DISTINCT ROLE OF 2-O-SULFATE, N-SULFATE, AND 6-O-SULFATE GROUPS OF HEPARIN IN THE FORMATION OF THE TERNARY COMPLEX WITH BASIC FIBROBLAST GROWTH-FACTOR AND SOLUBLE FGF RECEPTOR-1
M. Rusnati et al., DISTINCT ROLE OF 2-O-SULFATE, N-SULFATE, AND 6-O-SULFATE GROUPS OF HEPARIN IN THE FORMATION OF THE TERNARY COMPLEX WITH BASIC FIBROBLAST GROWTH-FACTOR AND SOLUBLE FGF RECEPTOR-1, Biochemical and biophysical research communications, 203(1), 1994, pp. 450-458
Interaction of basic fibroblast growth factor (bFGF) with heparan sulf
ate proteoglycans (HSPGs) plays an important role in the binding of bF
GF to its tyrosine kinase receptor (FGFR). The molecular bases of this
interaction were investigated by evaluating the capacity of conventio
nal and selectively desulfated heparins i) to affect the binding of bF
GF to FGFR and HSPGs of NIH 3T3 cells transfected with FGFR-1/flg cDNA
, ii) to facilitate the interaction of bFGF with a recombinant soluble
form of the extracellular domain of FGFR-1/flg (xcFGFR-1), and iii) t
o protect xcFGFR-1 from tryptic cleavage. 6-O-desulfated (6-O-DS) hepa
rin, but not 2-O-desulfated (2-O-DS) and N-desulfated/N-acetylated (N-
DS/N-Ac) heparins, retains the capacity to bind bFGF, as assessed by i
ts ability to inhibit bFGF-binding to cell-associated FGFR-1 and HSPGs
. On the other hand, at variance with conventional heparin, 2-O-DS, N-
DS/N-Ac, and 6-O-DS heparins are all ineffective in potentiating the b
inding of bFGF to xcFGFR-1 and protecting xcFGFR-1 from tryptic cleava
ge. The data indicate that 6-O-sulfate groups are not essential for th
e interaction of heparin with bFGF but are involved in the interaction
with xcFGFR-1. Our findings support the hypothesis that HSPGs modulat
e the binding of bFGF to FGFR through the formation of a ternary compl
ex in which the glycosaminoglycan chains interact with bFGF via 2-O- a
nd N-sulfate groups and with FGFR also via 6-O-sulfate groups. (C) 199
4 Academic Press, Inc.