Number and brightness image analysis reveals ATF-induced dimerization kinetics of uPAR in the cell membrane

FASEB J. 2011 Sep;25(9):2883-97. doi: 10.1096/fj.11-181537. Epub 2011 May 20.

Abstract

We studied the molecular forms of the GPI-anchored urokinase plasminogen activator receptor (uPAR-mEGFP) in the human embryo kidney (HEK293) cell membrane and demonstrated that the binding of the amino-terminal fragment (ATF) of urokinase plasminogen activator is sufficient to induce the dimerization of the receptor. We followed the association kinetics and determined precisely the dimeric stoichiometry of uPAR-mEGFP complexes by applying number and brightness (N&B) image analysis. N&B is a novel fluctuation-based approach for measuring the molecular brightness of fluorophores in an image time sequence in live cells. Because N&B is very sensitive to long-term temporal fluctuations and photobleaching, we have introduced a filtering protocol that corrects for these important sources of error. Critical experimental parameters in N&B analysis are illustrated and analyzed by simulation studies. Control experiments are based on mEGFP-GPI, mEGFP-mEGFP-GPI, and mCherry-GPI, expressed in HEK293. This work provides a first direct demonstration of the dimerization of uPAR in live cells. We also provide the first methodological guide on N&B to discern minor changes in molecular composition such as those due to dimerization events, which are involved in fundamental cell signaling mechanisms.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Cell Membrane / metabolism*
  • Computer Simulation
  • Gene Expression Regulation / physiology
  • Green Fluorescent Proteins / metabolism
  • HEK293 Cells
  • Humans
  • Image Processing, Computer-Assisted*
  • Immunoblotting
  • Microscopy, Fluorescence / instrumentation
  • Microscopy, Fluorescence / methods*
  • Protein Multimerization
  • Receptors, Urokinase Plasminogen Activator / metabolism*
  • Reproducibility of Results
  • Vitronectin / metabolism

Substances

  • Receptors, Urokinase Plasminogen Activator
  • Vitronectin
  • enhanced green fluorescent protein
  • Green Fluorescent Proteins