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Screening and Identification of Small Peptides Targeting Fibroblast Growth Factor Receptor2 using a Phage Display Peptide Library
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Small Molecule Inhibitors Targeting Tec Kinase Block Unconventional Secretion of Fibroblast Growth Factor 2

Giuseppe La Venuta1, Sabine Wegehingel1, Peter Sehr2

  • 1From the Heidelberg University Biochemistry Center (BZH), Im Neuenheimer Feld 328, 69120 Heidelberg, Germany.

The Journal of Biological Chemistry
|July 7, 2016
PubMed

Insights

Researchers identified small molecules that inhibit Fibroblast Growth Factor 2 (FGF2) secretion. These compounds target the interaction between FGF2 and Tec kinase, offering potential for anti-cancer drug development by blocking tumor growth and metastasis.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Fibroblast Growth Factor 2 (FGF2) is a key mitogen driving tumor cell survival and angiogenesis.
  • FGF2 utilizes an unconventional secretory pathway involving direct plasma membrane translocation.
  • Tec kinase plays a crucial role in FGF2 secretion by promoting membrane pore formation through FGF2 tyrosine phosphorylation.

Purpose of the Study:

  • To biochemically characterize the interaction between FGF2 and Tec kinase.
  • To identify small molecules inhibiting FGF2-Tec interaction, FGF2 phosphorylation, and FGF2 secretion.
  • To validate the role of Tec kinase in FGF2 unconventional secretion and assess inhibitor specificity.

Main Methods:

  • Biochemical assays to characterize FGF2-Tec kinase interaction.
  • In vitro and cellular assays to assess inhibition of FGF2 tyrosine phosphorylation.
  • Assays to measure unconventional FGF2 secretion from cells.
  • Testing inhibitor specificity against other Tec kinase substrates.

Main Results:

  • Direct interaction between FGF2 and Tec kinase was biochemically characterized.
  • Specific small molecule inhibitors were identified that block FGF2-Tec interaction and FGF2 tyrosine phosphorylation.
  • These inhibitors effectively reduced unconventional FGF2 secretion from cells.
  • Inhibitors demonstrated specificity for FGF2, leaving other Tec kinase substrates unaffected.

Conclusions:

  • Tec kinase is confirmed to be essential for the unconventional secretion of FGF2.
  • Identified small molecules are potent inhibitors of FGF2 secretion and phosphorylation.
  • These compounds serve as promising lead candidates for developing drugs targeting FGF2-driven tumor growth and metastasis.
Keywords:
FGF2Tec kinasefibroblast growth factor (FGF)phosphoinositideprotein phosphorylationprotein secretionprotein translocationprotein translocation across membranesunconventional protein secretion

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