Common and Specific Determinants for Fibroblast Growth Factors in the Ectodomain of the Receptor Kinase Complex

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• 作者：Fen Wang ; Weiqin Lu ; Kerstin McKeehan ; Khalid Mohamedali ; Jerome L. Gabriel ; Mikio Kan ; and Wallace L. McKeehan
• 刊名：Biochemistry
• 出版年：1999
• 出版时间：January 5, 1999
• 年：1999
• 卷：38
• 期：1
• 页码：160 - 171
• 全文大小：260K
• 年卷期：v.38,no.1(January 5, 1999)
• ISSN：1520-4995

文摘

The assembly and activation of oligomeric complexes of FGF, the transmembrane receptorkinase (FGFR), and heparan sulfate transmit intracellular signals regulating growth and function of cells.An understanding of the structural relationships between the three subunits and their redundancy andspecificity is essential for understanding the ubiquitous FGF signaling system in health and disease.Previously, we reported that a primary heparin or heparan sulfate binding site resides in a distinct sequencein immunoglobulin (Ig)-like module II of the three modules of FGFR. Here we report that in the absenceof flanking sequences, isolated Ig module II of FGFR1 supports the binding of FGF-1, FGF-2, and FGF-7in respective order of affinity. None of the three FGFs detectably bind Ig module I or the IIIb and IIIcsplice variants of Ig module III in the absence of flanking sequences. Ig module I and the C-terminus ofIg module III are dispensable for high-affinity binding of FGF-1, FGF-2, and FGF-7. Alterations in highlyconserved Ig module II in the heparin binding domain and substitution of individual sequence domainsspanning the entire sequence of Ig module II with those from Ig module I obliterated FGF binding. Additionof a specific number of FGFR sequences to the C-terminus of Ig module II resulted in a gain in affinityfor FGF-7. Several site-specific alterations in the C-terminus of full-length FGFR1IIIc, an isoform thatotherwise absolutely rejects FGF-7, resulted in gain of FGF-7 binding. These results suggest that a complexof Ig module II and heparan sulfate is the base common active core of the FGFR ectodomain and thatflanking structural domains modify FGF affinity and determine specificity.