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.

Syndecan-4 Deficiency Limits Neointimal Formation After Vascular Injury by Regulating Vascular Smooth Muscle Cell Proliferation and Vascular Progenitor Cell Mobilization

“…40 In this study, we also found that expression of Syn4 on VPCs was upregulated soon after vascular injury and then returned to the control level ( Figure 6D). It is attempting to speculate that the shedding of upregulated Syn4 from BM cells contributes to the mobilization of VPCs and subsequent neointimal formation.…”

“…It should be noted that both stromal cell-derived factor-1 and its receptor CXCR4 play a crucial role in the mobilization and homing of BM-VPCs after vascular injury 28,39 and that Syn4 is a signaling molecule for the stromal cell-derived factor-1/ CXCR4 pathway. 40 In this study, we also found that expression of Syn4 on VPCs was upregulated soon after vascular injury and then returned to the control level ( Figure 6D). It is attempting to speculate that the shedding of upregulated Syn4 from BM cells contributes to the mobilization of VPCs and subsequent neointimal formation.…”

Possible Regulation of Migration of Intrahepatic Cholangiocarcinoma Cells by Interaction of CXCR4 Expressed in Carcinoma Cells with Tumor Necrosis Factor-α and Stromal-Derived Factor-1 Released in Stroma

“…Recent studies showed that several other factors such as syndecan and IFN-␥, influence the SDF-1/CXCR4 signaling system. 16,43 Essential physiological and pathological roles of SDF-1/CXCR4 interactions have been increasingly demonstrated in various tissues and culture systems. 11,16 -19,43 SDF-1 is broadly and constitutively expressed in stromal cells and endothelial cells in numerous tissues.…”

“…52,53 Our previous study showed that heparan sulfate proteoglycan was abundant in fibrous stroma of ICC, whereas heparan sulfate proteoglycan expression was negligible in the surrounding liver. 54 Furthermore, Charnaux and colleagues 43 reported that a proteoglycan, syndecan-4, behaves as a SDF-1 receptor, and is selectively involved in signal transduction induced by SDF-1. Taken together, it seems possible that the specific interactions of SDF-1 and TNF-␣ with their receptors expressed on ICC cells are likely to occur in such tumor-stromal microenvironments, and that these interactions are responsible for the characteristic biological behaviors of ICC such as invasion and migration.…”

A role for Syndecan-4 in neural induction involving ERK- and PKC-dependent pathways

“…Syndecan-4 (Syn4) is a heparan sulphate PG reported to modulate FGF signalling in vitro (Iwabuchi and Goetinck, 2006;Tkachenko et al, 2004;Tkachenko and Simons, 2002). In addition, Syn4 interacts with chemokines (Brule et al, 2006;Charnaux et al, 2005) and with the planar cell polarity (PCP) pathway (Matthews et al, 2008;Muñoz et al, 2006). As Syn4 also interacts with fibronectin and integrins and is required for the formation of focal adhesions (Woods and Couchman, 2001), its main role has been thought to be in cell migration.…”