title: The kinetics of FGF-2 binding to heparan sulfate proteoglycans and MAP kinase signaling.
abstract: Binding of growth factors to specific cell surface receptors is the first step in initiating cell signaling cascades that ultimately result in diverse activities such as proliferation, differentiation, and apoptosis. Dimerization and phosphorylation of tyrosine kinase transmembrane receptors is the typical paradigm for this activation but, for many growth factors, cell surface interactions are not limited to a single receptor type. In particular, heparin-binding growth factors, such as fibroblast growth factor-2 (FGF-2), bind to heparan sulfate proteoglycans (HSPG) on the cell surface and within the extracellular matrix (ECM), and these molecules have been viewed as accessory co-receptors serving to facilitate tyrosine kinase receptor binding. Recent studies, however, have indicated that HSPG can directly participate in signal transduction in response to FGF-2 binding. Thus, in the present study, we used mathematical modeling to examine whether the kinetics of formation of the various FGF-2 bound complexes on the cell surface correlate with the activation of the downstream mediators of FGF-2 response, Erk1/2. We find that FGF-2 binding to its receptor correlates well with Erk1/2 activation and that HSPG can modulate this response through its ability to stabilize these ligand receptor complexes. Moreover, we also observed that FGF-2 binding to HSPG correlates strongly with Erk1/2 activation under conditions where there is a loss of receptor activity, and we demonstrate that the relative amounts of signaling and non-signaling HSPG on the cell surface, as well as the presence of competing HSPG in the ECM, can impact the signal potential via this pathway. Thus, the selective regulation of specific HSPG might provide a mechanism for fine tuned modulation of heparin-binding growth factor signaling in cells where signal intensity and duration could direct cellular response toward growth, migration or differentiation.
authors.affiliation: Department of Chemical Engineering and Virginia Tech-Wake Forest University School of Biomedical Engineering and Sciences, Virginia Polytechnic Institute & State University, 141 Randolph Hall, Blacksburg, VA 24061, USA. kfw@vt.edu
authors.forename: Kimberly
authors.initials: K
authors.lastname: Forsten-Williams
authors.forename: Ceres C
authors.initials: CC
authors.lastname: Chua
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Nugent
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000378:metabolism*; D003198:Computer Simulation; D004789:Enzyme Activation; D005109:Extracellular Matrix / Q000378:metabolism*; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008954:Models, Biological; D011485:Protein Binding
chemical_list: D019812:Heparan Sulfate Proteoglycans; D016222:Fibroblast Growth Factor 2