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Increased Src kinase level results in increased protein tyrosine phosphorylation in scrapie-infected neuronal cell lines.
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
2006 (English)In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 580, no 11, 2603-8 p.Article in journal (Refereed) Published
Abstract [en]

We have studied how prion infection may affect the Src kinase activity in three different neuronal cell lines, ScGT1 and ScN2a, where ScGT1 were generated in our laboratory. By immunoblotting, using clone 28 - a monoclonal antibody recognizing active Src, we have found a 32+/-6.3% and 75+/-7.7% elevation in Src activity in ScGT1 and ScN2a cells, respectively, compared to uninfected cells. Immunocomplex in vitro kinase assay confirmed the increased Src activity. The increased Src kinase activity in scrapie-infected cells was further shown to correlate to an increased level of Src protein. In addition, an important increase in the protein tyrosine phosphorylation signal was observed in ScGT1 and ScN2a cells, which was further shown to be Src-dependent, as treatment with PP2 - a Src family kinase specific inhibitor, reversed the protein tyrosine phosphorylation profile. Abnormal Src-kinase activation and subsequent protein tyrosine phosphorylation may be key elements in the neuropathology of the prion diseases.

Place, publisher, year, edition, pages
Elsevier , 2006. Vol. 580, no 11, 2603-8 p.
Keyword [en]
Animals, Cell Line, Mice, Neurons/drug effects/*metabolism, Phosphorylation, Phosphotyrosine/*metabolism, Prions/*metabolism, Protein Binding, Protein Kinase Inhibitors/pharmacology, Pyrimidines/pharmacology, Scrapie/enzymology/*metabolism/pathology, Substrate Specificity, src-Family Kinases/antagonists & inhibitors/*metabolism
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:su:diva-14845DOI: 10.1016/j.febslet.2006.03.092PubMedID: 16647068OAI: oai:DiVA.org:su-14845DiVA: diva2:181365
Available from: 2008-11-06 Created: 2008-11-06 Last updated: 2017-12-13Bibliographically approved
In thesis
1. Interactions of Prion Proteins and PrP-derived Peptides in Scrapie infection
Open this publication in new window or tab >>Interactions of Prion Proteins and PrP-derived Peptides in Scrapie infection
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Prion diseases are fatal and incurable spongiform encephalopathies that occur amongst mammals. The central pathological event is the misfolding of the cellular prion protein (PrPC) into an amyloid, neurotoxic isoform called scrapie (PrPSc). PrPSc is the main, or sole, constituent of infectious prions. PrPSc resists cellular degradation and also induces misfolding of PrPC via a process called conversion. Conversion seems to be an endocytotic event implicating auxiliary cellular cofactors interacting with PrPC and/or PrPSc. The aim of this thesis is to decipher and modulate key events involved in prion conversion and cytopathology, by studying persistently scrapie infected murine neuronal cell cultures. This work shows that cell penetrating peptides derived from the prion protein (PrP-CPPs) can suppress cellular PrPSc levels. The PrP-CPPs assert these actions on two prion strains regardless of peptide configuration and do not inhibit any PrP-interaction with heparan sulfate (HS) proteoglycans (PG). A polybasic motif in the PrP-CPPs may interact with PrPSc, but the anti-prion effect is controlled by a signal peptide sequence. The PrP-CPPs represents a novel form of prion antagonizing compound. Prion-induced alterations in protein expression, cellular localization, activity and metabolism, designate putative mediators of disease or neuroprotective defence mechanisms. We report on interplay between the HSPG glypican-1 (Gpc-1) and scrapie-infection. Gpc-1 is aberrantly distributed in scrapie-infected cells and HS degradation by autocatalytic deaminative cleavage is elevated, suggestively in order to restrain PrPSc levels. Additionally, we demonstrate that scrapie-infection elevates the activity of Src family kinase members Src and Fyn, in part by affecting Src expression and Fyn membrane distribution. This causes an uncontrolled tyrosine phosphorylation which could contribute to neuronal loss in vivo.

Place, publisher, year, edition, pages
Stockholm: Department of Biochemistry and Biophysics, Stockholm University, 2010. 132 p.
Keyword
Spongiform encephalopathy, Creutzfeldt-Jakob disease, Amyloidosis, Neurodegeneration, Cell penetrating peptide, Protein Transduction Domain, Heparan sulfate, Proteoglycan, Glypican, Src family kinase, Fyn
National Category
Biochemistry and Molecular Biology
Research subject
Biochemistry
Identifiers
urn:nbn:se:su:diva-45736 (URN)978-91-7447-179-3 (ISBN)
Public defence
2010-12-21, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 13:00 (English)
Opponent
Supervisors
Note
At the time of the doctoral defence the following paper was unpublished and had a status as follows: Paper nr. 5: ManuscriptAvailable from: 2010-11-29 Created: 2010-11-10 Last updated: 2010-12-03Bibliographically approved

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