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Expression Profile and Activation of Components for a Novel Signaling Module Mediating EGFR Transactivation

  • Author(s): Lynch, Rebecca Marrie
  • et al.
Abstract

Activation of G protein-coupled receptors (GPCRs) mediates the transactivation of epidermal growth factor receptor (EGFR)-dependent signaling pathways, yet the mechanisms underlying this phenomenon are not fully understood. EGFR transactivation can occur via protease "shedding" of EGFR ligands (e.g., heparin-binding EGF [hb-EGF]) from the cell surface. Work in the Insel laboratory has shown the direct activation of MT1-MMP (membrane type-1 matrix metalloprotease) via GPCRs and heterotrimeric G proteins and in support of the hypothesis that transactivation of EGFR might occur via components of a novel, membrane- associated signaling module (GPCR/MT1-MMP/HB-EGF/EGFR). In order to identify and quantify GPCRs that might regulate this proposed mechanism, I conducted targeted GPCR arrays using NIH 3T3 and HeLa cells. Next, I assessed the expression of the components in the putative signaling module by using whole cell lysates and isolated membranes from various cell types (NIH 3T3 fibroblasts, HeLa cells, and primary rat cardiac myocytes). I found that these signaling components localize to the plasma membrane and that bradykinin, a GPCR agonist, can activate EGFR in isolated HeLa cell membranes. This response was attenuated by AG1478, an inhibitor of EGFR, and by Peptide G, a selective inhibitor of MT1-MMP. Taken together, these findings provide evidence in support of the hypothesis that components of a plasma membrane-delimited signaling module that mediates EGFR transactivation can be activated by GPCR stimulation. Because over-activation of EGFR has been implicated in a variety of disease states, such as the progression of cancer and cardiovascular disease, further understanding of this mechanism may lead to the discovery of novel therapeutic targets

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