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Related Experiment Videos

Heparan sulfate fibroblast growth factor receptor complex: structure-function relationships

W L McKeehan1, M Kan

  • 1Center for Cancer Biology, Albert B. Alkek Institute of Biosciences and Technology, Texas A & M University, Houston 77030.

Molecular Reproduction and Development
|September 1, 1994
PubMed
Summary

Fibroblast Growth Factor Receptor (FGFR) splice variants alter receptor function and ligand binding. Models reveal FGF receptor complex involves FGF, heparan sulfate, and tyrosine kinase for signal transduction.

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Structural Biology

Background:

  • Fibroblast Growth Factor Receptors (FGFRs) are transmembrane tyrosine kinases crucial for cellular processes.
  • Alternative splicing of FGFR genes generates diverse isoforms with distinct functional domains.

Purpose of the Study:

  • To elucidate the structural and functional roles of FGFR splice variants.
  • To model the molecular interactions within the high-affinity FGF receptor complex.
  • To understand the mechanisms of FGF-mediated signal transduction.

Main Methods:

  • Expression of recombinant FGFR isoforms in baculoviral-infected insect cells.
  • Biochemical analysis of distinct FGFR isoforms.
  • Structural modeling of the FGFR ectodomain.

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  • Analysis of tyrosine phosphorylation sites and their regulation.

    • Main Results:

    • A structural model for the FGFR ectodomain was proposed, highlighting the roles of Ig Loops I, II, and III.
    • A 19-residue heparin-binding domain in Loop II is essential for FGF binding.
    • The high-affinity FGF receptor complex is a ternary interaction of FGFR, heparan sulfate, and FGF.
    • Alternative splicing of Loop III determines FGF ligand specificity.
    • FGFR type 2 splice variant demonstrated dominant-negative suppression of specific tyrosine phosphorylation events.
    • Tyrosine phosphorylation at Y766 and Y653 occurs via distinct cis-intramolecular and trans-intermolecular mechanisms.

    Conclusions:

    • FGFR splice variants significantly impact ligand binding affinity and signal transduction pathways.
    • The formation of a ternary complex involving FGFR, heparan sulfate, and FGF is critical for high-affinity binding.
    • Combinatorial alternative splicing of FGFR monomers regulates FGF-mediated signal transduction through heterodimerization.