Abstract
Polypeptides of the fibroblast growth factor (FGF) family are ubiquitous bioregulators within tissues whose activity is controlled by heparan sulfates within the pericellular matrix. FGF and the ectodomain of their transmembrane tyrosine kinase receptors (FGFR) exhibit heparin-binding domains that when juxtaposed in a FGF middle dotFGFR complex can accommodate a single, potentially bivalent, decameric polysaccharide chain in a ternary complex. Here we show that the interaction of heparin with FGF ligands is not affected by divalent cations. In contrast, the high affinity interaction (apparent Kd = 10 nM) of heparin with FGFR requires Ca2+ or Mg2+ at physiological concentrations. Divalent cations maintain FGFR in a heparan sulfate-dependent state in respect to FGF binding and an FGF- and heparan sulfate-dependent state in respect to autophosphorylation. A model is proposed where divalent cations and heparan sulfate cooperate to maintain FGFR in a conformation that restricts trans-phosphorylation between intracellular kinase domains. The restriction is overcome by FGF or constitutively as a common consequence of diverse mutations in FGFR associated with skeletal and craniofacial abnormalities.
Highlights
Members of the fibroblast growth factor (FGF)1 families of polypeptide effectors and transmembrane tyrosine kinase receptors mediate the action of circulating hormones and other extrinsic agents [1, 2] and cell-to-cell communication within tissues [3, 4]
Divalent cations had no effect on the heparin-dependent protection of FGF-1 against proteolysis (Fig. 3A), while stability of the active FGFR1 ectodomain at 37 °C, both on the cell surface or in purified form, was increased by their presence (Fig. 3B)
FGFR1␣(⌬AE), which is a mutant FGFR1␣ in which the inter-Ig loop I and II sequence containing the characteristic “acidic box” of FGFR was deleted, exhibits the same affinity as FGFR1 for both heparin and FGF [28]. These results suggest that the interaction of FGFR with divalent cations and heparin described in this study is not influenced by the presence of the acidic box sequence [29]
Summary
Members of the fibroblast growth factor (FGF)1 families of polypeptide effectors (hereafter referred to as FGF) and transmembrane tyrosine kinase receptors (hereafter referred to as FGFR) mediate the action of circulating hormones and other extrinsic agents [1, 2] and cell-to-cell communication within tissues [3, 4]. A model is proposed where divalent cations and heparan sulfate cooperate to maintain FGFR in a conformation that restricts trans-phosphorylation between intracellular kinase domains.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
