Under Pressure to Increase EGF

Science's STKE  18 May 2004:
Vol. 2004, Issue 233, pp. tw175-TW175
DOI: 10.1126/stke.2332004TW175

Tschumperlin et al. investigated the effects of compressive stress on epithelial cells and uncovered an intriguing mechanism whereby mechanical stimuli could provoke a biochemical response by modulating extracellular-fluid volume. Bronchial epithelial cells undergo compressive stress during airway constriction; this stimulates the production of proinflammatory and profibrotic cytokines, a response that may contribute to the pathogenesis of asthma. Tschumperlin et al. used Western analysis to show that transcellular pressure applied to cultured human bronchial epithelial (HBE) cells promoted phosphorylation of extracellular signal-regulated kinase (ERK). The authors used pharmacological analysis and function-blocking antibodies to demonstrate that ERK phosphorylation required metalloprotease-dependent shedding of the heparin-binding epidermal growth factor (HB-EGF) ectodomain. This led to autocrine stimulation of the ErbB1 epidermal growth factor receptor, which was present on the basolateral surfaces of HBE surrounding the lateral intercellular spaces (LIS) between cells. Two-photon microscopy revealed that transcellular pressure substantially decreased the volume of the LIS, without affecting cell volume per se. Exposure to different concentrations of soluble HB-EGF elicited increases in ERK phosphorylation consistent with increases in the local concentration of HB-EGF in the LIS predicted on the basis of the observed changes in volume. Thus, pressure appears to modulate bronchial epithelial cell signaling through a localized increase in the concentration of ligand, a mechanism that could apply to other systems with similar morphology.

D. J. Tschumperlin, G. Dai, I. V. Maly, T. Kikuchi, L. H. Lalho, A. K. McVittie, K. J. Haley, C. M. Lilly, P. T. C. So, D. A. Lauffenburger, R. D. Kamm, J. M. Drazen, Mechanotransduction through growth-factor shedding into the extracellular space. Nature 429, 83-86 (2004). [Online Journal]