Ligand-induced internalization of TNF receptor 2 mediated by a di-leucin motif is dispensable for activation of the NFκB pathway

Fischer, Roman; Maier, Olaf; Naumer, Matthias; Krippner‐Heidenreich, Anja; Scheurich, Peter; Pfizenmaier, Klaus

doi:10.1016/j.cellsig.2010.08.016

Cited by 38 publications

(38 citation statements)

References 31 publications

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“…5C). This IL motif in CXCR4 was previously identified as homologous to the "dileucine motif" that regulates GPCR endocytosis in other cell types (Orsini et al, 2000;Fischer et al, 2011;Guo and Jose, 2011). Flow cytometric analysis indicated that these mutations did not inhibit the cell-surface expression of CXCR4, since the CXCR4 mutants studied were expressed on the cell surface at levels comparable to the wild-type CXCR4 construct (Supplemental Fig.…”

Section: Resultsmentioning

confidence: 97%

β-Arrestin1 and Distinct CXCR4 Structures Are Required for Stromal Derived Factor-1 to Downregulate CXCR4 Cell-Surface Levels in Neuroblastoma

et al. 2014

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CXC chemokine receptor 4 (CXCR4) is a G protein-coupled receptor (GPCR) located on the cell surface that signals upon binding the chemokine stromal derived factor-1 (SDF-1; also called CXCL 12). CXCR4 promotes neuroblastoma proliferation and chemotaxis. CXCR4 expression negatively correlates with prognosis and drives neuroblastoma growth and metastasis in mouse models. All functions of CXCR4 require its expression on the cell surface, yet the molecular mechanisms that regulate CXCR4 cell-surface levels in neuroblastoma are poorly understood. We characterized CXCR4 cell-surface regulation in the related SH-SY5Y and SK-N-SH human neuroblastoma cell lines. SDF-1 treatment caused rapid down-modulation of CXCR4 in SH-SY5Y cells. Pharmacologic activation of protein kinase C similarly reduced CXCR4, but via a distinct mechanism. Analysis of CXCR4 mutants delineated two CXCR4 regions required for SDF-1 treatment to decrease cell-surface CXCR4 in neuroblastoma cells: the isoleucine-leucine motif at residues 328 and 329 and residues 343-352. In contrast, and unlike CXCR4 regulation in other cell types, serines 324, 325, 338, and 339 were not required. Arrestin proteins can bind and regulate GPCR cell-surface expression, often functioning together with kinases such as G protein-coupled receptor kinase 2 (GRK2). Using SK-N-SH cells which are naturally deficient in b-arrestin1, we showed that b-arrestin1 is required for the CXCR4 343-352 region to modulate CXCR4 cell-surface expression following treatment with SDF-1. Moreover, GRK2 overexpression enhanced CXCR4 internalization, via a mechanism requiring both b-arrestin1 expression and the 343-352 region. Together, these results characterize CXCR4 structural domains and b-arrestin1 as critical regulators of CXCR4 cell-surface expression in neuroblastoma. b-Arrestin1 levels may therefore influence the CXCR4-driven metastasis of neuroblastoma as well as prognosis.

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Section: Resultsmentioning

confidence: 97%

β-Arrestin1 and Distinct CXCR4 Structures Are Required for Stromal Derived Factor-1 to Downregulate CXCR4 Cell-Surface Levels in Neuroblastoma

et al. 2014

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“…Previous work had further suggested that mTNFα stabilized membrane protein expression of TNFR2, 40 thus potentially explaining why the levels of membrane TNFR2 but not TNFR1 were higher in the Adam17 mutants. Because it is TNFR2 signaling and not TNFR1 signaling, that is preferentially activated by mTNFα, 25 an overactivation of TNFR2 signaling through both higher mTNFα and mTNFR2 protein ( Figure 3) might, thus, promote atherosclerosis.…”

Section: Discussionmentioning

confidence: 99%

Adam17 Deficiency Promotes Atherosclerosis by Enhanced TNFR2 Signaling in Mice

Nicolaou

Zhang

Northoff

et al. 2017

ATVB

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Objective— ADAM17 (a disintegrin and metalloproteinase 17) is a sheddase releasing different types of membrane-bound proteins, including adhesion molecules, cytokines, and their receptors as well as inflammatory mediators. Because these substrates modulate important mechanisms of atherosclerosis, we hypothesized that ADAM17 might be involved in the pathogenesis of this frequent disease. Approach and Results— Because Adam17 -knockout mice are not viable, we studied the effect of Adam17 deficiency on atherosclerosis in Adam17 hypomorphic mice ( Adam17 ex/ex ), which have low residual Adam17 expression. To induce atherosclerosis, mice were crossed onto the low-density lipoprotein receptor ( Ldlr )-deficient background. We found that Adam17 ex/ex .Ldlr −/− mice developed ≈1.5-fold larger atherosclerotic lesions, which contained more macrophages and vascular smooth muscle cells than wild-type littermate controls ( Adam17 wt/wt .Ldlr −/− ). Reduced Adam17 -mediated shedding led to significantly increased protein levels of membrane-resident TNFα (tumor necrosis factor) and TNFR2 (tumor necrosis factor receptor 2), resulting in a constitutive activation of TNFR2 signaling. At the same time, Adam17 deficiency promoted proatherosclerotic cellular functions, such as increased proliferation and reduced apoptosis in cultured macrophages and vascular smooth muscle cells and increased adhesion of macrophages to vascular endothelial cells. Because siRNA (small interfering RNA)-mediated knockdown of Tnfr2 rescued from aberrant proliferation and from misregulation of apoptosis in Adam17 -depleted cells, our data indicate that TNFR2 is an important effector of ADAM17 in our mouse model. Conclusions— Our results provide evidence for an atheroprotective role of ADAM17, which might be mediated by cleaving membrane-bound TNFα and TNFR2, thereby preventing overactivation of endogenous TNFR2 signaling in cells of the vasculature.

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“…The presence of immunohistochemical reactions for TNFR1 and TNFR2 has also in other situations been found to be confined both to cell membrane locations and to a cytoplasmic location, i.e. being internalized [Fischer et al, 2011;Maddahi et al, 2011]. In order to complement the findings of TNF-␣ expression in tendon tissue, specimens of Achilles tendinosis tendons were also examined concerning levels of TNF-␣ by the use of ELISA.…”

Section: Discussionmentioning

confidence: 99%

Evidence of the TNF-α System in the Human Achilles Tendon: Expression of TNF-α and TNF Receptor at both Protein and mRNA Levels in the Tenocytes

Gaida

Bagge²,

Purdam³

et al. 2012

Cells Tissues Organs

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Understanding adaption to load is essential for prevention and treatment of tendinopathy/tendinosis. Cytokine release in response to load is one mechanism involved in mechanotransduction. The cytokine tumor necrosis factor alpha (TNF-α) is implicated in tendinosis and can induce apoptotic effects via tumor necrosis factor receptor 1 (TNFR1). The complete absence of information concerning the TNF-α system in Achilles tendon is a limitation as mid-portion Achilles tendinosis is very frequent. Purpose: To examine expression patterns of TNF-α and its two receptors (TNFR1 and TNFR2) in human Achilles tendinosis and control tissue and to biochemically confirm the presence of TNF-α in tendinosis tissue. Methods: TNF-α and TNFR1 mRNA were detected via in situ hybridization. TNF-α, TNFR1, and TNFR2 were demonstrated immunohistochemically. Apoptosis markers were utilized. ELISA was used to detect TNF-α. Results: TNF-α and TNFR1 mRNA was detected in tenocytes of both tendinosis and control tendons. Tenocytes from both groups displayed specific immunoreactions for TNF-α, TNFR1, and TNFR2. The widened/rounded tenocytes of tendinosis samples exhibited the most intense immunoreactions. Apoptosis was detected in only a subpopulation of the tenocytes in tendinosis tissue. TNF-α was measurable in tendinosis tissue. Inflammatory cells were not seen. Conclusion: This is the first evidence of the existence of the TNF-α system in the human Achilles tendon. Findings are confirmed at mRNA and protein levels as well as biochemically. The TNF-α system was in principle confined to the tenocytes. The connection between tenocyte morphology and the expression pattern of TNF-α, TNFR1, and TNFR2 suggests that the TNF-α system may be involved in tenocyte activation in Achilles tendinosis.

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Ligand-induced internalization of TNF receptor 2 mediated by a di-leucin motif is dispensable for activation of the NFκB pathway

Cited by 38 publications

References 31 publications

β-Arrestin1 and Distinct CXCR4 Structures Are Required for Stromal Derived Factor-1 to Downregulate CXCR4 Cell-Surface Levels in Neuroblastoma

β-Arrestin1 and Distinct CXCR4 Structures Are Required for Stromal Derived Factor-1 to Downregulate CXCR4 Cell-Surface Levels in Neuroblastoma

Adam17 Deficiency Promotes Atherosclerosis by Enhanced TNFR2 Signaling in Mice

Evidence of the TNF-α System in the Human Achilles Tendon: Expression of TNF-α and TNF Receptor at both Protein and mRNA Levels in the Tenocytes

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