Glycosylation Provides Both Stimulatory and Inhibitory Effects on Cell Surface and Soluble CD44 Binding to Hyaluronan

doi:10.1083/jcb.140.2.431

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© The Rockefeller University Press, 0021-9525/1998//431 $5.00
The Journal of Cell Biology, Volume 140, Number 2, , 1998 431-446

Article

Glycosylation Provides Both Stimulatory and Inhibitory Effects on Cell Surface and Soluble CD44 Binding to Hyaluronan

Timothy P. Skelton, Chunxun Zeng, Aaron Nocks, and Ivan Stamenkovic

Department of Pathology, Harvard Medical School and Pathology Research, Massachusetts General Hospital, Charlestown Navy Yard, Boston, Massachusetts 02129

Glycosylation has been implicated in the regulation of CD44-mediatedcell binding of hyaluronan (HA). However, neither the relativecontribution of N- and O-linked glycans nor the oligosaccharidestructures that alter CD44 affinity for HA have been elucidated. To determine the effect of selective alteration of CD44 oligosaccharidecomposition on the affinity of CD44 for HA, we developed anovel strategy based on the use of affinity capillary electrophoresis(ACE). Soluble recombinant CD44–immunoglobulin fusionproteins were overproduced in the mutant CHO cell line ldl-D, which has reversible defects in both N- and O-linked oligosaccharidesynthesis. Using this cell line, a panel of recombinant glycosidases,and metabolic glycosidase inhibitors, CD44 glycoforms withdefined oligosaccharide structures were generated and testedfor HA affinity by ACE. Because ldl-D cells express endogenous cell surface CD44, the effect of any given glycosylation changeon the ability of cell surface and soluble CD44 to bind HAcould be compared. Four distinct oligosaccharide structureswere found to effect CD44-mediated HA binding: (a) the terminal ${alpha}$ 2,3-linked sialic acid on N-linked oligosaccharides inhibitedbinding; (b) the first N-linked N-acetylglucosamine residueenhanced binding; (c) O-linked glycans on N-deglycosylated CD44 enhanced binding; and (d) N-acetylgalactosamine incorporationinto non–N-linked glycans augmented HA binding by cellsurface CD44. The first three structures induced up to a 30-foldalteration in the intrinsic CD44 affinity for HA (K_d = 5 to>150 µM). The fourth augmented CD44-mediated cellular HA avidity without changing the intrinsic HA affinity of solubleCD44.

Abbreviations used in this paper: ACE, affinity capillary electrophoresis; CE, capillary electrophoresis; dMM, deoxymannojirimycin; Endo H, endoglycosidase H; GAG, glycosaminoglycan; Gal, galactose; GalNAc, N-acetylgalactosamine; GlcNAc, N-acetylglucosamine; HA, hyaluronan; HA60, hyaluronan 60-mer; K_d, dissociation constant; KIF, kifunensine; MO, mesityl oxide; PNGase-F, peptide N-glycosidase-F; Rg, receptorglobulin; R_M, relative mobility; wt, wild type.

Address all correspondence to Ivan Stamenkovic, Department ofPathology, Harvard Medical School and Pathology Research, Massachusetts General Hospital East, 149 13th Street, Charlestown Navy Yard,Boston, MA 02129. Tel: (617) 726-5634. Fax: (617) 726-5684.

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