Further evidence for a common mechanism for shedding of cell surface proteins

Mullberg, Jürgen; Rauch, Charles T.; Wolfson, Martin F.; Castner, Beverly J.; Fitzner, Jeffrey N.; Otten-Evans, Carol; Mohler, Kendall M.; Cosman, David; Black, Roy A.

doi:10.1016/s0014-5793(96)01480-9

Cited by 59 publications

(42 citation statements)

References 34 publications

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“…It seems likely that the introduction of oligosaccharide chains into the chimeric receptors hindered access to proteases since many integral membrane proteins are shed by proteolytic cleavage. [34][35][36] Our results clearly demonstrate that the level of surface expression correlated with the degree of linker glycosylation (Fig 2c). Control of surface shedding by variation of glycosylation may be useful for tuning the retention of chimeric proteins on cells.…”

Section: Discussionsupporting

confidence: 62%

Stable expression of chimeric anti-CD3 receptors on mammalian cells for stimulation of antitumor immunity

Liao¹,

Chen²,

Liu³

et al. 2003

Cancer Gene Ther

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Expression of CD80 or CD86 costimulatory molecules on tumor cells can produce rejection of immunogenic but not poorly immunogenic tumors. We have previously shown that anti-CD3 single-chain antibodies expressed on the surface of cells can directly activate T cells. We therefore investigated whether anti-CD3 ''receptors'' could enhance CD86-mediated rejection of poorly immunogenic tumors. Expression of anti-CD3 receptors on cells was increased by introduction of membrane-proximal ''spacer'' domains containing glycosylation sites between the single-chain antibody and the transmembrane domain of the chimeric receptors. Removal of glycosylation sites in the spacer reduced surface expression due to increased shedding of chimeric receptors from the cell surface. Induction of T-cell proliferation by anti-CD3 receptors did not correlate with the expression level of chimeric protein, but rather depended on the physical properties of the spacer. Anti-CD3 receptors effectively induced T-cell cytotoxicity, whereas coexpression with CD80 or CD86 was required for generating T-cell proliferation and IL-2 secretion. Although expression of CD86 did not significantly delay the growth of poorly immunogenic B16-F1 tumors, expression of anti-CD3 receptors with CD86 produced complete tumor rejections in 50% of mice and induced significant protection against wild-type B16-F1 tumor cells. Our results show that spacer domains can dramatically influence the surface expression and the biological activity of chimeric antibody receptors. The strong antitumor activity produced by anti-CD3 receptors and CD86 on tumor cells indicates that this strategy may be beneficial for the gene-mediated therapy of poorly immunogenic tumors.

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Section: Discussionsupporting

confidence: 62%

Stable expression of chimeric anti-CD3 receptors on mammalian cells for stimulation of antitumor immunity

Liao¹,

Chen²,

Liu³

et al. 2003

Cancer Gene Ther

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“…3A, lane 1) or increase in BB-94-treated cells. Taken together, these results provide the first evidence that TRANCE, like TNF-␣, ␤APP, and other shed proteins can be released in response to phorbol esters (12,24,25), and that this release can be inhibited by a hydroxamate-based metalloprotease inhibitor.To test for a potential role of TACE in the shedding of TRANCE, metabolically labeled full-length TRANCE was immunoprecipitated and incubated in vitro with recombinant TACE. This treatment yielded polypeptides of 23 and 26 kDa (Fig.…”

mentioning

confidence: 53%

Evidence for a Role of a Tumor Necrosis Factor-α (TNF-α)-converting Enzyme-like Protease in Shedding of TRANCE, a TNF Family Member Involved in Osteoclastogenesis and Dendritic Cell Survival

Lum¹,

Wong²,

Josien³

et al. 1999

Journal of Biological Chemistry

390

293

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Tumor necrosis factor (TNF)-related activation-induced cytokine (TRANCE), a member of the TNF family, is a dendritic cell survival factor and is essential for osteoclastogenesis and osteoclast activation. In this report we demonstrate (i) that TRANCE, like TNF-␣, is made as a membrane-anchored precursor, which is released from the plasma membrane by a metalloprotease; (ii) that soluble TRANCE has potent dendritic cell survival and osteoclastogenic activity; (iii) that the metalloprotease-disintegrin TNF-␣ convertase (TACE) can cleave immunoprecipitated TRANCE in vitro in a fashion that mimics the cleavage observed in tissue culture cells; and (iv) that in vitro cleavage of a TRANCE ectodomain/CD8 fusion protein and of a peptide corresponding to the TRANCE cleavage site by TACE occurs at the same site that is used when TRANCE is shed from cells into the supernatant. We propose that the TRANCE ectodomain is released from cells by TACE or a related metalloprotease-disintegrin, and that this release is an important component of the function of TRANCE in bone and immune homeostasis. Tumor necrosis factor (TNF)1 -related activation-induced cytokine (TRANCE), a recently identified member of the TNF family, is a dendritic cell survival factor that also has a role in bone homeostasis (1-4). Like TNF-␣, TRANCE is a type II integral membrane glycoprotein of ϳ45 kDa with a long extracellular stalk region followed by a receptor-binding core domain (5). TRANCE expression in osteoblasts and stromal cells can be induced with vitamin D3, prostaglandin E 2 , interleukin-1, or glucocorticoids (4). In turn, TRANCE is known to induce differentiation and activation of osteoclasts. This suggests that TRANCE provides an important link between the action of hormones and physiological cytokines and bone resorption. TRANCE is also expressed on activated T cells (5), where it induces dendritic cell survival, thereby enhancing T cell priming (1, 2). Therefore TRANCE may also regulate antigen presentation during an immune response. TRANCE mediates its effects through the membrane-anchored TRANCE receptor (TRANCE-R, also referred to as RANK (receptor activator of nuclear factor-B)), which results in activation of c-Jun Nterminal kinase and nuclear factor-B (2, 5). Finally TRANCE is known to bind to a soluble receptor, termed osteoprotegerin or osteoclast inhibitory factor (OPG/OCIF), which is a member of the TNF-␣ receptor family (6). OPG/OCIF presumably functions as a decoy receptor, since systemic overexpression or injection of OPG/OCIF causes osteopetrosis in mice (7), whereas OPG/OCIF deficiency results in osteoporosis (8).Similar to TNF-␣, which is thought to be released from the plasma membrane by the metalloprotease-disintegrin TNF-␣ convertase (TACE) (9 -11), TRANCE may also be shed by TACE or a related metalloprotease. Metalloproteases have been implicated in the shedding or release of several different cell surface proteins from the plasma membrane. These proteins include various cytokines, cytokine receptors, adhesion proteins, and...

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“…However, NO-induced ectodomain shedding did not appear to require any of the known potential signaling pathways for NO. NO-induced TNF p75 receptor shedding was not affected by an inhibitor of cyclic GMP (1H- [1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one), 8-bromo cyclic GMP, chelerythrin (a calcium-dependent protein kinase C inhibitor), genistein (a tyrosine kinase inhibitor), or dibutryl cyclic AMP, which increases intracellular cAMP (data not shown). Moreover, flow cytometry analysis with a monoclonal antibody against the catalytic domain of TACE revealed that PAPA/NO does not alter the TACE signal on the cell surface (mean channel fluorescence, 53 Ϯ 4.3 versus 55 Ϯ 5.2 after a 2-h exposure to 1 mM PAPA/NO).…”

Section: Involvement Of Tace In No-induced Ectodomainmentioning

confidence: 94%

“…G -monomethyl-L-arginine (NMA), and 1H- [1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one were obtained from Alexis Biochemicals (San Diego, CA). Actinomycin D and oxyhemoglobin were from Sigma.…”

Section: Chemicals-(z)-1-[n-(3-ammoniopropyl)-n-(n-propyl)-amino]-diamentioning

confidence: 99%

“…Shedding of ligand/receptor families is involved in diverse processes such as inflammation, hematopoiesis, and normal development (2, 3). Ectodomain shedding can be stimulated by protein kinase C activation and endotoxin (4,5). TACE 1 is a member of a disintegrin and metalloproteinase (ADAM) family, a group of unique zinc-binding transmembrane metalloproteinases (6 -8).…”

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confidence: 99%

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Activation of Tumor Necrosis Factor-α-converting Enzyme-mediated Ectodomain Shedding by Nitric Oxide

Zhang¹,

Kolls²,

Oliver³

et al. 2000

Journal of Biological Chemistry

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Ectodomain shedding of cell surface proteins is an important process in a wide variety of physiological and developmental events. Recently, tumor necrosis factor-␣-converting enzyme (TACE) has been found to play an essential role in the shedding of several critical surface proteins, which is evidenced by multiple developmental defects exhibited by TACE knockout mice. However, little is known about the physiological activation of TACE. Here, we show that nitric oxide (NO) activates TACEmediated ectodomain shedding. Using an in vitro model of TACE activation, we show that NO activates TACE by nitrosation of the inhibitory motif of the TACE prodomain. Thus, NO production activates the release of cytokines, cytokine receptors, and adhesion molecules, and NO may be involved in other ectodomain shedding processes.Ectodomain shedding is an essential phenomenon involved in the cleavage and release of cell membrane-bound molecules ranging from Alzheimer's amyloid precursor protein to angiotensin-converting enzyme (1). Shedding of ligand/receptor families is involved in diverse processes such as inflammation, hematopoiesis, and normal development (2, 3). Ectodomain shedding can be stimulated by protein kinase C activation and endotoxin (4,5). TACE 1 is a member of a disintegrin and metalloproteinase (ADAM) family, a group of unique zinc-binding transmembrane metalloproteinases (6 -8). TACE has been shown to mediate cleavage of TNF␣ as well as a variety of ectodomains including the TNF p75 receptor, L-selectin, and transforming growth factor-␣ (3). Despite its importance, the physiological regulation of TACE activity remains undefined. Endotoxin does not alter TACE transcription, steady-state mRNA levels, or the level of processed TACE at the cell surface (3). However, endotoxin can induce both nitric oxide (NO) and free radical production (9 -11). It has been shown that both hydrogen peroxide and NO can enhance macrophage production and the secretion of TNF␣ (12-16). However, the mechanism of this effect remains unclear. Many metalloproteinases can be activated by oxidation and dissociation of the cysteine thiol-zinc linkage from a latent enzymatic site, with this complex referred to as a "cysteine zinc switch" mechanism (17). TACE contains a consensus cysteine switch motif in the prodomain, and it has been shown previously that the cysteine in this portion of the molecule is required for the inhibition of TACE activity (18). In the present study, we tested the hypothesis that NO, a molecule produced in a variety of inflammatory conditions, regulates TACE activity and ectodomain shedding. EXPERIMENTAL PROCEDURES Chemicals-(Z)-1-[N-(3-ammoniopropyl)-N-(n-propyl)-amino]-diazen-, and 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one were obtained from Alexis Biochemicals (San Diego, CA). Actinomycin D and oxyhemoglobin were from Sigma. Murine interferon-␥ was provided by Genentech (South San Francisco, CA). Escherichia coli LPS 026:B6 was from Difco. All other chemicals were purchased from Sigma.Cell Culture-Mono Mac 6 and Jurkat...

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Further evidence for a common mechanism for shedding of cell surface proteins

Cited by 59 publications

References 34 publications

Stable expression of chimeric anti-CD3 receptors on mammalian cells for stimulation of antitumor immunity

Stable expression of chimeric anti-CD3 receptors on mammalian cells for stimulation of antitumor immunity

Evidence for a Role of a Tumor Necrosis Factor-α (TNF-α)-converting Enzyme-like Protease in Shedding of TRANCE, a TNF Family Member Involved in Osteoclastogenesis and Dendritic Cell Survival

Activation of Tumor Necrosis Factor-α-converting Enzyme-mediated Ectodomain Shedding by Nitric Oxide

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