The Elastin Receptor Complex Transduces Signals through the Catalytic Activity of Its Neu-1 Subunit

Abstract

The binding of elastin peptides on the elastin receptor complex leads to the formation of intracellular signals but how this is achieved remains totally unknown. Using pharmacological inhibitors of the enzymatic activities of its subunits, we show here that the elastin peptide-driven ERK1/2 activation and subsequent pro-MMP-1 production, observed in skin fibroblasts when they are cultured in the presence of these peptides, rely on a membrane-bound sialidase activity. As lactose blocked this effect, the elastin receptor sialidase subunit, Neu-1, seemed to be involved. The use of a catalytically inactive form of Neu-1 and the small interfering RNA-mediated decrease of Neu-1 expression strongly support this view. Finally, we report that N-acetyl neuraminic acid can reproduce the effects of elastin peptides on both ERK1/2 activation and pro-MMP-1 production. Altogether, our results indicate that the enzymatic activity of the Neu-1 subunit of the elastin receptor complex is responsible for its signal transduction, presumably through sialic acid generation from undetermined substrates.Elastin is the extracellular matrix protein responsible for the elasticity of tissues. It is more abundant in tissues where resilience is required, such as skin, lung, ligaments, or large arteries (1). Elastin is constituted of tropoelastin molecules covalently bound to each other by covalent cross-links (2) and its hydrophobic and highly cross-linked nature make of it a very durable polymer experiencing essentially no turnover in healthy tissues (3).The biological role of elastin was originally thought to be restricted to this mechanical function. However, when Senior et al. (4) demonstrated that elastin digestion products were chemotactic for neutrophils and macrophages, it became suddenly apparent that peptides derived from amorphous elastin could modulate cell physiology. In fact, it has been shown because that fibroblasts (5-12), smooth muscle cells (7, 13-15), endothelial cells (16 -19), leukocytes (20, 21), and lymphocytes (22) were sensitive to the presence of these peptides yielding a broad range of biological activities (see Ref. 23 for a review). A corollary of these observations was that those cells do express a receptor for elastin peptides.The elastin receptor complex is constituted of three subunits, one peripheral 67-kDa subunit, which actually binds elastin, and two membrane-associated proteins of 61 and 55 kDa, respectively (10). The 67-kDa elastin-binding protein (EBP) 2 binds the VGVAPG elastin sequence with high affinity. Additionally, EBP can be eluted from elastin affinity column by galactosugars suggesting that the elastin-EBP interaction could be regulated by galactosugars bound on a lectin site on EBP (10, 24). Consequently, galactosugars such as lactose are commonly used antagonists of EBP.Later, the nature of this subunit was revealed by the work of Privitera et al. (25) who have shown that EBP is an enzymatically spliced variant of lysosomal ␤-galactosidase (␤-Gal, EC 3.2.1.23). Consequently, it was hypot...

NEU1 Sialidase Expressed in Human Airway Epithelia Regulates Epidermal Growth Factor Receptor (EGFR) and MUC1 Protein Signaling

“…In other studies, NEU1 was targeted to the plasma membrane of phorbol 12-myristate 13-acetate-differentiated human monocytes (47) and activated human T lymphocytes (49). In each case, NEU1 was accompanied by cathepsin A. NEU1 activation has been coupled to ligand engagement of TLR4 (36), the elastin receptor complex (37,38), and Trk A (39). In addition to EGFR (Fig.…”

“…Endotoxin engagement of TLR4 is coupled to NEU1 activation and desialylation of the TLR4 ectodomain, permitting TLR4 dimerization and activation (36,69). The elastin receptor complex comprises three subunits, including elastin-binding protein, a spliced variant of lysosomal ␤-galactosidase, cathepsin A, and NEU1 (37,38). Elastase-generated elastin peptides bind to the receptor complex to up-regulate NEU1 activity.…”

Interaction between the Elastin Peptide VGVAPG and Human Elastin Binding Protein

“…Validation of the Biological System-Following elastin peptide stimulation, the MEK/ERK pathway is activated in COS-7 cells, and this activation could be monitored using a luciferase assay of MMP-1 promoter activity (20).…”

“…It is required for both elastin assembly (9) and elastin peptide signaling (20). Importantly, this activity requires the presence of EBP.…”

Mechanistic Effects of Long-Term Ultraviolet B Irradiation Induce Epidermal and Dermal Changes in Human Skin Xenografts

“…These results are in consistent with the induction of pro-MMP-1 by elastin peptides in skin fibroblasts. 72,73 Throughout the dermis, collagen remodeling, including collagen disruptions and collagen production, was observed. The imbalance between MMPs and collagen production may contribute to the unusual punctate collagen bundles that were observed 4 weeks after halt irradiation.…”