Abstract
Binding of the secreted axon guidance cue Slit to its Robo receptor results in inactivation of the neural, calcium-dependent cell-cell adhesion molecule N-cadherin, providing a rapid epigenetic mechanism for integrating guidance and adhesion information. This requires the formation of a multimolecular complex containing Robo, Abl tyrosine kinase and N-cadherin. Here we show that on binding of Slit to Robo, the adaptor protein Cables is recruited to Robo-associated Abl and forms a multimeric complex by binding directly to N-cadherin-associated beta-catenin. Complex formation results in Abl-mediated phosphorylation of beta-catenin on tyrosine 489, leading to a decrease in its affinity for N-cadherin, loss of N-cadherin function, and targeting of phospho-Y489-beta-catenin to the nucleus. Nuclear beta-catenin combines with the transcription factor Tcf/Lef and activates transcription. Thus, Slit-induced formation of the Robo-N-cadherin complex results in a rapid loss of cadherin-mediated adhesion and has more lasting effects on gene transcription.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Cadherins / genetics
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Cadherins / metabolism*
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Cell Adhesion / physiology*
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Cell Nucleus / metabolism
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Cells, Cultured
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Chick Embryo
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Cyclin-Dependent Kinase 5 / genetics
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Cyclin-Dependent Kinase 5 / metabolism
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Cyclins / genetics
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Cyclins / metabolism*
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Drosophila Proteins / genetics
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Drosophila Proteins / metabolism*
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Drosophila melanogaster
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Humans
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Multiprotein Complexes
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism*
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Phosphoproteins / genetics
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Phosphoproteins / metabolism
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Protein Binding
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Protein Subunits / genetics
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Protein Subunits / metabolism
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Proto-Oncogene Proteins c-abl / genetics
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Proto-Oncogene Proteins c-abl / metabolism*
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Receptors, Immunologic / genetics
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Receptors, Immunologic / metabolism*
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Retina / cytology
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Roundabout Proteins
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Transcription, Genetic
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beta Catenin / genetics
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beta Catenin / metabolism*
Substances
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Cadherins
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Carrier Proteins
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Cyclins
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Drosophila Proteins
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Multiprotein Complexes
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Nerve Tissue Proteins
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Phosphoproteins
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Protein Subunits
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Receptors, Immunologic
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Recombinant Fusion Proteins
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beta Catenin
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sli protein, Drosophila
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Proto-Oncogene Proteins c-abl
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Cyclin-Dependent Kinase 5