm for how signaling crosstalk enables balanced growth and differentiation in multicellular organisms. |
| Databáze: | OpenAIRE |
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