Distinct heparan sulfate glycosaminoglycans are responsible for mediating fibroblast growth factor‐2 biological activity through different fibroblast growth factor receptors

Abstract

Fibroblast growth factor (FGF) signaling is involved in many important biological processes such as smooth muscle cell (SMC) proliferation, a key event leading to atherosclerosis. It is well known that heparin/heparan sulfate‐like glycosaminoglycans (HLGAGs), found ubiquitously on the cell surface and in the extracellular matrix, modulate FGF signaling by interacting with both FGF and FGF receptor (FGFR). To study the modulatory effect of SMC‐derived HLGAGs on FGF2 signaling, we employed a panel of HLGAG‐degrading enzymes, or heparinases, to depolymerize cell surface HLGAGs isolated from SMCs and assayed their abilities to modulate FGF2 activity on engineered cell lines expressing defined FGFR isoforms. Our findings indicate that FGF2‐mediated proliferation is dependent on the composition of the SMC‐derived HLGAG fragments as well as the type of FGFR isoform expressed. We postulate that the chemical composition and sequence of HLGAGs dictate the specificity of interactions between FGF2 and a given FGFR.

Two‐Phase Electrospinning to Incorporate Polyelectrolyte Complexes and Growth Factors into Electrospun Chitosan Nanofibers

“…In the ECM of many tissues, glycosaminoglycan (GAG) side chains of proteoglycans, such as aggrecan, versican, and perlecan, serve as a repository of stabilized growth factors, and direct signaling by interacting with growth factor receptors on the cell surface. [36][37][38][39][40][41][42][43] The GAG side chains, including heparan sulfate and chondroitin sulfate, bind, stabilize, and enhance the delivery of many growth factors including members of the FGF family, the transforming growth factor-β superfamily, vascular endothelial growth factor, nerve growth factor, and platelet-derived growth factor. [ 35,44 ] A general scheme for preparing tissue engineering scaffolds might take advantage of these interactions by using GAGs to bind, stabilize, and deliver growth factors, thereby providing growth factor signaling in a stabilized and biomimetic context.…”

“…In the ECM of many tissues, glycosaminoglycan (GAG) side chains of proteoglycans, such as aggrecan, versican, and perlecan, serve as a repository of stabilized growth factors, and direct signaling by interacting with growth factor receptors on the cell surface . The GAG side chains, including heparin sulfate and chondroitin sulfate, bind, stabilize, and enhance the delivery of many growth factors including members of the FGF family, the transforming growth factor‑β superfamily, vascular endothelial growth factor, nerve growth factor, and platelet‐derived growth factor .…”

Heparan sulphate glycosaminoglycans derived from endothelial cells and smooth muscle cells differentially modulate fibroblast growth factor-2 biological activity through fibroblast growth factor receptor-1

“…Previous work from our laboratory has demonstrated that SMCderived HSGAGs modulate FGF2-HSGAG interactions through specific FGF receptor (FGFR) isoforms in a sequence-dependent manner [18]. The present study serves to extend these findings by determining how specific HSGAG structures on the cell surface of SMC, as opposed to those found on EC, influence FGF-induced proliferation.…”

Chlamydia trachomatis Co-opts the FGF2 Signaling Pathway to Enhance Infection

“…FGF2 binds to and activates most isoforms of FGFR (FGFR1 IIIb and IIIc, FGFR2 IIIc, FGFR3 IIIc, and FGFR4)[28], [29], [30], resulting in activation of their tyrosine kinase activity, autophosphorylation of tyrosine 653/654, and phosphorylation of the scaffolding protein, FRS2α, which is constitutively associated with FGFR. Upon tyrosine phosphorylation, FRS2α functions as a site for coordinated assembly of a multi-protein signaling complex, including Grb and Shp2, leading to activation of the PI3K and the Ras/Erk pathways [26].…”