Schwann cell heparan sulfate proteoglycans play a critical role in glial growth factor/neuregulin signaling

Glial growth factors are proteins encoded by the neuregulin gene and are thought to signal via receptor tyrosine kinases. Many neuregulin gene products bind heparin, and we hypothesize that affinity for heparin may implicate cell surface heparan sulfate proteoglycans (HeSPGs) as co‐receptors for the soluble neuregulin gene product, recombinant human glial growth factor 2 (rhGGF2). Using primary rat Schwann cell cultures, we show that exogenous heparin and heparan sulfate block rhGGF2‐induced phosphorylation of putative neuregulin receptors, and block subsequent DNA synthesis; other glycosaminoglycans show no such effect. Inhibition of Schwann cell HeSPG biosynthesis by administration of β‐xyloside also blocks responsiveness to rhGGF2. In cell‐free binding assays, rhGGF2 binds heparin and heparan sulfate with high affinity, while suramin and suramin‐like molecules block this binding. These suramin‐like molecules reversibly block Schwann cell responsiveness to rhGGF2 with a rank order of potency identical to that in the cell‐free binding assay. Thus we demonstrate high affinity and specificity in the interaction of rhGGF2 with heparin‐like molecules, and show that three distinct perturbations of this interaction on Schwann cells (exogenous heparin/heparan sulfate treatment, inhibition of HeSPG biosynthesis, and treatment with suramin‐like molecules) result in a loss of responsiveness to rhGGF2. These results support a model in which HeSPGs are critical components that modulate extracellular rhGGF2 signaling interactions with appropriate receptor tyrosine kinases. © 1996 Wiley‐Liss, Inc.