α-ENaC is a functional element of the hypertonicity-induced cation channel in HepG2 cells and it mediates proliferation

Bondarava, Maryna; Li, Tongju; Endl, Elmar; Wehner, Frank

doi:10.1007/s00424-009-0649-z

Cited by 49 publications

(53 citation statements)

References 42 publications

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“…However, PcTX-1 prevented a regulatory volume increase in glioma cells following a hyperosmotic challenge (19). It has previously been suggested that in addition ENaC plays an important role in wound healing (33,34) and proliferation (35). Both ASIC and ENaC channels contribute to migration of vascular smooth muscle cells (36,37), although in neither case are the underlying mechanisms well understood.…”

Section: Discussionmentioning

confidence: 99%

Glioma-specific Cation Conductance Regulates Migration and Cell Cycle Progression

Rooj

McNicholas

Bartoszewski

et al. 2012

Journal of Biological Chemistry

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Background: Cation transport contributes to migration and proliferation of tumor cells. Results: Sodium current block decreased ERK phosphorylation and increased expression of cell cycle inhibitors. Conclusion: Activity of an ENaC/ASIC cation channel is required to maintain the glioma cell phenotype. Significance: Activity of a membrane cation channel influences signaling pathways to effect changes in migration and proliferation of glioma cells.

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Section: Discussionmentioning

confidence: 99%

Glioma-specific Cation Conductance Regulates Migration and Cell Cycle Progression

Rooj

McNicholas

Bartoszewski

et al. 2012

Journal of Biological Chemistry

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“…Disruption of Mβ in mice affects embryonic viability, birth weight, and renal gene expression profiles (19). The enzyme was further identified as a sheddase or proteolytic regulator at the plasma membrane of interleukin-1β (20), interleukin-18 (21), tumor growth factor α (22), procollagen III (23), epithelial sodium channel (24), E-cadherin (25), tenascin-C (26), and vascular endothelial growth factor A (27). Further substrates include fibroblast growth factor 19 and connective tissue growth factor.…”

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confidence: 99%

Structural basis for the sheddase function of human meprin β metalloproteinase at the plasma membrane

Arolas

Broder²,

Jefferson³

et al. 2012

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

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Ectodomain shedding at the cell surface is a major mechanism to regulate the extracellular and circulatory concentration or the activities of signaling proteins at the plasma membrane. Human meprin β is a 145-kDa disulfide-linked homodimeric multidomain type-I membrane metallopeptidase that sheds membrane-bound cytokines and growth factors, thereby contributing to inflammatory diseases, angiogenesis, and tumor progression. In addition, it cleaves amyloid precursor protein (APP) at the β-secretase site, giving rise to amyloidogenic peptides. We have solved the X-ray crystal structure of a major fragment of the meprin β ectoprotein, the first of a multidomain oligomeric transmembrane sheddase, and of its zymogen. The meprin β dimer displays a compact shape, whose catalytic domain undergoes major rearrangement upon activation, and reveals an exosite and a sugar-rich channel, both of which possibly engage in substrate binding. A plausible structure-derived working mechanism suggests that substrates such as APP are shed close to the plasma membrane surface following an "N-like" chain trace. P hysiological processes in the extracellular milieu and the circulation require finely tuned concentrations of signal molecules such as cytokines, growth factors, receptors, adhesion molecules, and peptidases. Many of these proteins are synthesized as type-I membrane protein variants or precursors consisting of a glycosylated N-terminal ectoprotein, a transmembrane helix, and a Cterminal cytosolic tail. Their localization at the cell surface restricts their field of action to autocrine or juxtacrine processes. However, to act at a distance in paracrine, synaptic, or endocrine events, they have to be released from the plasma membrane into the extracellular space as soluble factors through "protein ectodomain shedding" (1, 2). This entails limited proteolysis and is a major posttranslational regulation mechanism that affects 2-4% of the proteins on the cell surface, occurs at or near the plasma membrane (3), and apparently follows a common release mechanism (2). It may also proteolytically inactivate proteins to terminate their function on the cell surface (4). Peptidases engaged in such processing are "sheddases" and the most studied transmembrane sheddases are members of the adamalysin/ADAMs (4, 5) and matrix-metalloproteinase (MMP) (6) families within the metzincin clan of metallopeptidases (MPs) (7-9). These include ADAM

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“…To date, only a few potential in vivo substrates of meprin ␤ have been described, e.g. interleukin-1␤ (11), interleukin-18 (12), pro-collagen III (10), tumor growth factor ␣ (TGF-␣) (13), epithelial sodium channel (14), and vascular endothelial growth factor A (VEGF-A) (15). Other reports have revealed an involvement of meprin ␤ in immunological mechanisms due to its expression in intestinal leukocytes of the lamina propria (16).…”

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confidence: 99%

Metalloprotease Meprin β Generates Nontoxic N-terminal Amyloid Precursor Protein Fragments in Vivo

Jefferson

Čaušević

Keller³

et al. 2011

Journal of Biological Chemistry

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Identification of physiologically relevant substrates is still the most challenging part in protease research for understanding the biological activity of these enzymes. The zinc-dependent metalloprotease meprin ␤ is known to be expressed in many tissues with functions in health and disease. Here, we demonstrate unique interactions between meprin ␤ and the amyloid precursor protein (APP). Although APP is intensively studied as a ubiquitously expressed cell surface protein, which is involved in Alzheimer disease, its precise physiological role and relevance remain elusive. Based on a novel proteomics technique termed terminal amine isotopic labeling of substrates (TAILS), APP was identified as a substrate for meprin ␤. Processing of APP by meprin ␤ was subsequently validated using in vitro and in vivo approaches. N-terminal APP fragments of about 11 and 20 kDa were found in human and mouse brain lysates but not in meprin ␤ ؊/؊ mouse brain lysates. Although these APP fragments were in the range of those responsible for caspase-induced neurodegeneration, we did not detect cytotoxicity to primary neurons treated by these fragments. Our data demonstrate that meprin ␤ is a physiologically relevant enzyme in APP processing.

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α-ENaC is a functional element of the hypertonicity-induced cation channel in HepG2 cells and it mediates proliferation

Cited by 49 publications

References 42 publications

Glioma-specific Cation Conductance Regulates Migration and Cell Cycle Progression

Glioma-specific Cation Conductance Regulates Migration and Cell Cycle Progression

Structural basis for the sheddase function of human meprin β metalloproteinase at the plasma membrane

Metalloprotease Meprin β Generates Nontoxic N-terminal Amyloid Precursor Protein Fragments in Vivo

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