Autocrine signaling and feedback loops in the EGF receptor system

H. Steven Wiley (Pacific Northwest National Laboratry)

Abstract

The epidermal growth factor receptor (EGFR) is a central player in the signaling system of epithelial cells and regulates diverse biological responses such as proliferation, migration and differentiation. Human epithelial cells express multiple members of the EGFR family as well as various cognate ligands, such as TGF-alpha, amphiregulin and HB-EGF. To activate the EGFR, these ligands must undergo regulated proteolysis through a process that is dependent on multiple signal transduction pathways. We have recently found that a variety of different growth factors and hormones can stimulate autocrine signaling through the EGFR. This autocrine loop, in turn, stimulates the expression of EGFR ligands as well as genes for a variety of other growth factors and cytokines. We have analyzed the EGFR autocrine response using image analysis, whole-genome microarrays and quantitative proteomics. Our data suggest that autocrine signaling is part of a recursive, modular network that is controled by changes in the extracellular environment. Using an ERK1-GFP fusion protein, we investigated this network at the single cell level. We found that EGFR activation induced oscillation of ERK between the nucleus and cytoplasm, apparently due to a negative feedback loop between ERK and Raf1. These oscillations were remarkably persistent (>45 cycles), were independent cell cycle phase, displayed a periodicity of approximately 15 minutes and were highly dependent on cell density. Activated cells also broadcast secondary growth factors and cytokines to neighboring cells, suggesting that regulated ligand production and shedding is part of an extracellular signaling network that coordinates the response of cell communities to a given stimulus.

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