Chalmers Conferences, 9th European Conference on Mathematical and Theoretical Biology

Regulation RTK signaling specificity by tuning early endosome distribution
Yannis Kalaidzidis, Roberto Villaseñor, Marino Zerial

Last modified: 2014-04-07


Receptor tyrosine kinases (RTKs) signals lead to different cell-fate decisions dependent on specific ligand-receptor complexes, despite that downstream cascade is mostly common. It was shown [Santos et al., 2007] that amplitude and duration of pErk1/2 kinetic defines signal specificity. The endocytosis of ligand-receptor complexes is considered as an essential part of signal duration tuning.  In the work of J.Gruenberg  with co-authors  [Brankatschk et al, 2012] was shown that ligand-receptor complex  (EGF-EGFR) internalization into early endosomes is essential for signal regulation, but transition from early to late endosomes (i.e. receptor degradation per se) does not influence signaling. We have shown experimentally, that pEGFR is distributed in the early endosomes in such specifically regulated manner, that mean amount of pEGFR (phosphor-EGFR) per endosome is not dependent on concentration of EGF in the extracellular medium.  We developed mathematical model that explain such peculiar behavior. This model predicts that 1) endocytic systems suppress the influence of EGF fluctuation on signaling; 2) modulation of endosome distribution provides a mean for tuning signaling specificity; 3) regulation of endosome fusion/fission rates by RTKs provides a mean for integration different signals to single cell fate decision.


MAPK, RTK, EGF, signalling