Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.11.18 (MAP)
 7,412 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:An unexpected biochemical and functional interaction between gp130 and the EGF receptor family in breast cancer cells. 1182 58

Oncostatin M (OSM), an IL-6 family cytokine, has previously been shown to increase migration of several breast cancer cell lines in vitro. Our studies report additional effects of OSM treatment on the human breast carcinoma cell line T-47D. OSM treatment alters T-47D cell morphology from a normal epithelial phenotype to a mesenchymal-like phenotype that is associated with cell detachment from substratum. These effects are also seen with H3922 human breast cancer cells. OSM treatment of T-47D cells for 5-8 days leads to a three-fold increase in cell detachment. OSM-induced detachment of T-47D cells is blocked by the protein kinase inhibitors UO126 and bisindolylmaleimide, indicating a role for MAP kinases and protein kinase C in OSM signaling events that regulate cell detachment. T-47D cells induced to detach by OSM have a reduced capacity to re-adhere to laminin in comparison to other extracellular matrix components. Detached multi-cell aggregates of T-47D cells are viable, whereas detached single cells appear apoptotic. In addition, OSM treatment induces the secretion of the lysosomal proteases cathepsins D and L from T-47D cells, which have been implicated in invasion and metastasis. Importantly, OSM-treated T-47D cells show a 250% increase in invasive capacity as measured by the Matrigel invasion chamber assay. Collectively, these data demonstrate that OSM induces a motile/invasive phenotype in T-47D cells in vitro, and suggest that OSM may enhance metastasis in vivo. Our results suggest that OSM itself may be a valid therapeutic target.
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PMID:Oncostatin M induces cell detachment and enhances the metastatic capacity of T-47D human breast carcinoma cells. 1671 83