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Stefan Hart, Oliver M. Fischer, Norbert Prenzel, Esther Zwick-Wallasch, Matthias Schneider, Lothar Hennighausen, Axel Ullrich
GPCR-induced migration of breast carcinoma cells depends on both EGFR signal transactivation and EGFR-independent pathways
Keywords: ADAM, breast cancer, cross-talk, HB-EGF, shedding, sphingosine kinase (SPHK)
The epidermal growth factor receptor (EGFR) plays a key role in the regulation of important cellular processes under normal and pathophysiological conditions such as cancer. In human mammary carcinomas the EGFR is involved in regulating cell growth, survival, migration and metastasis and its activation correlates with the lack of response in hormone therapy. Here, we demonstrate in oestrogen receptor-positive and -negative human breast cancer cells and primary mammary epithelial cells a cross-communication between G protein-coupled receptors (GPCRs) and the EGFR. We present evidence that specific inhibition of ADAM15 or TACE blocks GPCR-induced and proHB-EGF-mediated EGFR tyrosine phosphorylation, downstream mitogenic signalling and cell migration. Notably, activation of the PI3K downstream mediator PKB/Akt by GPCR ligands involves the activity of sphingosine kinase (SPHK) and is independent of EGFR signal transactivation. We conclude that GPCR-induced chemotaxis of breast cancer cells is mediated by EGFR-dependent and -independent signalling pathways, with both parallel pathways having to act in concert to achieve a complete migratory response.
Biological Chemistry, Walter de Gruyter
Print ISSN: 1431-6730
Volume: 386, 09/2005
Pages: 845 - 855