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Alpha Cleavage

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Victoria A Lawson – 1st expert on this subject based on the ideXlab platform

  • prpc related signal transduction is influenced by copper membrane integrity and the Alpha Cleavage site
    Cell Research, 2009
    Co-Authors: Cathryn L Haigh, Victoria A Lawson, Victoria Lewis, Laura J Vella, Colin L Masters, Andrew F Hill

    Abstract:

    PrP C -related signal transduction is influenced by copper, membrane integrity and the Alpha Cleavage site

  • PrP^C-related signal transduction is influenced by copper, membrane integrity and the Alpha Cleavage site
    Cell Research, 2009
    Co-Authors: Cathryn L Haigh, Victoria A Lawson, Laura J Vella, Colin L Masters, Andrew F Hill, Victoria A Lewis, Steven J. Collins

    Abstract:

    The copper-binding, membrane-anchored, cellular prion protein (PrP^C) has two constitutive Cleavage sites producing distinct N- and C-terminal fragments (N1/C1 and N2/C2). Using RK13 cells expressing either human PrP^C, mouse PrP^C or mouse PrP^C carrying the 3F4 epitope, this study explored the influence of the PrP^C primary sequence on endoproteolytic Cleavage and one putative PrP^C function, MAP kinase signal transduction, in response to exogenous copper with or without a perturbed membrane environment. PrP^C primary sequence, especially that around the N1/C1 Cleavage site, appeared to influence basal levels of proteolysis at this location and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation, with increased processing demonstrating an inverse relationship with basal ERK1/2 activation. Human PrP^C showed increased N1/C1 Cleavage in response to copper alone, accompanied by specific p38 and JNK/SAPK phosphorylation. Combined exposure to copper plus the cholesterol-sequestering antibiotic filipin resulted in a mouse PrP^C-specific substantial increase in signal protein phosphorylation, accompanied by an increase in N1/C1 Cleavage. Mouse PrP^C harboring the human N1/C1 Cleavage site assumed more human-like profiles basally and in response to copper and altered membrane environments. Our results demonstrate that the PrP^C primary sequence around the N1/C1 Cleavage site influences endoproteolytic processing at this location, which appears linked to MAP kinase signal transduction both basally and in response to copper. Further, the primary sequence appears to confer a mutual dependence of N1/C1 Cleavage and membrane integrity on the fidelity of PrP^C-related signal transduction in response to exogenous stimuli.

  • PrPC-related signal transduction is influenced by copper, membrane integrity and the Alpha Cleavage site.
    Cell Research, 2009
    Co-Authors: Cathryn L Haigh, Victoria A Lawson, Victoria Lewis, Laura J Vella, Colin L Masters, Andrew F Hill, Steven J. Collins

    Abstract:

    The copper-binding, membrane-anchored, cellular prion protein (PrP(C)) has two constitutive Cleavage sites producing distinct N- and C-terminal fragments (N1/C1 and N2/C2). Using RK13 cells expressing either human PrP(C), mouse PrP(C) or mouse PrP(C) carrying the 3F4 epitope, this study explored the influence of the PrP(C) primary sequence on endoproteolytic Cleavage and one putative PrP(C) function, MAP kinase signal transduction, in response to exogenous copper with or without a perturbed membrane environment. PrP(C) primary sequence, especially that around the N1/C1 Cleavage site, appeared to influence basal levels of proteolysis at this location and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation, with increased processing demonstrating an inverse relationship with basal ERK1/2 activation. Human PrP(C) showed increased N1/C1 Cleavage in response to copper alone, accompanied by specific p38 and JNK/SAPK phosphorylation. Combined exposure to copper plus the cholesterol-sequestering antibiotic filipin resulted in a mouse PrP(C)-specific substantial increase in signal protein phosphorylation, accompanied by an increase in N1/C1 Cleavage. Mouse PrP(C) harboring the human N1/C1 Cleavage site assumed more human-like profiles basally and in response to copper and altered membrane environments. Our results demonstrate that the PrP(C) primary sequence around the N1/C1 Cleavage site influences endoproteolytic processing at this location, which appears linked to MAP kinase signal transduction both basally and in response to copper. Further, the primary sequence appears to confer a mutual dependence of N1/C1 Cleavage and membrane integrity on the fidelity of PrP(C)-related signal transduction in response to exogenous stimuli.

Atanasio Pandiella – 2nd expert on this subject based on the ideXlab platform

  • autocrine regulation of membrane transforming growth factor Alpha Cleavage
    Journal of Biological Chemistry, 1996
    Co-Authors: Jose Baselga, John Mendelsohn, Atanasio Pandiella

    Abstract:

    Abstract Transforming growth factor α (TGF-α) is biosynthesized as a membrane-bound precursor protein, pro-TGF-α, that undergoes sequential endoproteolytic Cleavages to release a soluble form of the factor. In the present study, we have analyzed the biosynthesis and regulation of TGF-α production in human tumor-derived cell lines that endogenously express pro-TGF-α and the epidermal growth factor (EGF) receptor. These cells biosynthesized membrane-anchored forms of the TGF-α that accumulated on the cell surface. Membrane-bound pro-TGF-α interacted with the EGF receptor, and complexes of receptor and pro-TGF-α contained tyrosine-phosphorylated receptor. Activation of the EGF receptor by soluble EGF or TGF-α had a dual effect on TGF-α production: an increase in pro-TGF-α mRNA levels and an increase in pro-TGF-α Cleavage. These effects were largely prevented by preincubation with an anti-EGF receptor monoclonal antibody that blocked ligand binding. Growth factor autoinduction of Cleavage could be stimulated by several second messenger pathways that are activated by the EGF receptor, including protein kinase C and intracellular calcium, and by other alternative mechanisms. EGF-stimulated Cleavage of pro-TGF-α could be partially blocked by inhibition of these second messenger pathways. These results suggest that juxtacrine stimulation takes place in human tumor cells that coexpress both the EGF receptor and membrane-anchored TGF-α and that TGF-α is able to induce its own endoproteolytic Cleavage by activating the EGF receptor.

  • Activated release of membrane-anchored TGF-Alpha in the absence of cytosol.
    Journal of Cell Biology, 1993
    Co-Authors: Marcus W. Bosenberg, Atanasio Pandiella, Joan Massague

    Abstract:

    The ectodomain of proTGF-Alpha, a membrane-anchored growth factor, is converted into soluble TGF-Alpha by a regulated cellular proteolytic system that recognizes proTGF-Alpha via the C-terminal valine of its cytoplasmic tail. In order to define the biochemical components involved in proTGF-Alpha Cleavage, we have used cells permeabilized with streptolysin O (SLO) that have been extensively washed to remove cytosol. PMA, acting through a Ca(2+)-independent protein kinase C, activates Cleavage as efficiently in permeabilized cells as it does in intact cells. ProTGF-Alpha Cleavage is also stimulated by GTP gamma S through a mechanism whose pharmacological properties suggest the involvement of a heterotrimeric G protein acting upstream of the PMA-sensitive Ca(2+)-independent protein kinase C. Activated proTGF-Alpha Cleavage is dependent on ATP hydrolysis, appears not to require vesicular traffic, and acts specifically on proTGF-Alpha that has reached the cell surface. These results indicate that proTGF-Alpha is cleaved from the cell surface by a regulated system whose signaling, recognition, and proteolytic components are retained in cells devoid of cytosol.

  • multiple signals activate Cleavage of the membrane transforming growth factor Alpha precursor
    Journal of Biological Chemistry, 1991
    Co-Authors: Atanasio Pandiella, Joan Massague

    Abstract:

    Abstract Cleavage of the membrane-anchored precursor for transforming growth factor-Alpha (TGF-Alpha), a rate-limiting step in the generation of soluble TGF-Alpha, can be stimulated by phorbol esters acting via protein kinase C. In the present study, activators of other intracellular signaling pathways were tested for their ability to stimulate pro-TGF-Alpha Cleavage in Chinese hamster ovary cells transfected with a pro-TGF-Alpha cDNA. Treatment with the Ca2+ ionophore, A23187, rapidly increased the rate of pro-TGF-Alpha Cleavage over 25-fold. This effect of A23187 on pro-TGF-Alpha Cleavage was dependent on the influx of extracellular calcium and was largely independent of protein kinase C activation. In contrast, phorbol 12-myristate 13-acetate stimulation of pro-TGF-Alpha Cleavage via activation of protein kinase C did not require extracellular calcium. Stimulation of pro-TGF-Alpha Cleavage by serum was largely independent of both protein kinase C and extracellular calcium influx, whereas activators of protein kinase A and protein kinase G did not stimulate pro-TGF-Alpha Cleavage. These results suggest that regulation of pro-TGF-Alpha Cleavage is a complex process that can be controlled by extracellular agents via at least three distinct signal transduction pathways.

Cathryn L Haigh – 3rd expert on this subject based on the ideXlab platform

  • prpc related signal transduction is influenced by copper membrane integrity and the Alpha Cleavage site
    Cell Research, 2009
    Co-Authors: Cathryn L Haigh, Victoria A Lawson, Victoria Lewis, Laura J Vella, Colin L Masters, Andrew F Hill

    Abstract:

    PrP C -related signal transduction is influenced by copper, membrane integrity and the Alpha Cleavage site

  • PrP^C-related signal transduction is influenced by copper, membrane integrity and the Alpha Cleavage site
    Cell Research, 2009
    Co-Authors: Cathryn L Haigh, Victoria A Lawson, Laura J Vella, Colin L Masters, Andrew F Hill, Victoria A Lewis, Steven J. Collins

    Abstract:

    The copper-binding, membrane-anchored, cellular prion protein (PrP^C) has two constitutive Cleavage sites producing distinct N- and C-terminal fragments (N1/C1 and N2/C2). Using RK13 cells expressing either human PrP^C, mouse PrP^C or mouse PrP^C carrying the 3F4 epitope, this study explored the influence of the PrP^C primary sequence on endoproteolytic Cleavage and one putative PrP^C function, MAP kinase signal transduction, in response to exogenous copper with or without a perturbed membrane environment. PrP^C primary sequence, especially that around the N1/C1 Cleavage site, appeared to influence basal levels of proteolysis at this location and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation, with increased processing demonstrating an inverse relationship with basal ERK1/2 activation. Human PrP^C showed increased N1/C1 Cleavage in response to copper alone, accompanied by specific p38 and JNK/SAPK phosphorylation. Combined exposure to copper plus the cholesterol-sequestering antibiotic filipin resulted in a mouse PrP^C-specific substantial increase in signal protein phosphorylation, accompanied by an increase in N1/C1 Cleavage. Mouse PrP^C harboring the human N1/C1 Cleavage site assumed more human-like profiles basally and in response to copper and altered membrane environments. Our results demonstrate that the PrP^C primary sequence around the N1/C1 Cleavage site influences endoproteolytic processing at this location, which appears linked to MAP kinase signal transduction both basally and in response to copper. Further, the primary sequence appears to confer a mutual dependence of N1/C1 Cleavage and membrane integrity on the fidelity of PrP^C-related signal transduction in response to exogenous stimuli.

  • PrPC-related signal transduction is influenced by copper, membrane integrity and the Alpha Cleavage site.
    Cell Research, 2009
    Co-Authors: Cathryn L Haigh, Victoria A Lawson, Victoria Lewis, Laura J Vella, Colin L Masters, Andrew F Hill, Steven J. Collins

    Abstract:

    The copper-binding, membrane-anchored, cellular prion protein (PrP(C)) has two constitutive Cleavage sites producing distinct N- and C-terminal fragments (N1/C1 and N2/C2). Using RK13 cells expressing either human PrP(C), mouse PrP(C) or mouse PrP(C) carrying the 3F4 epitope, this study explored the influence of the PrP(C) primary sequence on endoproteolytic Cleavage and one putative PrP(C) function, MAP kinase signal transduction, in response to exogenous copper with or without a perturbed membrane environment. PrP(C) primary sequence, especially that around the N1/C1 Cleavage site, appeared to influence basal levels of proteolysis at this location and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation, with increased processing demonstrating an inverse relationship with basal ERK1/2 activation. Human PrP(C) showed increased N1/C1 Cleavage in response to copper alone, accompanied by specific p38 and JNK/SAPK phosphorylation. Combined exposure to copper plus the cholesterol-sequestering antibiotic filipin resulted in a mouse PrP(C)-specific substantial increase in signal protein phosphorylation, accompanied by an increase in N1/C1 Cleavage. Mouse PrP(C) harboring the human N1/C1 Cleavage site assumed more human-like profiles basally and in response to copper and altered membrane environments. Our results demonstrate that the PrP(C) primary sequence around the N1/C1 Cleavage site influences endoproteolytic processing at this location, which appears linked to MAP kinase signal transduction both basally and in response to copper. Further, the primary sequence appears to confer a mutual dependence of N1/C1 Cleavage and membrane integrity on the fidelity of PrP(C)-related signal transduction in response to exogenous stimuli.