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

Abstract:

: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 beta-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.

journal_name

Glia

journal_title

Glia

authors

Sudhalter J,Whitehouse L,Rusche JR,Marchionni MA,Mahanthappa NK

doi

10.1002/(SICI)1098-1136(199605)17:1<28::AID-GLIA3>

subject

Has Abstract

pub_date

1996-05-01 00:00:00

pages

28-38

issue

1

eissn

0894-1491

issn

1098-1136

pii

10.1002/(SICI)1098-1136(199605)17:1<28::AID-GLIA3>

journal_volume

17

pub_type

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