Neuraminidase-1, a Subunit of the Cell Surface Elastin Receptor, Desialylates and Functionally Inactivates Adjacent Receptors Interacting with the Mitogenic Growth Factors PDGF-BB and IGF-2

Abstract

We recently established that the elastin-binding protein, which is identical to the spliced variant of ␤-galactosidase, forms a cell surface-targeted complex with two proteins considered "classic lysosomal enzymes": protective protein/cathepsin A and neuraminidase-1 (Neu1). We also found that cell surface-residing Neu1 can desialylate neighboring microfibrillar glycoproteins and facilitate the deposition of insoluble elastin, which contributes to the maintenance of cellular quiescence. Here we provide evidence that cell surfaceresiding Neu1 contributes to a novel mechanism that limits cellular proliferation by desialylating cell membrane-residing sialoglycoproteins that directly propagate mitogenic signals. We demonstrated that treatment of cultured human aortic smooth muscle cells (SMCs) with either a sialidase inhibitor or an antibody that blocks Neu1 activity induced significant up-regulation in SMC proliferation in response to fetal bovine serum. Conversely, treatment with Clostridium perfringens neuraminidase (which is highly homologous to Neu1) decreased SMC proliferation, even in cultures that did not deposit elastin. Further, we found that pretreatment of aortic SMCs with exogenous neuraminidase abolished their mitogenic responses to recombinant platelet-derived growth factor (PDGF)-BB and insulin-like growth factor (IGF)-2 and that sialidosis fibroblasts (which are exclusively deficient in Neu1) were more responsive to PDGF-BB and IGF-2 compared with normal fibroblasts. Furthermore , we provide direct evidence that neuraminidase caused the desialylation of both PDGF and IGF-1 receptors and diminished the intracellular signals induced by the mitogenic ligands

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

“…4) and MUC1 (Fig. 6), NEU1 has also been shown to desialylate TLR4 (36) and the receptors for platelet-derived growth factor-BB and insulin growth factor (40). These combined data indicate that NEU1 can be strategically co-localized in close proximity to surface receptor substrates.…”

Regulation of Phagocytosis in Macrophages by Neuraminidase 1

“…In particular, the components of the multienzyme complex, Neu1, CathA, and ␤-galactosidase (or its alternatively spliced elastin-binding form), participate in processing of endothelin-1 (21,33), assembly of the elastic fibers (21,34,35), pro-inflammatory response in macrophages (36), migration, invasion, and adhesion of cancer cells (37), proliferation of aortic smooth muscle cells (38), and exocytosis (39). In humans, genetic defects in CathA cause disruption of the complex and trigger galactosialidosis (MIM 256540), a severe multisystemic disease characterized by combined deficiency of Neu1, ␤-galactosidase, and CathA (for review, see Ref.…”

Sialidase NEU4 Hydrolyzes Polysialic Acids of Neural Cell Adhesion Molecules and Negatively Regulates Neurite Formation by Hippocampal Neurons

“…NEU1 showed slight degradation of polySia in Neuro2a cells in one test (once in five separate experiments), independent of protective protein expression, although the results could not be confirmed in other in vitro analyses. However, it may not be excluded the possibility that NEU1 degrades polySia in cellular level together with some protein factors including ␤-galactosidase, as reported in facilitation of elastic fiber assembly (45). Compared with NEU4 levels, endogenous expression of NEU1 is very high in a number of tissues, including brain (25), where it was found to be ϳ7-fold higher (Fig.…”