FGF9, a Potent Mitogen, Is a New Ligand for Integrin αvβ3, and the FGF9 Mutant Defective in Integrin Binding Acts as an Antagonist
FGF9 is a potent mitogen and survival factor, but FGF9 protein levels are generally low and restricted to a few adult organs. Aberrant expression of FGF9 usually results in cancer. However, the mechanism of FGF9 action has not been fully established. Previous studies showed that FGF1 and FGF2 direct...
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MDPI AG
2024-02-01
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| Online Access: | https://www.mdpi.com/2073-4409/13/4/307 |
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| author | Chih-Chieh Chang Yoko K. Takada Chao-Wen Cheng Yukina Maekawa Seiji Mori Yoshikazu Takada |
| author_facet | Chih-Chieh Chang Yoko K. Takada Chao-Wen Cheng Yukina Maekawa Seiji Mori Yoshikazu Takada |
| author_sort | Chih-Chieh Chang |
| collection | DOAJ |
| description | FGF9 is a potent mitogen and survival factor, but FGF9 protein levels are generally low and restricted to a few adult organs. Aberrant expression of FGF9 usually results in cancer. However, the mechanism of FGF9 action has not been fully established. Previous studies showed that FGF1 and FGF2 directly bind to integrin αvβ3, and this interaction is critical for signaling functions (FGF–integrin crosstalk). FGF1 and FGF2 mutants defective in integrin binding were defective in signaling, whereas the mutants still bound to FGFR suppressed angiogenesis and tumor growth, indicating that they act as antagonists. We hypothesize that FGF9 requires direct integrin binding for signaling. Here, we show that docking simulation of the interaction between FGF9 and αvβ3 predicted that FGF9 binds to the classical ligand-binding site of αvβ3. We show that FGF9 bound to integrin αvβ3 and generated FGF9 mutants in the predicted integrin-binding interface. An FGF9 mutant (R108E) was defective in integrin binding, activating FRS2α and ERK1/2, inducing DNA synthesis, cancer cell migration, and invasion in vitro. R108E suppressed DNA synthesis and activation of FRS2α and ERK1/2 induced by WT FGF9 (dominant-negative effect). These findings indicate that FGF9 requires direct integrin binding for signaling and that R108E has potential as an antagonist to FGF9 signaling. |
| first_indexed | 2024-03-07T22:37:38Z |
| format | Article |
| id | doaj.art-614fb72014324302bdc8aa35442eed17 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-07T22:37:38Z |
| publishDate | 2024-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-614fb72014324302bdc8aa35442eed172024-02-23T15:11:40ZengMDPI AGCells2073-44092024-02-0113430710.3390/cells13040307FGF9, a Potent Mitogen, Is a New Ligand for Integrin αvβ3, and the FGF9 Mutant Defective in Integrin Binding Acts as an AntagonistChih-Chieh Chang0Yoko K. Takada1Chao-Wen Cheng2Yukina Maekawa3Seiji Mori4Yoshikazu Takada5Department of Dermatology, University of California, Davis School of Medicine, Sacramento, CA 95817, USADepartment of Dermatology, University of California, Davis School of Medicine, Sacramento, CA 95817, USAGraduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 110, TaiwanDepartment of Medical Technology, Faculty of Health Science, Morinomiya University of Medical Sciences, Osaka 536-0025, JapanDepartment of Medical Technology, Faculty of Health Science, Morinomiya University of Medical Sciences, Osaka 536-0025, JapanDepartment of Dermatology, University of California, Davis School of Medicine, Sacramento, CA 95817, USAFGF9 is a potent mitogen and survival factor, but FGF9 protein levels are generally low and restricted to a few adult organs. Aberrant expression of FGF9 usually results in cancer. However, the mechanism of FGF9 action has not been fully established. Previous studies showed that FGF1 and FGF2 directly bind to integrin αvβ3, and this interaction is critical for signaling functions (FGF–integrin crosstalk). FGF1 and FGF2 mutants defective in integrin binding were defective in signaling, whereas the mutants still bound to FGFR suppressed angiogenesis and tumor growth, indicating that they act as antagonists. We hypothesize that FGF9 requires direct integrin binding for signaling. Here, we show that docking simulation of the interaction between FGF9 and αvβ3 predicted that FGF9 binds to the classical ligand-binding site of αvβ3. We show that FGF9 bound to integrin αvβ3 and generated FGF9 mutants in the predicted integrin-binding interface. An FGF9 mutant (R108E) was defective in integrin binding, activating FRS2α and ERK1/2, inducing DNA synthesis, cancer cell migration, and invasion in vitro. R108E suppressed DNA synthesis and activation of FRS2α and ERK1/2 induced by WT FGF9 (dominant-negative effect). These findings indicate that FGF9 requires direct integrin binding for signaling and that R108E has potential as an antagonist to FGF9 signaling.https://www.mdpi.com/2073-4409/13/4/307FGF9integrindominant-negative effectsignalingFGFR3mutagenesis |
| spellingShingle | Chih-Chieh Chang Yoko K. Takada Chao-Wen Cheng Yukina Maekawa Seiji Mori Yoshikazu Takada FGF9, a Potent Mitogen, Is a New Ligand for Integrin αvβ3, and the FGF9 Mutant Defective in Integrin Binding Acts as an Antagonist Cells FGF9 integrin dominant-negative effect signaling FGFR3 mutagenesis |
| title | FGF9, a Potent Mitogen, Is a New Ligand for Integrin αvβ3, and the FGF9 Mutant Defective in Integrin Binding Acts as an Antagonist |
| title_full | FGF9, a Potent Mitogen, Is a New Ligand for Integrin αvβ3, and the FGF9 Mutant Defective in Integrin Binding Acts as an Antagonist |
| title_fullStr | FGF9, a Potent Mitogen, Is a New Ligand for Integrin αvβ3, and the FGF9 Mutant Defective in Integrin Binding Acts as an Antagonist |
| title_full_unstemmed | FGF9, a Potent Mitogen, Is a New Ligand for Integrin αvβ3, and the FGF9 Mutant Defective in Integrin Binding Acts as an Antagonist |
| title_short | FGF9, a Potent Mitogen, Is a New Ligand for Integrin αvβ3, and the FGF9 Mutant Defective in Integrin Binding Acts as an Antagonist |
| title_sort | fgf9 a potent mitogen is a new ligand for integrin αvβ3 and the fgf9 mutant defective in integrin binding acts as an antagonist |
| topic | FGF9 integrin dominant-negative effect signaling FGFR3 mutagenesis |
| url | https://www.mdpi.com/2073-4409/13/4/307 |
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