title: An ultrasensitive sorting mechanism for EGF receptor endocytosis.
abstract: BACKGROUND
  The Epidermal Growth Factor (EGF) receptor has been shown to internalize via clathrin-independent endocytosis (CIE) in a ligand concentration dependent manner. From a modeling point of view, this resembles an ultrasensitive response, which is the ability of signaling networks to suppress a response for low input values and to increase to a pre-defined level for inputs exceeding a certain threshold. Several mechanisms to generate this behaviour have been described theoretically, the underlying assumptions of which, however, have not been experimentally demonstrated for the EGF receptor internalization network.
  
  
  RESULTS
  Here, we present a mathematical model of receptor sorting into alternative pathways that explains the EGF-concentration dependent response of CIE. The described mechanism involves a saturation effect of the dominant clathrin-dependent endocytosis pathway and implies distinct steady-states into which the system is forced for low vs high EGF stimulations. The model is minimal since no experimentally unjustified reactions or parameter assumptions are imposed. We demonstrate the robustness of the sorting effect for large parameter variations and give an analytic derivation for alternative steady-states that are reached. Further, we describe extensibility of the model to more than two pathways which might play a role in contexts other than receptor internalization.
  
  
  CONCLUSIONS
  Our main result is that a scenario where different endocytosis routes consume the same form of receptor corroborates the observation of a clear-cut, stimulus dependent sorting. This is especially important since a receptor modification discriminating between the pathways has not been found experimentally. The model is not restricted to EGF receptor internalization and might account for ultrasensitivity in other cellular contexts.
authors.affiliation: Division Theoretical Bioinformatics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. H.Schmidt-Glenewinkel@dkfz.de
authors.forename: Hannah
authors.initials: H
authors.lastname: Schmidt-Glenewinkel
authors.forename: Ivayla
authors.initials: I
authors.lastname: Vacheva
authors.forename: Daniela
authors.initials: D
authors.lastname: Hoeller
authors.forename: Ivan
authors.initials: I
authors.lastname: Dikic
authors.forename: Roland
authors.initials: R
authors.lastname: Eils
mesh_terms: D001667:Binding, Competitive; D002966:Clathrin / Q000737:chemistry / Q000378:metabolism; D003034:Coated Pits, Cell-Membrane / Q000378:metabolism; D004705:Endocytosis / Q000502:physiology*; D004815:Epidermal Growth Factor / Q000737:chemistry / Q000378:metabolism; D066246:ErbB Receptors / Q000819:agonists / Q000737:chemistry / Q000378:metabolism*; D007700:Kinetics; D008954:Models, Biological; D011485:Protein Binding; D015398:Signal Transduction / Q000502:physiology; D022161:Transport Vesicles
chemical_list: D002966:Clathrin; D004815:Epidermal Growth Factor; D066246:ErbB Receptors