Chimeric molecules between keratinocyte growth factor and basic fibroblast growth factor define domains that confer...

Area of Science:

• Molecular Biology
• Cell Signaling
• Protein Engineering

Background:

• Basic fibroblast growth factor (FGF) and keratinocyte growth factor (KGF) are related but have different receptor binding specificities.
• Basic FGF binds FGFR1, FGFR2, and FGFR4, while KGF binds only KGFR, an FGFR2 isoform.
• Basic FGF binds KGFR with lower affinity than KGF.

Purpose of the Study:

• To identify the specific domains responsible for the distinct receptor binding specificities of basic FGF and KGF.
• To analyze the receptor recognition and biological activity of reciprocal chimeric growth factors.

Main Methods:

• Generation of four reciprocal chimeric growth factors (BK1, BK2, KB1, KB2) between basic FGF and KGF.
• Analysis of chimera binding affinity to various fibroblast growth factor receptors (FGFRs), including KGFR.
• Assessment of biological activity, such as DNA synthesis induction in keratinocytes.

Main Results:

• BK chimeras showed similar binding to FGFR1 and FGFR4 but differed in KGFR recognition.
• KB chimeras exhibited KGF-like receptor binding and activation properties.
• Specific segments within KGF (residues 91-110) and the amino-terminal regions of both growth factors were implicated in receptor specificity and KGFR interaction.

Conclusions:

• The amino-terminal portions of basic FGF and KGF are crucial for determining their respective receptor binding specificities.
• A middle segment of KGF (residues 91-110) contributes significantly to KGFR recognition and activation.
• Chimeric analysis provides insights into the molecular basis of differential receptor binding among growth factors.