Abstract
Wnt-1, a secreted glycoprotein, participates in development of the nervous system and contributes to mammary oncogenesis when overexpressed. We show that GSK3 activity is decreased in mouse mammary cells transformed by Wnt-1. These cells also exhibit a substantial Wnt-1 dependent increase in the uncomplexed population of beta-catenin. Wnt-1 signaling does not change the steady state level of either GSK3 alpha or GSK3 beta but instead leads to an increased association between GSK3 beta and beta-catenin. HGF/SF treatment of mouse mammary cells also leads to a transient decrease in GSK3 activity and a parallel, selective increase in the uncomplexed pool of beta-catenin. Both Wnt-1 and HGF/SF lead to nuclear accumulation of beta-catenin and activation of a LEF/Tcf responsive reporter gene. This study defines a pivotal signal transduction pathway, activated by both Wnt-1 and HGF/SF, leading to decreased GSK3 beta activity and consequently an increase in the free pool and nuclear accumulation of beta-catenin and changes in gene expression.
MeSH terms
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Amino Acid Sequence
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Animals
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
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Cell Differentiation / physiology
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Cell Line
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Cytoskeletal Proteins / metabolism*
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DNA-Binding Proteins / metabolism
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Genes, Reporter / genetics
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Glycogen Synthase Kinase 3
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Hepatocyte Growth Factor / metabolism
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Lymphoid Enhancer-Binding Factor 1
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Mice
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Molecular Sequence Data
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Proto-Oncogene Proteins / physiology*
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Proto-Oncogene Proteins c-met / metabolism
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Signal Transduction / physiology
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Trans-Activators*
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Transcription Factors / metabolism
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Transcriptional Activation / physiology
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Transformation, Genetic / genetics
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Wnt Proteins
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Wnt1 Protein
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Zebrafish Proteins*
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beta Catenin
Substances
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CTNNB1 protein, mouse
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Cytoskeletal Proteins
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DNA-Binding Proteins
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Lymphoid Enhancer-Binding Factor 1
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Proto-Oncogene Proteins
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Trans-Activators
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Transcription Factors
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Wnt Proteins
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Wnt1 Protein
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Wnt1 protein, mouse
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Zebrafish Proteins
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beta Catenin
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Hepatocyte Growth Factor
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Proto-Oncogene Proteins c-met
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Calcium-Calmodulin-Dependent Protein Kinases
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Glycogen Synthase Kinase 3