Sphingolipid hydrolase activator proteins and their precursors

Sano, Akira; Hineno, Takashi; Mizuno, Tatsuo; Kondoh, Keiji; Ueno, Shu‐ichi; Kakimoto, Yasuo; Inui, Koji

doi:10.1016/0006-291x(89)92728-9

Cited by 77 publications

(48 citation statements)

References 24 publications

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“…We report here a mechanism by which tumor cell secretion of prosaposin (Psap), the precursor form of the lipid hydrolase activators saposin A-D (8)(9)(10)(11), inhibits the metastatic process. The expression of Psap was elevated in nonmetastatic prostate and breast cancer cells compared to metastatic cell lines.…”

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confidence: 99%

Prosaposin inhibits tumor metastasis via paracrine and endocrine stimulation of stromal p53 and Tsp-1

Kang

Halvorsen

Gravdal

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

102

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Metastatic tumors can prepare a distant site for colonization via the secretion of factors that act in a systemic manner. We hypothesized that non- or weakly metastatic human tumor cells may act in an opposite fashion by creating a microenvironment in distant tissues that is refractory to colonization. By comparing cell lines with different metastatic potential, we have identified a tumor-secreted inhibitor of metastasis, prosaposin (Psap), which functions in a paracrine and endocrine fashion by stimulating the expression of thrombospondin-1 (Tsp-1) in fibroblasts present in both primary tumors and distant organs, doing so in a p53-dependent manner. Introduction of Psap in highly metastatic cells significantly reduced the occurrence of metastases, whereas inhibition of Psap production by tumor cells was associated with increased metastatic frequency. In human prostate cancer, decreased Psap expression was significantly associated with metastatic tumors. Our findings suggest that prosaposin, or other agents that stimulate p53 activity in the tumor stroma, may be an effective therapy by inhibition of the metastatic process.

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mentioning

confidence: 99%

Prosaposin inhibits tumor metastasis via paracrine and endocrine stimulation of stromal p53 and Tsp-1

Kang

Halvorsen

Gravdal

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

102

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“…Previous investigations showed that the removal of oligosaccharides from saposin A [6] and saposin C [5] did not affect their stimulating activity on acid /3-glucosidase. More recent studies on saposin B demonstrated that removal of its oligosaccharide chains did not alter its stimulative activity on hydrolysis of GM1 ganglioside and sulfatide or its binding to gangliosides [19].…”

Section: Discussionmentioning

confidence: 99%

“…The functions of the oligosaccharide moiety of saposins in vitro were studied by Sano et al [5] and Morimoto et al [6] who demonstrated that removal of the oligosaccharide side chain had no effect upon the functional 'activator' activities of saposins C and A, respectively. On the other hand, a point mutation of saposin B protein which resulted in replacement of a threonine residue by isoleucine, thus eliminating its glycosylation site, was found in a patient with a variant of metachromatic leukodystrophy [3].…”

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confidence: 99%

Structural study of the oligosaccharide moieties of sphingolipid activator proteins, saposins A, C and D obtained from the spleen of a Gaucher patient

Ito

Takahashi

et al. 1993

European Journal of Biochemistry

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We have determined and compared the structures of the oligosaccharide moieties of saposin A, C and D purified from the spleen of a patient with Gaucher disease. These saposins, together with saposin B, are small glycoproteins, derived from separate domains of a single precursor, prosaposin, and are required for the lysosomal hydrolysis of various sphingolipids. The characteristic features of the oligosaccharide moieties of saposin A are (a) the predominance of a fucosylated trimannosyl core structure and (b) the occurrence of several different oligomannose‐type and N‐acetyllactosamine‐type oligosaccharides. Saposin C contains (a) a predominance of oligomannose‐type oligosaccharides and monoantennary oligosaccharides and (b) the presence of four different oligosaccharides having bisecting N‐acetylglucosamine residues (found only in this saposin). Saposin D is distinguished by the occurrence of oligomannose‐type oligosaccharides, which comprise nearly 90% of its total oligosaccharides. The possible reasons for the unique glycosylation of each saposin is discussed.

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“…In addition to its role as a lysosomal precursor, prosaposin is presumed to have additional functions, since it exists as a secretory protein in human milk, cerebrospinal fluid, and seminal plasma (3)(4)(5); it is present in unprocessed form in high concentrations in human (6) and rat (7) brain; its mRNA is abundant in brain and dorsal root ganglia during embryonic development (8); it is present predominantly in neurons after immunostaining (9); and it occurs as an integral membrane component (10).…”

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confidence: 99%

Identification of prosaposin as a neurotrophic factor.

O’Brien

Carson

Seo

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

216

171

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Prosaposin was identified as a neurotrophic factor stimulating neurite outgrowth in murine neuroblastoma (NS20Y) cells and choline acetyltranferase (ChAT) activity in human neuroblastoma (SK-N-MC) cells. The four naturally occurring saposs, which are derived by proteolytic processing of prosaposin, were tested for activity. Saposin C was found to be active, whereas saposns A, B, and D were inactive as neurotrophic factors. Dose-response curves demonstrated that nanomolar concentrations of prosaposin and saposin C stimulated neurite outgrowth and increased ChAT activity. Prosaposin and saposin C exerted activity by a mechanlsm independent of nerve growth factor, brain-derived neurotrophic factor, and neurotrophin 3. Binding assays uing saposin C as a ilgand gave two saturable binding constants, a hig-affnity (Kd = 19 pM) and a low-affinity (Kd = 1 uM) constant, with 2000 and 15,000 sites per NS20Y cell, respectively. Phosphorylation stimulation experiments demonstrated that brief treatment with prosaposin or saposin C enhanced phospholation of a variety of proteins, some of which contained phosphorylated tyrosine(s). Since both cell lines were also stimulated by ciary neurotrophic factor (CNTF) as well as prosaposin, inhibition was tested by utilizing an anti-gpl30 monoclonal antibody, which s lly inhibited CNTF stimulation; thls antibody did not inhibit prosaposin or saposi C smulation. These results indicate that prosaposin and saposin C are neurotrophic factors which initiate signal transduction by binding to a high-afinity receptor that induces protein phosphorylation.Prosaposin is the precursor of the lysosomal saposin proteins, which are required for hydrolysis ofglycosphingolipids by lysosomal hydrolases (1, 2). In addition to its role as a lysosomal precursor, prosaposin is presumed to have additional functions, since it exists as a secretory protein in human milk, cerebrospinal fluid, and seminal plasma (3-5); it is present in unprocessed form in high concentrations in human (6) and rat (7) brain; its mRNA is abundant in brain and dorsal root ganglia during embryonic development (8); it is present predominantly in neurons after immunostaining (9); and it occurs as an integral membrane component (10).Recently we demonstrated that prosaposin binds gangliosides with high affinity and facilitates their transfer from micelles to membranes (11). Since gangliosides have been shown to promote neurite outgrowth in cultured neuronal cells (12-14), we investigated whether prosaposin was also active. In this report we identify prosaposin as a potent neurotrophic factor and locate the active region to the saposin C domain. (PBS), and fixed in Bouins solution (30 min). After the fixative had been removed, neurite outgrowth was scored under a phase-contrast microscope. Cells bearing neurites longer than 1 cell diameter were scored as positive, and 100 cells were counted in triplicate from different portions of each dish. Each assay was carried out in duplicate dishes. The average error of duplicates (40 assay...

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Sphingolipid hydrolase activator proteins and their precursors

Cited by 77 publications

References 24 publications

Prosaposin inhibits tumor metastasis via paracrine and endocrine stimulation of stromal p53 and Tsp-1

Prosaposin inhibits tumor metastasis via paracrine and endocrine stimulation of stromal p53 and Tsp-1

Structural study of the oligosaccharide moieties of sphingolipid activator proteins, saposins A, C and D obtained from the spleen of a Gaucher patient

Identification of prosaposin as a neurotrophic factor.

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