Abstract
Many uncertainties remain regarding the physiological function of the prion protein PrP and the consequences of its conversion into the pathological scrapie isoform in prion diseases. Here, we show for the first time that different signal transduction pathways are involved in neurite outgrowth and neuronal survival elicited by PrP in cell culture of primary neurons. These pathways include the nonreceptor Src-related family member p59(Fyn), PI3 kinase/Akt, cAMP-dependent protein kinase A, and MAP kinase. Regulation of Bcl-2 and Bax expression also correlates with the survival effect elicited by PrP. The combined results, along with our observation that PrP carries the recognition molecule-related HNK-1 carbohydrate, argue strongly for a role of the molecule in neural recognition by interacting with yet unknown heterophilic neuronal receptors, as shown by comparison of neurite outgrowth from neurons of PrP-deficient and wild-type mice.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Brain / cytology
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Brain / growth & development*
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Brain / metabolism*
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CD57 Antigens / metabolism
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Cell Differentiation / drug effects
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Cell Differentiation / physiology*
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Cell Survival / drug effects
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Cell Survival / physiology*
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Cells, Cultured
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Cyclic AMP-Dependent Protein Kinases / drug effects
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Cyclic AMP-Dependent Protein Kinases / metabolism
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Humans
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MAP Kinase Signaling System / drug effects
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MAP Kinase Signaling System / physiology
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Mice
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Mitogen-Activated Protein Kinase 1 / drug effects
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Mitogen-Activated Protein Kinase 1 / metabolism
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Neurites / drug effects
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Neurites / metabolism*
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Neurites / ultrastructure
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Phosphatidylinositol 3-Kinases / drug effects
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Phosphatidylinositol 3-Kinases / metabolism
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PrPC Proteins / metabolism*
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PrPC Proteins / pharmacology
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Proto-Oncogene Proteins / drug effects
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-bcl-2 / drug effects
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Proto-Oncogene Proteins c-fyn
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Signal Transduction / drug effects
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Signal Transduction / physiology*
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bcl-2-Associated X Protein
Substances
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BAX protein, human
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Bax protein, mouse
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CD57 Antigens
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PrPC Proteins
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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bcl-2-Associated X Protein
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Phosphatidylinositol 3-Kinases
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FYN protein, human
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Fyn protein, mouse
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Proto-Oncogene Proteins c-fyn
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Cyclic AMP-Dependent Protein Kinases
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Mitogen-Activated Protein Kinase 1