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Glycobiology Advance Access published online on September 8, 2004

Glycobiology, doi:10.1093/glycob/cwh148
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Received June 8, 2004
Revised August 3, 2004
Accepted September 3, 2004

ORIGINAL ARTICLES

RANTES (CCL5) induces a CCR5-dependent accelerated shedding of syndecan-1 (CD138) and syndecan-4 from HeLa cells and forms complexes with the shed ectodomains of these proteoglycans as well as with those of CD44

Nathalie Charnaux 1, Séverine Brule 1, Thomas Chaigneau 1, Line Saffar 1, Angela Sutton 1, Morgan Hamon 1, Catherine Prost 1, Nicole Lievre 1, Claudio Vita 2, and Liliane Gattegno 1*

1 Laboratoire de Biologie Cellulaire, Biothérapies Bénéfices et Risques, UPRES 3410, Université Paris XIII, 74, rue Marcel Cachin, 93017, Bobigny, France; Hôpital Jean Verdier, 93017, Bondy, et, France
2 CEA, Saclay, Département d'Ingénierie et d'Etudes des Protéines, 91191 Gif-sur-Yvette, France

* To whom correspondence should be addressed. E-mail: liliane.gattegno{at}jvr.ap-hop-paris.fr.


   Abstract

We recently demonstrated that RANTES forms complexes with CCR5, syndecan-1, syndecan-4 and CD44 expressed by human primary macrophages and that syndecan-1 and syndecan-4, but neither CD44 nor syndecan-2, coimmunoprecipitate with CCR5. Here, we show that RANTES directly binds, in a glycosaminoglycan-dependent manner, to syndecan-1, syndecan-4 and CD44. Moreover, RANTES accelerates the shedding of syndecan-1 and syndecan-4 ectodomains from HeLa cells expressing CCR5 and by contrast, has no effect on the constitutive shedding of CD44 from these cells. These accelerated sheddings are prevented by the MEK1/2 inhibitor, U0126, and by the protein kinase C inhibitor, bisindolylmaleimide I. This indicates that both, mitogen-activated protein kinase- and protein kinase C-dependent signaling pathways are involved in these RANTES-induced accelerated sheddings. RANTES also induces a decreased expression of syndecan-1 and syndecan-4 by HeLa cells expressing CCR5, and on contrary an increased expression of CD44 by these cells. By contrast, RANTES does neither accelerate the shedding of syndecan-1 and syndecan-4 ectodomains from HeLa cells lacking CCR5, nor change the syndecan-1-, syndecan-4-, and CD44- plasma membrane expressions of these cells. CCR5 is therefore involved in the RANTES-induced accelerated shedding of syndecan-1 and syndecan-4 ectodomains. Nevertheless, the fact that RANTES stimulates in Hela cells, expressing or lacking CCR5, the mRNA synthesis of syndecan-1 and syndecan-4, indicates that the molecular events which follow the synthesis of these PGs differ, according to the presence or not of CCR5. Finally, RANTES forms glycosaminoglycan-dependent complexes with the shed ectodomains of syndecan-1, syndecan-4 as well as with those of CD44. The role of these events, in the pathophysiology of RANTES, deserves further studies.

Keywords: RANTES; Proteoglycan; Syndecan-1; Syndecan-4; Shedding; Chemokine.
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