Interaction of Nerve Growth Factor β with Adiponectin and SPARC Oppositely Modulates its Biological Activity.

Yuu Okura,Yuko Okamatsu-Ogura,Masayuki Saito,Haruki Shibata,Seisuke Murashima,Akihiro Kamikavwa,Kazuhiro Kimura,Takeshi Imao

doi:10.3390/ijms20071541

Abstract

Both adiponectin and secreted protein, acidic and rich in cysteine (SPARC) inhibit platelet-derived growth factor-BB (PDGF-BB)-induced and basic fibroblast growth factor (FGF2)-induced angiogenic activities through direct and indirect interactions. Although SPARC enhances nerve growth factor (NGF)-dependent neurogenesis, the physical interaction of NGFβ with adiponectin and SPARC remains obscure. Therefore, we first examined their intermolecular interaction by surface plasmon resonance method. NGFβ bound to immobilized SPARC with the binding constant of 59.4 nM, comparable with that of PDGF-BB (24.5 nM) but far less than that of FGF2 (14.4 µM). NGFβ bound to immobilized full length adiponectin with the binding constant of 103 nM, slightly higher than those of PDGF-BB (24.3 nM) and FGF2 (80.2 nM), respectively. Treatment of PC12 cells with SPARC did not cause mitogen-activated protein kinase (MAPK) activation and neurite outgrowth. However, simultaneous addition of SPARC with NGFβ enhanced NGFβ-induced MAPK phosphorylation and neurite outgrowth. Treatment of the cells with adiponectin increased AMP-activated protein kinase (AMPK) phosphorylation but failed to induce neurite outgrowth. Simultaneous treatment with NGFβ and adiponectin significantly reduced cell size and the number of cells with neurite, even after silencing the adiponectin receptors by their siRNA. These results indicate that NGFβ directly interacts with adiponectin and SPARC, whereas these interactions oppositely regulate NGFβ functions.

Highlights

Adiponectin, a member of the C1q/tumor necrosis factor (TNF)-related proteins, is secreted exclusively by adipocytes
We showed the apparent interaction of SPARC with NGFβ, platelet-derived growth factor-BB (PDGF-BB) and FGF2 with the KD of 59.4 nM, 24.3 nM and 14.4 μM, respectively
As SPARC is reported to interfere with FGF2-induced functions not through direct binding [16], the interaction between SPARC and FGF2 on the sensor chip was unexpected its KD value was a triple-digit difference from those of two other growth factors tested

Summary

Introduction

Adiponectin, a member of the C1q/tumor necrosis factor (TNF)-related proteins, is secreted exclusively by adipocytes. Administration of adiponectin has been shown to be beneficial in animal models of diabetes, obesity and atherosclerosis [1,2,3,4,6]. The hallmark of atherosclerosis is the uncontrolled proliferation and migration of vascular smooth muscle cells, resulting in thickening of the vascular wall [7]. Physiological concentrations of adiponectin significantly suppress both the proliferation and migration of vascular smooth muscle cells induced by platelet-derived growth factor (PDGF)-BB, through direct interaction between adiponectin and PDGF-BB [8]. It was shown that adiponectin binds with basic fibroblast growth factor (FGF2), thereby precluding the biological activity [9]

Methods

Results

Conclusion