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J. Biol. Chem., Vol. 277, Issue 22, 19315-19321, May 31, 2002

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Heparin Amplifies Platelet-derived Growth Factor (PDGF)- BB-induced PDGF -Receptor but Not PDGF -Receptor Tyrosine Phosphorylation in Heparan Sulfate-deficient Cells
EFFECTS ON SIGNAL TRANSDUCTION AND BIOLOGICAL RESPONSES^*

Charlotte Rolny, Dorothe Spillmann^§, Ulf Lindahl^§, and Lena Claesson-Welsh^¶

From the  Department of Genetics and Pathology, Uppsala University, Rudbeck Laboratory, Dag Hammarskjölds v. 20, 751 85 Uppsala, Sweden and ^§ Department of Biochemistry and Microbiology, Biomedical Center, Box 582, 751 23 Uppsala, Sweden

Platelet-derived growth factor (PDGF) induces mitogenic and migratory responses in a wide variety of cells, by activating specific receptor tyrosine kinases denoted the PDGF - and -receptors. Different PDGF isoforms bind in a distinct manner to glycosaminoglycans, particularly heparan sulfate. In the present study, we show potentiation by exogenous heparin of PDGF-BB-induced PDGF -receptor tyrosine phosphorylation in heparan sulfate-deficient Chinese hamster ovary (CHO) 677 cells. This effect was not seen for PDGF-AA treatment, and heparin lacked a potentiating effect on PDGF-BB stimulation of the PDGF -receptor. Heparin did not affect the affinity of PDGF-BB binding for the PDGF receptors on CHO 677 cells. The PDGF-BB-stimulated PDGF -receptor phosphorylation was enhanced in a dose-dependent fashion by heparin at low concentration. The effect was modulated by 2-O- and 6-O-desulfation of the polysaccharide. Maximal induction of PDGF -receptor tyrosine phosphorylation (6-fold) in CHO 677 cells was achieved by treatment with a heparin decasaccharide, but shorter oligosaccharides consisting of four or more monosaccharide units were also able to augment PDGF -receptor phosphorylation, albeit at higher concentrations. Heparin potentiated PDGF-BB-induced activation of mitogen-activated protein kinase and protein kinase B (Akt) and allowed increased chemotaxis of the CHO 677 cells toward PDGF-BB. In conclusion, heparin modulates PDGF-BB-induced PDGF -receptor phosphorylation and downstream signaling, with consequences for cellular responsiveness to the growth factor.

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