Expression of the activated p185erbB2 tyrosine kinase in human epithelial cells leads to MAP kinase activation but does not confer oncogenicity.
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.
Nowak
F
F
Faculté de Pharmacie, INSERM U 461, Châtenay Malabry, France.
Jacquemin-Sablon
A
A
Pierre
J
J
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000230:Adenocarcinoma / Q000201:enzymology* / Q000473:pathology; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D003094:Collagen; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000473:pathology; D004789:Enzyme Activation; D004790:Enzyme Induction / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology; D004847:Epithelial Cells; D004848:Epithelium / Q000201:enzymology; D005260:Female; D005782:Gels; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D009368:Neoplasm Transplantation; D009857:Oncogenes; D010766:Phosphorylation; D017354:Point Mutation; D011499:Protein Processing, Post-Translational; D011506:Proteins / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D014162:Transfection; D014407:Tumor Cells, Cultured
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D003094:Collagen; D004815:Epidermal Growth Factor; D005782:Gels; D009363:Neoplasm Proteins; D011506:Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D011993:Recombinant Fusion Proteins; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; C528024:SHC1 protein, human; C528034:Shc1 protein, mouse