A Switch-like Activation Relay of EGFR-ERK Signaling Regulates a Wave of Cellular Contractility for Epithelial Invagination

Dev Cell. 2018 Jul 16;46(2):162-172.e5. doi: 10.1016/j.devcel.2018.06.004. Epub 2018 Jul 5.


The dynamics of extracellular signal-regulated kinase (ERK) signaling underlies its versatile functions in cell differentiation, cell proliferation, and cell motility. Classical studies in Drosophila established that a gradient of epidermal growth factor receptor (EGFR)-ERK signaling is essential for these cellular responses. However, we challenge this view by the real-time monitoring of ERK activation; we show that a switch-like ERK activation is essential for the invagination movement of the Drosophila tracheal placode. This switch-like ERK activation stems from the positive feedback regulation of the EGFR-ERK signaling and a resultant relay of EGFR-ERK signaling among tracheal cells. A key transcription factor Trachealess (Trh) permissively regulates the iteration of the relay, and the ERK activation becomes graded in trh mutant. A mathematical model based on these observations and a molecular link between ERK activation dynamics and myosin shows that the relay mechanism efficiently promotes epithelial invagination while the gradient mechanism does not.

Keywords: Drosophila; EGF receptor; ERK signaling; FRET; invagination; mathematical modeling; morphogenesis; trachea.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Movement
  • Cell Proliferation
  • Drosophila / metabolism
  • Drosophila Proteins / metabolism*
  • Epidermal Growth Factor / metabolism
  • ErbB Receptors / metabolism*
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • MAP Kinase Signaling System / physiology*
  • Myosins / metabolism
  • Phosphorylation
  • Receptors, Invertebrate Peptide / metabolism*
  • Rho Factor / metabolism
  • Transcription Factors / metabolism


  • Drosophila Proteins
  • Receptors, Invertebrate Peptide
  • Rho Factor
  • Transcription Factors
  • Epidermal Growth Factor
  • Egfr protein, Drosophila
  • ErbB Receptors
  • Extracellular Signal-Regulated MAP Kinases
  • Myosins