1. Academic Validation
  2. RANTES/CCL5 mediated-biological effects depend on the syndecan-4/PKCα signaling pathway

RANTES/CCL5 mediated-biological effects depend on the syndecan-4/PKCα signaling pathway

  • Biol Open. 2014 Sep 26;3(10):995-1004. doi: 10.1242/bio.20148227.
Loïc Maillard 1 Naoaki Saito 2 Hanna Hlawaty 1 Véronique Friand 1 Nadine Suffee 1 Fanny Chmilewsky 1 Oualid Haddad 1 Christelle Laguillier 3 Erwan Guyot 3 Takehiko Ueyama 2 Olivier Oudar 1 Angela Sutton 3 Nathalie Charnaux 4
Affiliations

Affiliations

  • 1 Inserm U1148, Laboratory for Vascular Translational Science, Bio-ingénierie Cardio-vasculaire, UFR SMBH, Université Paris 13, Sorbonne Paris Cité, 74 rue Marcel Cachin, 93017 Bobigny, France.
  • 2 Laboratory of Molecular Pharmacology, Biosignal Research Center, Kobe University, Kobe 657-8501, Japan.
  • 3 Inserm U1148, Laboratory for Vascular Translational Science, Bio-ingénierie Cardio-vasculaire, UFR SMBH, Université Paris 13, Sorbonne Paris Cité, 74 rue Marcel Cachin, 93017 Bobigny, France Laboratoire de Biochimie, Hôpital Jean Verdier, AP-HP, 93143 Bondy, France.
  • 4 Inserm U1148, Laboratory for Vascular Translational Science, Bio-ingénierie Cardio-vasculaire, UFR SMBH, Université Paris 13, Sorbonne Paris Cité, 74 rue Marcel Cachin, 93017 Bobigny, France Laboratoire de Biochimie, Hôpital Jean Verdier, AP-HP, 93143 Bondy, France nathalie.charnaux@jvr.aphp.fr.
Abstract

The perpetuation of angiogenesis is involved in certain chronic inflammatory diseases. The accelerated neovascularisation may result from an inflammatory status with a response of both endothelial cells and monocytes to inflammatory mediators such as chemokines. We have previously described in vitro and in vivo the pro-angiogenic effects of the chemokine Regulated on Activation, Normal T Cell Expressed and Secreted (RANTES)/CCL5. The effects of RANTES/CCL5 may be related to its binding to G protein-coupled receptors and to proteoglycans such as syndecan-1 and -4. The aim of this study was to evaluate the functionality of syndecan-4 as a co-receptor of RANTES/CCL5 by the use of mutated syndecan-4 constructs. Our data demonstrate that site-directed mutations in syndecan-4 modify RANTES/CCL5 biological activities in endothelial cells. The SDC4S179A mutant, associated with an induced protein kinase C (PKC)α activation, leads to higher RANTES/CCL5 pro-angiogenic effects, whereas the SDC4L188QQ and the SDC4A198del mutants, leading to lower phosphatidylinositol 4,5-bisphosphate (PIP2) binding or to lower PDZ protein binding respectively, are associated with reduced RANTES/CCL5 cellular effects. Moreover, our data highlight that the intracellular domain of SDC-4 is involved in RANTES/CCL5-induced activation of the PKCα signaling pathway and biological effect. As RANTES/CCL5 is involved in various physiopathological processes, the development of a new therapeutic strategy may be reliant on the mechanism by which RANTES/CCL5 exerts its biological activities, for example by targeting the binding of the chemokine to its proteoglycan receptor.

Keywords

Chemokine; Endothelial cell; PKC; RANTES/CCL5; Syndecan-4.

Figures
Products