Abstract
Src family kinases are central regulators of a large number of signaling pathways. To adapt to the idiosyncrasies of different cell types, these kinases may need a fine-tuning of their intrinsic molecular control mechanisms. Here, we describe on a molecular level how the Fyn kinase uses alternative splicing to adapt to different cellular environments. Using structural analysis, site-directed mutagenesis, and functional analysis, we show how the inclusion of either exon 7A or 7B affects the autoinhibition of Fyn and how this changes the SH3-dependent interaction and tyrosine phosphorylation of Sam68, with functional consequences for the Sam68-regulated survival of epithelial cells. Our results illustrate a novel mechanism of evolution that may contribute to the complexity of Src kinase regulation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism
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Alternative Splicing*
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Amino Acid Sequence
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Animals
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Apoptosis / physiology
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Cell Line
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Evolution, Molecular
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Exons
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Humans
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Isoenzymes / antagonists & inhibitors
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Isoenzymes / genetics
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Isoenzymes / metabolism
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Molecular Sequence Data
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Mutagenesis, Site-Directed
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Proto-Oncogene Proteins c-fyn / antagonists & inhibitors*
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Proto-Oncogene Proteins c-fyn / genetics
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Proto-Oncogene Proteins c-fyn / metabolism*
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RNA-Binding Proteins / genetics
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RNA-Binding Proteins / metabolism
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Sequence Alignment
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Signal Transduction / physiology
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Tissue Distribution
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bcl-X Protein / genetics
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bcl-X Protein / metabolism
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src Homology Domains
Substances
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Adaptor Proteins, Signal Transducing
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DNA-Binding Proteins
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Isoenzymes
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KHDRBS1 protein, human
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RNA-Binding Proteins
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Recombinant Fusion Proteins
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bcl-X Protein
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FYN protein, human
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Proto-Oncogene Proteins c-fyn