Abstract
The Alzheimer's disease-linked gene presenilin 1 (PS1) is required for intramembrane proteolysis of APP and Notch. In addition, recent observations strongly implicate PS1 as a negative regulator of the Wnt/beta-catenin signaling pathway, although the mechanism underlying this activity is unknown. Here, we show that presenilin functions as a scaffold that rapidly couples beta-catenin phosphorylation through two sequential kinase activities independent of the Wnt-regulated Axin/CK1alpha complex. Thus, presenilin deficiency results in increased beta-catenin stability in vitro and in vivo by disconnecting the stepwise phosphorylation of beta-catenin, both in the presence and absence of Wnt stimulation. These findings highlight an aspect of beta-catenin regulation outside of the canonical Wnt-regulated pathway and a function of presenilin separate from intramembrane proteolysis.
Publication types
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Comparative Study
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Alzheimer Disease / metabolism
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Animals
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Axin Protein
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Cell Line
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Cytoskeletal Proteins / metabolism*
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Humans
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Hyperplasia / genetics
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Hyperplasia / metabolism
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Hyperplasia / pathology
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Medulloblastoma / genetics
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Medulloblastoma / metabolism
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Medulloblastoma / pathology
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Mice
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Mice, Mutant Strains
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Models, Biological
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Mutation / genetics
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Neoplasms / etiology*
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Phenotype
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Phosphorylation
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Presenilin-1
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Protein-Tyrosine Kinases / metabolism
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Proteins / metabolism*
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Proto-Oncogene Proteins / metabolism
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Repressor Proteins*
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Signal Transduction
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Skin Neoplasms / genetics
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Skin Neoplasms / metabolism
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Skin Neoplasms / pathology
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Spinal Cord / embryology
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Spinal Cord / metabolism
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Spinal Cord / pathology
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Trans-Activators / metabolism*
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Wnt Proteins
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Zebrafish Proteins*
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beta Catenin
Substances
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Axin Protein
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CTNNB1 protein, human
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CTNNB1 protein, mouse
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Cytoskeletal Proteins
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Membrane Proteins
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PSEN1 protein, human
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Presenilin-1
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Proteins
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Proto-Oncogene Proteins
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Repressor Proteins
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Trans-Activators
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Wnt Proteins
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Zebrafish Proteins
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beta Catenin
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Protein-Tyrosine Kinases