Abstract
Amplification of the c-erbB2 gene and overexpression of p185erbB2 is found in approximately one-third of primary breast and ovarian cancers and also in some colon carcinomas. Moreover, a single point mutation in erbB2(V 664 E) confers transforming potential to erbB2 in NIH3T3 cells, even when expressed at low levels. To examine the transformation potential of erbB2 or erbB2(V-E) in colon epithelial cells, we have transfected a nontumorigenic clone of SW 613-S cells with either wild-type p185erbB2 or mutated p185erbB2(V-E). In contrast to p185erbB2, p185erbB2(V-E) associated constitutively with members of the Shc protein family, leading to phosphorylation of Shc and to stimulation of mitogen-activated protein kinase (MAP kinase). However, constitutive activation of MAP kinase activation in p185erbB2(V-E) expressing cells did not result in a tumorigenic phenotype. In addition, p185erbB2(V-E) expressing cells displayed a reduced ability to grow in soft agar compared to the parental cell line. In contrast these transfected cells were able to grow in three-dimensional collagen gels, whereas parental cells were not. Thus, expression of erbB2(V-E) in SW 613-S cells induced multiple changes in intracellular signaling and in growth requirement phenotype, particularly in response to the extracellular environment.
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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Adenocarcinoma / enzymology*
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Adenocarcinoma / pathology
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Animals
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
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Cell Differentiation / drug effects
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Cell Division / drug effects
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Cell Transformation, Neoplastic
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Collagen
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Colonic Neoplasms / enzymology*
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Colonic Neoplasms / pathology
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Enzyme Activation
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Enzyme Induction / drug effects
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Epidermal Growth Factor / pharmacology
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Epithelial Cells
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Epithelium / enzymology
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Female
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Gels
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Humans
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Intestinal Mucosa / drug effects
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Intestinal Mucosa / enzymology*
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Intestinal Mucosa / pathology
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Mice
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Neoplasm Proteins / biosynthesis*
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Neoplasm Proteins / genetics
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Neoplasm Proteins / physiology
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Neoplasm Transplantation
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Oncogenes
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Phosphorylation
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Point Mutation
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Protein Processing, Post-Translational
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Proteins / metabolism
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Receptor, ErbB-2 / biosynthesis*
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Receptor, ErbB-2 / genetics
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Receptor, ErbB-2 / physiology
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Recombinant Fusion Proteins / physiology
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Shc Signaling Adaptor Proteins
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Src Homology 2 Domain-Containing, Transforming Protein 1
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Transfection
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Tumor Cells, Cultured
Substances
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Adaptor Proteins, Signal Transducing
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Adaptor Proteins, Vesicular Transport
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Gels
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Neoplasm Proteins
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Proteins
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Recombinant Fusion Proteins
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SHC1 protein, human
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Shc Signaling Adaptor Proteins
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Shc1 protein, mouse
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Src Homology 2 Domain-Containing, Transforming Protein 1
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Epidermal Growth Factor
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Collagen
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Receptor, ErbB-2
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Calcium-Calmodulin-Dependent Protein Kinases