Syndecan‐4 is a signaling molecule for stromal cell‐derived factor‐1 (SDF‐1)/ CXCL12

• Published in: The FEBS journal Vol. 272; no. 8; pp. 1937 - 1951
• Main Authors: Charnaux, Nathalie, Brule, Séverine, Hamon, Morgan, Chaigneau, Thomas, Saffar, Line, Prost, Catherine, Lievre, Nicole, Gattegno, Liliane
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Science Ltd 01-04-2005; Blackwell Publishing Ltd
• Subjects: Calcium - metabolism; Cellular biology; Chemokine CXCL12; Chemokines, CXC - metabolism; Chemokines, CXC - pharmacology; CXCR4; Enzyme Activation - drug effects; Gene expression; Glycosaminoglycans - metabolism; HeLa Cells; Heparitin Sulfate - metabolism; Humans; MAP Kinase Signaling System - drug effects; Membrane Glycoproteins - chemistry; Membrane Glycoproteins - metabolism; Mitogen-Activated Protein Kinases - metabolism; Phosphorylation; Phosphotyrosine - metabolism; Polysaccharide-Lyases - metabolism; Protein Binding; Proteins; proteoglycan; Proteoglycans - chemistry; Proteoglycans - metabolism; Receptors, CXCR4 - metabolism; SDF‐1/CXCL12; Signal transduction; Signal Transduction - drug effects; Syndecan-4
• ISSN: 1742-464X; 1742-4658
• DOI: 10.1111/j.1742-4658.2005.04624.x

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.