title: Syndecan-4 is a signaling molecule for stromal cell-derived factor-1 (SDF-1)/ CXCL12.
abstract: Stromal cell-derived factor-1 (SDF-1)/CXCL12, the ligand for CXCR4, induces signal transduction. We previously showed that CXCL12 binds to high- and low-affinity sites expressed by primary cells and cell lines, and forms complexes with CXCR4 as expected and also with a proteoglycan, syndecan-4, but does not form complexes with syndecan-1, syndecan-2, CD44 or beta-glycan. We also demonstrated the occurrence of a CXCL12-independent heteromeric complex between CXCR4 and syndecan-4. However, our data ruled out the glycosaminoglycan-dependent binding of CXCL12 to HeLa cells facilitating the binding of this chemokine to CXCR4. Here, we demonstrate that CXCL12 directly binds to syndecan-4 in a glycosaminoglycan-dependent manner. We show that upon stimulation of HeLa cells by CXCL12, CXCR4 becomes tyrosine phosphorylated as expected, while syndecan-4 (but not syndecan-1, syndecan-2 or beta-glycan) also undergoes such tyrosine phosphorylation. Moreover, tyrosine-phosphorylated syndecan-4 from CXCL12-stimulated HeLa cells physically coassociates with tyrosine phosphorylated CXCR4. Pretreatment of the cells with heparitinases I and III prevented the tyrosine phosphorylation of syndecan-4, which suggests that the heparan sulfate-dependent binding of SDF-1 to this proteoglycan is involved. Finally, by reducing syndecan-4 expression using RNA interference or by pretreating the cells with heparitinase I and III mixture, we suggest the involvement of syndecan-4 and heparan sulfate in p44/p42 mitogen-activated protein kinase and Jun N-terminal/stress-activated protein kinase activation by action of CXCL12 on HeLa cells. However, these treatments did not modify the calcium mobilization induced by CXCL12 in these cells. Therefore, syndecan-4 behaves as a CXCL12 receptor, selectively involved in some transduction pathways induced by SDF-1, and heparan sulfate plays a role in these events.
authors.affiliation: Laboratoire de Biologie Cellulaire, Biothérapies Bénéfices et Risques, UPRES 3410 Université Paris XIII, Bobigny, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Charnaux
authors.forename: Séverine
authors.initials: S
authors.lastname: Brule
authors.forename: Morgan
authors.initials: M
authors.lastname: Hamon
authors.forename: Thomas
authors.initials: T
authors.lastname: Chaigneau
authors.forename: Line
authors.initials: L
authors.lastname: Saffar
authors.forename: Catherine
authors.initials: C
authors.lastname: Prost
authors.forename: Nicole
authors.initials: N
authors.lastname: Lievre
authors.forename: Liliane
authors.initials: L
authors.lastname: Gattegno
mesh_terms: D002118:Calcium / Q000378:metabolism; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000378:metabolism* / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D006025:Glycosaminoglycans / Q000378:metabolism; D006367:HeLa Cells; D006497:Heparan Sulfate / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011133:Polysaccharide-Lyases / Q000378:metabolism; D011485:Protein Binding; D011509:Proteoglycans / Q000737:chemistry / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D053671:Syndecan-4
chemical_list: D002118:Calcium; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D006025:Glycosaminoglycans; D006497:Heparan Sulfate; D008562:Membrane Glycoproteins; D020928:Mitogen-Activated Protein Kinases; D019000:Phosphotyrosine; D011133:Polysaccharide-Lyases; D011509:Proteoglycans; D019718:Receptors, CXCR4; D053671:Syndecan-4; C515255:CXCL12 protein, human; C508304:SDC4 protein, human; C021349:heparitinsulfate lyase