An unexpected biochemical and functional interaction between gp130 and the EGF receptor family in breast cancer cells.
Oncostatin M (OSM), an interleukin-6 type cytokine, acts via the gp130 signaling receptor to inhibit proliferation and induce differentiation of breast cancer cells. EGF, a mitogen for breast cells, signals via EGFR/ErbB tyrosine kinase receptors which are implicated in breast cancer pathogenesis. Here we show paradoxically that EGF enhanced the ... OSM-induced inhibition of proliferation and induction of cellular differentiation in both estrogen receptor positive and negative breast cancer cells. This functional synergism was also seen with heregulin but not SCF, PDGF or IGF-1, indicating that it was specific to EGF-related growth factors. Immunoprecipitation experiments revealed that gp130 was constitutively associated with ErbB-2 and ErbB-3. There was a similar association between the OSMRbeta and ErbB-2. Furthermore, EGF unexpectedly induced tyrosine phosphorylation of gp130. We show that OSM induced phosphorylation of STAT3. Both OSM and EGF activated the p42/44 MAP kinases, but while the MEK inhibitor, PD98059, ablated the OSM-induced inhibition, it only partially ablated the inhibitory effects of OSM plus EGF. Thus, we have demonstrated that the receptors and signalling pathways of two apparently unrelated growth factors were intimately linked, resulting in an unexpected biological effect. This provides a new mechanism for generating signalling diversity and has potential clinical implications in breast cancer.
Mesh Terms:
Antigens, CD, Breast Neoplasms, Cell Differentiation, Cell Division, Cytokine Receptor gp130, DNA-Binding Proteins, Epidermal Growth Factor, Female, Flow Cytometry, Gene Expression Regulation, Neoplastic, Humans, MAP Kinase Signaling System, Membrane Glycoproteins, Mitogen-Activated Protein Kinase Kinases, Oncostatin M, Peptides, Phosphorylation, Protein Binding, RNA, Messenger, Receptor, Epidermal Growth Factor, Receptor, erbB-2, Receptor, erbB-3, Receptors, Estrogen, STAT3 Transcription Factor, Substrate Specificity, Trans-Activators, Tumor Cells, Cultured
Antigens, CD, Breast Neoplasms, Cell Differentiation, Cell Division, Cytokine Receptor gp130, DNA-Binding Proteins, Epidermal Growth Factor, Female, Flow Cytometry, Gene Expression Regulation, Neoplastic, Humans, MAP Kinase Signaling System, Membrane Glycoproteins, Mitogen-Activated Protein Kinase Kinases, Oncostatin M, Peptides, Phosphorylation, Protein Binding, RNA, Messenger, Receptor, Epidermal Growth Factor, Receptor, erbB-2, Receptor, erbB-3, Receptors, Estrogen, STAT3 Transcription Factor, Substrate Specificity, Trans-Activators, Tumor Cells, Cultured
Oncogene
Date: Jan. 17, 2002
PubMed ID: 11821958
View in: Pubmed Google Scholar
Download Curated Data For This Publication
5863
Switch View:
- Interactions 4