The cell surface proteoglycan syndecan-1 mediates fibroblast growth factor-2 binding and activity

Abstract

Binding of fibroblast growth factors (FGFs) to receptor tyrosine kinases (FGFRs) and signaling is facilitated by binding of FGF to heparan sulfate proteoglycans (HSPGs). There are multiple families of HSPGs, including extracellular and cell surface forms. An important and potentially controversial question is whether cell surface forms of HSPGs act as positive or negative regulators of FGF signaling. This study examines the ability of the cell surface HSPG syndecan-1 to regulate FGF binding and signaling. HSPG-deficient Raji lymphoma cells, expressing a transfected syndecan-1 cDNA (Raji S1 cells), were used as HSPG "donor" cells. BaF3 cells, expressing an FGFR1 cDNA (FR1C-11 cells), were used as FGFR "reporter" cells. Using Raji S1 cells preincubated with FGF, it was found that they formed heterotypic aggregates with FR1C-11 cells in the presence of FGF-2, but not FGF-1. In addition, the FR1C-11 cells demonstrated FGF-2, but not FGF-1, dependent survival when cultured on fixed Raji S1 cells. Thus, Raji syndecan-1 1) differentially regulates the binding and signaling of FGFs 1 and 2 and 2) acts as a positive regulator of FGF-2 signaling.

Syndecan-1 expression is up-regulated in pancreatic but not in other gastrointestinal cancers

“…Syndecan-1 plays an important role in cell-cell adhesion, in cell motility and invasiveness as well as in cell proliferation (Bernfield and Sanderson, 1990;Filla et al, 1998;Inki and Jalkanen, 1996;Jalkanen et al, 1991;Mali et al, 1994;Rapraeger et al, 1986;Rapraeger and Ott, 1998;Salmivirta and Jalkanen, 1995;Stanley et al, 1995). Thus, it is not surprising that a number of studies have examined the role of syndecan-1 in oncogenesis.…”

“…Both of these growth factors are over-expressed in pancreatic cancer and, to a lesser extent, in chronic pancreatitis (Korc et al, 1992;Yamanaka et al, 1993). The binding of these growth factors to syndecan-1 might increase the local concentration and/or activation of these growth factors, stimulating their mitogenic activity (Aviezer and Yayon, 1994;Filla et al, 1998;Klagsbrun and Baird, 1991;Yayon et al, 1991). Two observations speak against this hypothesis.…”

“…Syndecans exert their effects by functioning as a matrix receptor on the basal surface of epithelial cells as well as a co-receptor for heparinbinding growth factors (Bernfield and Sanderson, 1990;Filla et al, 1998;Rapraeger et al, 1986;Rapraeger and Ott, 1998;Salmivirta and Jalkanen, 1995;Stanley et al, 1995). Syndecan-1, which is the most extensively studied member of this family, is constitutively expressed on the surface of many mature epithelial but not mesenchymal cells, and its expression is highly regulated during embryogenesis, wound healing, and oncogenesis (Bernfield and Sanderson, 1990;Inki and Jalkanen, 1996).…”

“…It also binds to a large number of heparin-binding polypeptide growth factors, including members of the EGF-related growth factor family and members of the FGF family of ligands (Bernfield and Sanderson, 1990;Filla et al, 1998;Inki and Jalkanen, 1996;Rapraeger et al, 1986;Rapraeger and Ott, 1998;Salmivirta and Jalkanen, 1995;Stanley et al, 1995). Previous studies on the role of syndecan-1 in malignant transformation have shown that syndecan-1 expression is associated with the maintenance of epithelial morphology, anchorage-dependent growth and inhibition of invasiveness (Dhodapkar et al, 1998;Levy et al, 1996;Rapraeger et al, 1986).…”

Effect of treatment of larynx and hypopharynx carcinomas on serum syndecan-1 concentrations

“…Syndecans bind soluble growth factors and act as low affinity coreceptors, concentrating ligands and presenting them to the high affinity cell surface receptors. Syndecans bind to a large number of heparin-binding polypeptide growth factors, including members of the epidermal growth factor (EGF)-related growth factor and basic fibroblast growth factor (bFGF) families, and the hepatocyte growth factor (Bernfield et al 1999;Filla et al 1998;Seidel et al 2000a). Syndecan-1 gene contains an FGF inducible response element (FiRE), which is stimulated in some cells by bFGF and in others by EGF (Jaakkola et al 1998).…”