Clipping, shedding and RIPping keep immunity on cue

Murphy, Gillian; Murthy, Aditya; Khokha, Rama

doi:10.1016/j.it.2007.10.009

Cited by 92 publications

(78 citation statements)

References 80 publications

(97 reference statements)

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“…5E). Although speculative, it seems likely that the most relevant in vivo cleavages in terms of immune dysfunction would be to antibodies already targeting cell surfaces as occurs in membrane receptor shedding by cellular proteases (52). Solution-phase competition can also be considered, and measurements of singlecleaved IgG derivatives vs. intact counterparts were undertaken using functional, cell-killing assays.…”

Section: The Loss-of-function Of Single-cleaved Igg Correlated With Dmentioning

confidence: 99%

Tumor-associated and microbial proteases compromise host IgG effector functions by a single cleavage proximal to the hinge

Brezski¹,

Vafa²,

Petrone³

et al. 2009

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

134

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The successful elimination of pathogenic cells and microorganisms by the humoral immune system relies on effective interactions between host immunoglobulins and Fc␥ receptors on effector cells, in addition to the complement system. Essential Ig motifs that direct those interactions reside within the conserved IgG lower hinge/CH2 interface. We noted that a group of tumor-related and microbial proteases cleaved human IgG1s in that region, and the ''nick'' of just one of the heavy chains profoundly inhibited IgG1 effector functions. We focused on IgG1 monoclonal antibodies (mAbs) since IgG1 is the most abundant human subclass and demonstrates robust Fc-mediated effector functions. The loss of Fc-mediated cell killing activities was correlated with diminished binding to the Fc␥ family of receptors, but a similar decrease in affinity was not observed toward the FcRn receptor that maintains IgG in circulation. Endogenous human IgG cleavage products of comparable size to mAbs with the single cleavage were detected by Western blot analysis in synovial fluid from patients with rheumatoid arthritis and in breast carcinoma extracts. Their detection is problematic under physiological conditions, since there is no loss of structure, and antigen-binding capability is unaffected. These findings suggest that within the hostile proteolytic microenvironments associated with many diseases, key effector functions of host IgGs, or therapeutic Abs, may be compromised.antibody-dependent cellular cytotoxicity ͉ complement-dependent cytotoxicity ͉ Fc gamma Receptors ͉ matrix metalloproteinases ͉ monoclonal antibodies

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Section: The Loss-of-function Of Single-cleaved Igg Correlated With Dmentioning

confidence: 99%

Tumor-associated and microbial proteases compromise host IgG effector functions by a single cleavage proximal to the hinge

Brezski¹,

Vafa²,

Petrone³

et al. 2009

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

134

View full text Add to dashboard Cite

show abstract

“…Further, a key part of the EGFR story involves sECD-HER 2/neu [23] and its proteolytic processing via protein ectodomain shedding by the ADAM family of proteins [24]. Post-translational processing of extracellular membrane components is a major mode of regulation [25]. The ALYGNSA assay, with its enhanced sensitivity, may be the vehicle that could drive these investigations.…”

Section: Secd-her 2/neu Detection: Assessment Of Normal Physiologicalmentioning

confidence: 99%

Enhanced immuno-detection of shed extracellular domain of HER-2/neu

Chourb¹,

Mackness²,

Farris³

et al. 2009

Health

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HER-2/neu oncogene is over-expressed and amplified in patients associated with metastatic breast cancer. An increased level (>15 ng/mL) in the shed extracellular domain (sECD-HER 2/neu) is indicative of the potential presence and associated progression of this disease. A fluorescent ELISA incorporating the newly developed ALYGNSA antibody-orientation system revealed a 10-fold increase in sensitivity (≤0.63 ng/mL) of sECD-HER 2/neu when compared to a control standard ELISA kit (≤7.5 ng/mL). This enhanced mode of detection has the potential to not only address breast and other cancers per se but also permit an in depth evaluation of "shed extracellular domains", in general, and the role of these "proteolytic derived factors" in physiological signalling at normal levels.

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“…However, as I discuss in this review, studies during the past two decades have revealed that ectodomain shedding is an essential post-translational mechanism with critical roles during development, in homeostasis, and under pathological conditions in vivo. [1][2][3] As its name suggests, tumor necrosis factor α (TNFα)-converting enzyme (TACE), also known as a disintegrin and metalloprotease 17 (ADAM17), was originally identified as an enzyme responsible for releasing the membrane-bound TNFα precursor to produce biologically active soluble TNFα. 4,5 However, studies over the past decade have identified a wide range of membrane-bound proteins in addition to TNFα as substrates for TACE, [1][2][3] including the ligands for epidermal growth factor receptor (EGFR), 6 which are also produced as membranebound precursors and are cleaved to become fully functional.…”

Section: Introductionmentioning

confidence: 99%

A Brief History of Tumor Necrosis Factor α – converting Enzyme: An Overview of Ectodomain Shedding

Horiuchi

2013

Keio J. Med.

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Many membrane-bound molecules are cleaved at the cell surface, thereby releasing their extracellular domains. This process, often referred to as ectodomain shedding, has emerged as a critical post-translational mechanism for various membrane-bound ligands, receptors, and adhesion molecules. Tumor necrosis factor α (TNFα)-converting enzyme (TACE/ADAM17) was originally identified as an enzyme responsible for releasing the membrane-bound TNFα precursor. However, subsequent studies found an exceptionally large number of target molecules of TACE, including the ligands for epidermal growth factor receptor, L-selectin, CD44, and vascular growth factor receptor 2. Furthermore, in vivo studies using TACE-conditional knockout mice demonstrated the crucial roles of TACE and ectodomain shedding under both physiological and pathological conditions. However, the potential clinical application of the manipulation of TACE activity remains to be investigated.

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Clipping, shedding and RIPping keep immunity on cue

Cited by 92 publications

References 80 publications

Tumor-associated and microbial proteases compromise host IgG effector functions by a single cleavage proximal to the hinge

Tumor-associated and microbial proteases compromise host IgG effector functions by a single cleavage proximal to the hinge

Enhanced immuno-detection of shed extracellular domain of HER-2/neu

A Brief History of Tumor Necrosis Factor α – converting Enzyme: An Overview of Ectodomain Shedding

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