Abstract
Polyoma virus middle T-antigen converts normal fibroblasts to a fully transformed, tumorigenic phenotype. It achieves this, at least in part, by binding and activating one of the non-receptor tyrosine kinases, pp60c-src, pp62c-yes or pp59c-fyn (reviewed in refs 2 and 3). As a result, middle T-antigen itself is phosphorylated on tyrosine residues, one of which (Tyr 315) acts as a binding site for the SH2 domains of phosphatidylinositol-3'OH kinase 85K subunit. Here we show that another tyrosine phosphorylation site in middle T-antigen (Tyr 250; refs 4, 5) acts as a binding region for the SH2 domain of the transforming protein Shc. This results in Shc also becoming tyrosine-phosphorylated and binding to the SH2 domain of Grb2 (ref. 10). This probably stimulates p21ras activity through the mammalian homologue of the Drosophila guanine-nucleotide-exchange factor Sos (reviewed in ref. 11). We suggest that middle T-antigen transforms cells by acting as a functional homologue of an activated tyrosine kinase-associated growth-factor receptor.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing*
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Adaptor Proteins, Vesicular Transport*
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Amino Acid Sequence
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Animals
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Antigens, Polyomavirus Transforming / genetics
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Antigens, Polyomavirus Transforming / metabolism*
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Cell Line
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Cell Transformation, Neoplastic*
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Cell Transformation, Viral*
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GRB2 Adaptor Protein
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Molecular Sequence Data
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Mutation
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Phosphatidylinositol 3-Kinases
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Phosphorylation
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Phosphotransferases (Alcohol Group Acceptor) / metabolism
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Protein Binding
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Proteins / metabolism*
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Proto-Oncogene Proteins pp60(c-src) / metabolism
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Rats
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Receptor Protein-Tyrosine Kinases / metabolism
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Receptors, Fibroblast Growth Factor / metabolism
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Shc Signaling Adaptor Proteins
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Src Homology 2 Domain-Containing, Transforming Protein 1
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Tyrosine / metabolism*
Substances
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Adaptor Proteins, Signal Transducing
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Adaptor Proteins, Vesicular Transport
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Antigens, Polyomavirus Transforming
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GRB2 Adaptor Protein
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Grb2 protein, rat
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Proteins
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Receptors, Fibroblast Growth Factor
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Shc Signaling Adaptor Proteins
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Shc1 protein, rat
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Src Homology 2 Domain-Containing, Transforming Protein 1
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Tyrosine
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Phosphatidylinositol 3-Kinases
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Phosphotransferases (Alcohol Group Acceptor)
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Receptor Protein-Tyrosine Kinases
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Proto-Oncogene Proteins pp60(c-src)