Distinct ADAM metalloproteinases regulate G protein-coupled receptor-induced cell proliferation and survival.
Cross-talk between G protein-coupled receptor ( GPCR) and epidermal growth factor receptor ( EGFR) signaling systems is widely established in a variety of normal and transformed cell types. Here, we demonstrate that the EGFR transactivation signal requires metalloproteinase cleavage of epidermal growth factor-like growth factor precursors in fibroblasts, ACHN kidney, and TccSup bladder carcinoma cells. Furthermore, we present evidence that blockade of the metalloproteinase-disintegrin tumor necrosis factor-alpha-converting enzyme (TACE/ADAM17) by a dominant negative ADAM17 mutant prevents angiotensin II-stimulated pro-HB-EGF cleavage, EGFR activation, and cell proliferation in ACHN tumor cells. Moreover, we found that in TccSup cancer cells, the lysophosphatidic acid-induced transactivation signal is mediated by ADAM15, demonstrating that distinct combinations of growth factor precursors and ADAMs (a disintegrin and metalloproteinases) regulate GPCR- EGFR cross-talk pathways in cell lines derived from urogenital cancer. Our data show further that activation of ADAMs results in discrete cellular responses; whereas GPCR agonists promote activation of the Ras/ MAPK pathway and cell proliferation via the EGFR in fibroblasts and ACHN cells, EGFR transactivation pathways regulate activation of the survival mediator Akt/ protein kinase B and the susceptibility of fibroblasts and TccSup bladder carcinoma cells to proapoptotic signals such as serum deprivation, death receptor stimulation, and the chemotherapeutic drug doxorubicin. Thus, ADAM15 and -17 function as effectors of GPCR-mediated signaling and define critical characteristics of cancer cells.[1]References
- Distinct ADAM metalloproteinases regulate G protein-coupled receptor-induced cell proliferation and survival. Schäfer, B., Marg, B., Gschwind, A., Ullrich, A. J. Biol. Chem. (2004) [Pubmed]
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