Proteoglycan
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Interaction of L- and P-Selectin and CD44 with Versican

 Versican (also called PG-M) consists of a hyaluronic acid binding domain at its N terminus, a glycosaminoglycan (GAG)-attachment domain at the middle, and a set of EGF-like, C-type lectin-like, and complement regulatory protein-like domains at its C terminus. Human versican gene consists of 15 exons. Alternative splicing of the versican gene generates four versican isoforms; V0, V1, and V2 bearing different length of the GAG-attachment domain, and V3 without GAG-attachment domain. Versican binds hyaluronic acid with high affinity through its hyaluronic acid-binding domain. Versican also binds sulfated glycolipids and extracellular matrix components, such as tenascin-R and fibulin-1, through its C-type lectin-like domain. The EGF-like domain of versican enhances cell proliferation, at least in part through binding to the EGF receptor. In addition, versican is known to have an anti-adhesive activity, which is mediated by its chondroitin sulfate chains.

We have previously shown that versican isolated from a human renal adenocarcinoma, ACHN, binds L- and P-selectin and CD44 through its chondroitin sulfate chains (1, 2). Versican does not bind E-selectin. Interestingly, binding of versican to L- and P-selectin is inhibited by a specific subset of GAGs including CS (chondroitin sulfate) B, CS E, and HS (heparan sulfate). In contrast, binding of versican to CD44 is inhibited by CS A, CS B, CS C, CS D, CS E, CH (chondroitin), and HA (hyaluronic acid) (2). Furthermore, L- and P-selectin directly bind immobilized CS B, CS E, and HS, whereas CD44 directly binds immobilized CS A, CS B, CS C, CS D, CS E, CH, and HA (Fig. 1). Versican from ACHN cells reactive with L- and P-selectin and CD44 is modified with CS B- and CS C-like structures. These results collectively suggest that versican modified with appropriate GAGs should be able to bind L- and P-selectin and/or CD44. We think it likely that proteoglycans modified with appropriate glycosaminoglycans have similar multifunctional activities, since L- and P-selectin and CD44 all appear to recognize specific glycosaminoglycans as described here. The clustering and sulfation of glycosaminoglycans are also likely to play an important role. Experimental verification is now required to assess the in vivo role of the interaction of versican with L- and P-selectin and CD44 under physiological as well as pathological conditions.
Fig. 1. Glycosaminoglycan-binding specificities of L- and P-selectin and CD44.
L- and P-selectin bind HS, CS B and CS E, while CD44 binds CH, CS A, CS B, CS C, CS D, CS E and HA.
HS: heparan sulfate, CS: chondroitin sulfate, CH: chondroitin, HA: hyaluronic acid
Hiroto Kawashima (Osaka University Graduate School of Medicine)
References(1)Kawashima H, Li Y-F, Watanabe N, Hirose J, Hirose M, Miyasaka M :Identification and characterization of ligands for L-selectin in the kidney.I.Versican, a large chondroitin sulfate proteoglycan, is a ligand for L-selectin. Int. Immunol. 11, 393-405, 1999
(2)Kawashima H, Hirose M, Hirose J, Nagakubo D, Plaas AHK, Miyasaka M :Binding of a large chondroitin sulfate/dermatan sulfate proteoglycan, versican, to L-selectin, P-selectin, and CD44. J. Biol. Chem. J. Biol. Chem. 275, 35448-35456, 2000
Dec.15, 2000

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