Abstract
Recent studies have suggested that members of the Abl interactor (Abi) protein family negatively regulate cell growth and transformation. To date, however, no specific role in these cellular processes has been identified for the Abi family. Here we describe the inhibition by overexpressed Abi-1 of a mitogenic pathway activated by both growth factors and v-Abl. We have identified the guanine nucleotide exchange factors Sos1 and Sos2 as novel binding partners of Abi-1. A domain that is required for interaction with Sos in vivo has been mapped to the amino terminus of Abi-1. Overexpression of Abi-1 inhibits epidermal growth factor (EGF)-induced activation of extracellular signal-regulated kinases (Erks) but does not affect EGF-induced activation of c-Jun N-terminal kinase or Akt. In addition, overexpression of Abi-1 blocks Erk activation induced by v-Abl. In both cases, the maximal inhibitory effect requires an intact amino-terminal Sos-binding domain in Abi-1. Finally, we demonstrate that tyrosine phosphorylation of endogenous Abi-1 in fibroblasts is induced by both v-Abl and serum stimulation, further suggesting a role for Abi-1 in signal transduction initiated by v-Abl and growth factors. Taken together, these findings suggest that overexpressed Abi proteins negatively regulate cell growth and transformation by specifically targeting the Erk pathway.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing*
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Animals
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Cell Line
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Cytoskeletal Proteins*
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Enzyme Activation
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Epidermal Growth Factor / antagonists & inhibitors*
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Epidermal Growth Factor / metabolism
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GRB2 Adaptor Protein
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Gene Expression
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism*
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Homeodomain Proteins / pharmacology
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Humans
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinases / metabolism*
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Oncogene Proteins v-abl / antagonists & inhibitors*
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Oncogene Proteins v-abl / metabolism
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Phosphorylation
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Phosphotyrosine / metabolism
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Protein Binding
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Protein Serine-Threonine Kinases / metabolism
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Proteins / metabolism
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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SOS1 Protein / metabolism*
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Son of Sevenless Proteins / metabolism*
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Transfection
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Two-Hybrid System Techniques
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src Homology Domains / genetics
Substances
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ABI1 protein, human
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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, human
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Homeodomain Proteins
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Oncogene Proteins v-abl
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Proteins
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Proto-Oncogene Proteins
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Recombinant Fusion Proteins
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SOS1 Protein
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SOS2 protein, human
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Son of Sevenless Proteins
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Phosphotyrosine
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Epidermal Growth Factor
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AKT1 protein, human
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinases