An EGFR autocrine loop encodes a slow-reacting but dominant mode of mechanotransduction in a polarized epithelium

Nikola Kojic, Euiheon Chung, Alvin T. Kho, Jin Ah Park, Austin Huang, Peter T.C. So, Daniel J. Tschumperlin

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

The mechanical landscape in biological systems can be complex and dynamic, with contrasting sustained and fluctuating loads regularly superposed within the same tissue. How resident cells discriminate between these scenarios to respond accordingly remains largely unknown. Here, we show that a step increase in compressive stress of physiological magnitude shrinks the lateral intercellular space between bronchial epithelial cells, but does so with strikingly slow exponential kinetics (time constant ∼110 s). We confirm that epidermal growth factor (EGF)-family ligands are constitutively shed into the intercellular space and demonstrate that a step increase in compressive stress enhances EGF receptor (EGFR) phosphorylation with magnitude and onset kinetics closely matching those predicted by constant-rate ligand shedding in a slowly shrinking intercellular geometry. Despite the modest degree and slow nature of EGFR activation evoked by compressive stress, we find that the majority of transcriptomic responses to sustained mechanical loading require ongoing activity of this autocrine loop, indicating a dominant role for mechanotransduction through autocrine EGFR signaling in this context. A slow deformation response to a step increase in loading, accompanied by synchronous increases in ligand concentration and EGFR activation, provides one means for cells to mount a selective and context-appropriate response to a sustained change in mechanical environment.

Original languageEnglish (US)
Pages (from-to)1604-1615
Number of pages12
JournalFASEB Journal
Volume24
Issue number5
DOIs
StatePublished - May 1 2010

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Keywords

  • Airway epithelium
  • Lateral intercellular space
  • Mechanical stress

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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