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

FEBS J. 2005 Apr;272(8):1937-51. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Calcium / metabolism
  • Chemokine CXCL12
  • Chemokines, CXC / metabolism*
  • Chemokines, CXC / pharmacology
  • Enzyme Activation / drug effects
  • 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
  • Proteoglycans / chemistry
  • Proteoglycans / metabolism*
  • Receptors, CXCR4 / metabolism
  • Signal Transduction* / drug effects
  • Syndecan-4


  • CXCL12 protein, human
  • Chemokine CXCL12
  • Chemokines, CXC
  • Glycosaminoglycans
  • Membrane Glycoproteins
  • Proteoglycans
  • Receptors, CXCR4
  • SDC4 protein, human
  • Syndecan-4
  • Phosphotyrosine
  • Heparitin Sulfate
  • Mitogen-Activated Protein Kinases
  • Polysaccharide-Lyases
  • heparitinsulfate lyase
  • Calcium