An unexpected biochemical and functional interaction between gp130 and the EGF receptor family in breast cancer cells

Grant, SL; Hammacher, A; Douglas, AM; Goss, GA; Mansfield, RK; Heath, JK; Begley, CG

Author(s): Grant, SL; Hammacher, A; Douglas, AM; Goss, GA; Mansfield, RK; Heath, JK; Begley, CG;
Details: Publication Year 2002-01-17,Volume 21,Issue #3,Page 460-474
Journal Title: ONCOGENE
Publication Type: Journal Article
Abstract: 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.
Publisher: NATURE PUBLISHING GROUP
Keywords: EPIDERMAL GROWTH-FACTOR; LEUKEMIA INHIBITORY FACTOR; ONCOSTATIN-M RECEPTOR; SIGNAL-TRANSDUCTION; ESTROGEN-RECEPTOR; TYROSINE KINASES; GENE-EXPRESSION; CARCINOMA-CELLS; DIFFERENTIATION; INTERLEUKIN-6
Publisher's Version: https://doi.org/10.1038/sj.onc.1205100
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2002-01-17 12:00:00