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Peer-reviewedCC BY-NC 4.0The Korean Journal of Physiology & Pharmacology : Official Journal of the Korean Physiological Society and the Korean Society of Pharmacology

βKlotho filters ligand-independent FGFR1/4-PLCγ signaling to prevent aberrant constitutive Ca2+ entry

  • Bao T. N. Dang1,2,3,4
  • Phan Anh Nguyen1,2,3,4
  • Subo Lee1,2,3,4
  • Hyungmin Jeong1,3,4,5
  • Seung-Kuy Cha1,2,3,4
5 affiliations
  1. 1Department of Physiology, Yonsei University Wonju College of Medicine Wonju 26426 Korea
  2. 2Department of Global Medical Science, Yonsei University Wonju College of Medicine Wonju 26426 Korea
  3. 3Organelle Medicine Research Center, Yonsei University Wonju College of Medicine Wonju 26426 Korea
  4. 4Institute of Mitochondrial Medicine, Yonsei University Wonju College of Medicine Wonju 26426 Korea
  5. 5Department of Medicine, Yonsei University Wonju College of Medicine Wonju 26426 Korea
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Abstract

Fibroblast growth factor receptors 1 and 4 (FGFR1/4) regulate diverse cellular processes, including proliferation, differentiation, and metabolic homeostasis. Although ligand-dependent FGFR signaling has been extensively characterized, the signaling properties of these receptors in their ligand-independent state remain poorly understood. Here, we investigated the intrinsic signaling outputs of FGFR1 and FGFR4 in the absence of ligands using quantitative immunoblotting and electrophysiological analyses. Overexpression of FGFR1 or FGFR4 alone robustly increased the phosphorylation of phospholipase Cγ (PLCγ) and extracellular signal-regulated kinase 1/2 (ERK1/2), whereas activation of the PI3K–Akt pathway was minimal. Strikingly, co-expression of the co-receptor βKlotho acted as a molecular switch, selectively suppressing FGFR-driven PLCγ phosphorylation while preserving ERK1/2 signaling. Functionally, this βKlotho-dependent attenuation of PLCγ signaling markedly reduced the sustained TRPC6-mediated currents observed in βKlotho-deficient cells, linking constitutive FGFR–PLCγ coupling to aberrant Ca²+ influx. Together, our findings identify βKlotho as a specialized signaling filter that safeguards FGFR signaling fidelity by uncoupling deleterious PLCγ–TRPC6 signaling while maintaining canonical MAPK output. These results reveal a previously unrecognized ligand-independent role of βKlotho in reconfiguring the FGFR signaling architecture.

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Cite

BibTeXRIS
BibTeX
@article{dang2026βklotho,
  title = {{βKlotho filters ligand-independent FGFR1/4-PLCγ signaling to prevent aberrant constitutive Ca2+ entry}},
  author = {Bao T. N. Dang and Phan Anh Nguyen and Subo Lee and Hyungmin Jeong and Seung-Kuy Cha},
  journal = {The Korean Journal of Physiology \& Pharmacology : Official Journal of the Korean Physiological Society and the Korean Society of Pharmacology},
  year = {2026},
  month = nov,
  doi = {10.4196/kjpp.26.060},
  url = {https://doi.org/10.4196/kjpp.26.060},
  note = {CC BY-NC 4.0},
}
RIS
TY  - JOUR
TI  - βKlotho filters ligand-independent FGFR1/4-PLCγ signaling to prevent aberrant constitutive Ca2+ entry
AU  - Bao T. N. Dang
AU  - Phan Anh Nguyen
AU  - Subo Lee
AU  - Hyungmin Jeong
AU  - Seung-Kuy Cha
PY  - 2026
DA  - 2026/11/01
JO  - The Korean Journal of Physiology & Pharmacology : Official Journal of the Korean Physiological Society and the Korean Society of Pharmacology
DO  - 10.4196/kjpp.26.060
UR  - https://doi.org/10.4196/kjpp.26.060
AB  - Fibroblast growth factor receptors 1 and 4 (FGFR1/4) regulate diverse cellular processes, including proliferation, differentiation, and metabolic homeostasis. Although ligand-dependent FGFR signaling has been extensively characterized, the signaling properties of these receptors in their ligand-independent state remain poorly understood. Here, we investigated the intrinsic signaling outputs of FGFR1 and FGFR4 in the absence of ligands using quantitative immunoblotting and electrophysiological analyses. Overexpression of FGFR1 or FGFR4 alone robustly increased the phosphorylation of phospholipase Cγ (PLCγ) and extracellular signal-regulated kinase 1/2 (ERK1/2), whereas activation of the PI3K–Akt pathway was minimal. Strikingly, co-expression of the co-receptor βKlotho acted as a molecular switch, selectively suppressing FGFR-driven PLCγ phosphorylation while preserving ERK1/2 signaling. Functionally, this βKlotho-dependent attenuation of PLCγ signaling markedly reduced the sustained TRPC6-mediated currents observed in βKlotho-deficient cells, linking constitutive FGFR–PLCγ coupling to aberrant Ca²+ influx. Together, our findings identify βKlotho as a specialized signaling filter that safeguards FGFR signaling fidelity by uncoupling deleterious PLCγ–TRPC6 signaling while maintaining canonical MAPK output. These results reveal a previously unrecognized ligand-independent role of βKlotho in reconfiguring the FGFR signaling architecture.
SN  - 1226-4512
SN  - 2093-3827
ER  -