Abstract
The Son of Sevenless 1 protein (sos1) is a guanine nucleotide exchange factor (GEF) for either the ras or rac1 GTPase. We show that p66shc, an adaptor protein that promotes oxidative stress, increases the rac1-specific GEF activity of sos1, resulting in rac1 activation. P66shc decreases sos1 bound to the growth factor receptor bound protein (grb2) and increases the formation of the sos1-eps8-e3b1 tricomplex. The NH(2)-terminal proline-rich collagen homology 2 (CH2) domain of p66shc associates with full-length grb2 in vitro via the COOH-terminal src homology 3 (C-SH3) domain of grb2. A proline-rich motif (PPLP) in the CH2 domain mediates this association. The CH2 domain competes with the proline-rich COOH-terminal region of sos1 for the C-SH3 domain of grb2. P66shc-induced dissociation of sos1 from grb2, formation of the sos1-eps8-e3b1 complex, rac1-specific GEF activity of sos1, rac1 activation, and oxidative stress are also mediated by the PPLP motif in the CH2 domain. This relationship between p66shc, grb2, and sos1 provides a novel mechanism for the activation of rac1.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / chemistry
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism*
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Amino Acid Motifs / physiology
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Animals
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COS Cells
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Cells, Cultured
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Chlorocebus aethiops
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Cytoskeletal Proteins
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Down-Regulation / genetics
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Enzyme Activation / genetics
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Fibroblasts
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GRB2 Adaptor Protein / chemistry
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GRB2 Adaptor Protein / genetics
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GRB2 Adaptor Protein / metabolism
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Macromolecular Substances / chemistry
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Macromolecular Substances / metabolism
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Mice
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Mice, Knockout
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Models, Molecular
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Protein Structure, Tertiary / physiology
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Shc Signaling Adaptor Proteins
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Son of Sevenless Proteins / genetics
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Son of Sevenless Proteins / metabolism*
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Src Homology 2 Domain-Containing, Transforming Protein 1
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rac1 GTP-Binding Protein / genetics
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rac1 GTP-Binding Protein / metabolism*
Substances
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Abi1 protein, mouse
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Adaptor Proteins, Signal Transducing
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Cytoskeletal Proteins
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GRB2 Adaptor Protein
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Grb2 protein, mouse
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Macromolecular Substances
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Shc Signaling Adaptor Proteins
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Shc1 protein, mouse
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Son of Sevenless Proteins
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Src Homology 2 Domain-Containing, Transforming Protein 1
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rac1 GTP-Binding Protein