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Kinetic model for FGF, FGFR, and proteoglycan signal transduction complex assembly
Omar A Ibrahimi1, Fuming Zhang, Sybil C Lang Hrstka
1Department of Pharmacology, New York University School of Medicine, New York, New York 10016, USA.
Biochemistry
|April 21, 2004
Summary
Fibroblast growth factor (FGF) binding to its receptor (FGFR) and heparin initiates a stepwise assembly of a ternary complex. This kinetic model explains how FGF binding to heparan sulfate proteoglycans (HSPGs) promotes FGFR association and receptor activation.
Area of Science:
- Biochemistry
- Molecular Biology
- Cell Signaling
Background:
- The fibroblast growth factor receptor (FGFR) pathway is crucial for cell growth and differentiation.
- Current models propose a ternary complex of fibroblast growth factor (FGF), FGFR, and heparin or heparan sulfate proteoglycan (HSPG) for receptor activation.
- The kinetics of this ternary complex assembly remain largely uncharacterized.
Purpose of the Study:
- To investigate the kinetics of ternary complex formation involving FGF2, FGFR1, and heparin.
- To elucidate the step-by-step mechanism of FGF-FGFR-HSPG complex assembly.
- To propose a refined model for FGFR activation based on kinetic data.
Main Methods:
- Surface Plasmon Resonance (SPR) was employed to quantify the binding kinetics of FGF2, FGFR1, and heparin interactions.
- Analysis of sensorgrams from sequential and equimolar injections of FGF2 and FGFR1 onto heparin surfaces.
- Determination of binding constants (KD) for binary interactions.
Main Results:
- Binary binding affinities were determined: FGF2/FGFR1 (KD = 62 nM), FGF2/heparin (KD = 39 nM), and FGFR1/heparin (KD = 3.2 µM).
- FGF2 significantly enhances the association of FGFR1 with heparin, indicating a sequential binding mechanism.
- The data supports a model where FGF first binds to HSPG, facilitating subsequent FGFR binding.
Conclusions:
- A stepwise model for ternary complex assembly is proposed, initiated by FGF binding to HSPG.
- FGFR and HSPG are likely unbound in the absence of FGF, with FGF acting as a crucial initiator.
- This kinetic model provides new insights into the mechanism of FGFR dimerization and activation.