ERK and MMPs sequentially regulate distinct stages of epithelial tubule development

Dev Cell. 2004 Jul;7(1):21-32. doi: 10.1016/j.devcel.2004.06.001.


Epithelial cells undergo tubulogenesis in response to morphogens such as hepatocyte growth factor (HGF). To organize into tubules, cells must execute a complex series of morphogenetic events; however, the mechanisms that underlie the timing and sequence of these events are poorly understood. Here, we show that downstream effectors of HGF coordinately regulate successive stages of tubulogenesis. Activation of extracellular-regulated kinase (ERK) is necessary and sufficient for the initial stage, during which cells depolarize and migrate. ERK becomes dispensable for the latter stage, during which cells repolarize and differentiate. Conversely, the activity of matrix metalloproteases (MMPs) is essential for the late stage but not the initial stage. Thus, ERK and MMPs define two regulatory subprograms that act in sequence. By inducing these reciprocal signals, HGF directs the morphogenetic progression of tubule development.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Body Patterning / physiology
  • Cell Differentiation / physiology
  • Cell Line
  • Cell Movement / physiology
  • Cell Polarity / physiology
  • Dogs
  • Epithelial Cells / cytology
  • Epithelial Cells / enzymology*
  • Hepatocyte Growth Factor / metabolism*
  • MAP Kinase Kinase 1
  • Matrix Metalloproteinases / metabolism*
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Mitogen-Activated Protein Kinases / metabolism*
  • Organogenesis / physiology*
  • Proto-Oncogene Proteins c-raf / metabolism
  • Viscera / cytology
  • Viscera / embryology*
  • Viscera / enzymology*


  • Hepatocyte Growth Factor
  • Proto-Oncogene Proteins c-raf
  • Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 1
  • Mitogen-Activated Protein Kinase Kinases
  • Matrix Metalloproteinases