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An ultrasensitive sorting mechanism for EGF receptor endocytosis.

Schmidt-Glenewinkel H, Vacheva I, Hoeller D, Dikic I, Eils R - BMC Syst Biol (2008)

Bottom Line: We demonstrate the robustness of the sorting effect for large parameter variations and give an analytic derivation for alternative steady-states that are reached.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division Theoretical Bioinformatics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. H.Schmidt-Glenewinkel@dkfz.de

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.

Conclusion: 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.

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Temporal Evolution of internalized receptors. Time trajectories of Ri_cde (blue) and Ri_cie (green) for three different classes of initial conditions. In case A (B) at least one of EGF0 or R0 stays below CDE0 (CDE0 + CIE0). In case C, both EGF0 and R0 exceed CDE0 + CIE0. Initial values were chosen arbitrarily such that these conditions are satisfied. In all three cases CDE0 = 2.0, CIE0 = 2.0 and (A) (EGF0, R0) = (1.2, 1.5), (1.6, 1.3), (2.3, 1.3), (1.4, 2.5); (B) (2.5, 3.0), (3.1, 2.4), (3.1, 4.5), (5.0, 2.8); (C) (4.3, 4.7), (5.0, 5.2), (5.5, 5.0), (5.3, 6.0).
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Figure 2: Temporal Evolution of internalized receptors. Time trajectories of Ri_cde (blue) and Ri_cie (green) for three different classes of initial conditions. In case A (B) at least one of EGF0 or R0 stays below CDE0 (CDE0 + CIE0). In case C, both EGF0 and R0 exceed CDE0 + CIE0. Initial values were chosen arbitrarily such that these conditions are satisfied. In all three cases CDE0 = 2.0, CIE0 = 2.0 and (A) (EGF0, R0) = (1.2, 1.5), (1.6, 1.3), (2.3, 1.3), (1.4, 2.5); (B) (2.5, 3.0), (3.1, 2.4), (3.1, 4.5), (5.0, 2.8); (C) (4.3, 4.7), (5.0, 5.2), (5.5, 5.0), (5.3, 6.0).

Mentions: We systematically scanned the space of initial values of the model (equations 1.1 – 1.7) to investigate the effect of EGF stimulation on receptor distribution into CDE or CIE (see Methods). Figure 2 shows the time trajectories of Ri_cde and Ri_cie for three different classes of initial conditions, each represented by four different sets of values (see Figure caption). The three classes of initial values have distinct effects on the internalization-behavior of R_EGF, the activated receptor. They represent assumptions on the relative quantities of EGF-molecules, unbound receptors and endocytosis adaptors.


An ultrasensitive sorting mechanism for EGF receptor endocytosis.

Schmidt-Glenewinkel H, Vacheva I, Hoeller D, Dikic I, Eils R - BMC Syst Biol (2008)

Temporal Evolution of internalized receptors. Time trajectories of Ri_cde (blue) and Ri_cie (green) for three different classes of initial conditions. In case A (B) at least one of EGF0 or R0 stays below CDE0 (CDE0 + CIE0). In case C, both EGF0 and R0 exceed CDE0 + CIE0. Initial values were chosen arbitrarily such that these conditions are satisfied. In all three cases CDE0 = 2.0, CIE0 = 2.0 and (A) (EGF0, R0) = (1.2, 1.5), (1.6, 1.3), (2.3, 1.3), (1.4, 2.5); (B) (2.5, 3.0), (3.1, 2.4), (3.1, 4.5), (5.0, 2.8); (C) (4.3, 4.7), (5.0, 5.2), (5.5, 5.0), (5.3, 6.0).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2377235&req=5

Figure 2: Temporal Evolution of internalized receptors. Time trajectories of Ri_cde (blue) and Ri_cie (green) for three different classes of initial conditions. In case A (B) at least one of EGF0 or R0 stays below CDE0 (CDE0 + CIE0). In case C, both EGF0 and R0 exceed CDE0 + CIE0. Initial values were chosen arbitrarily such that these conditions are satisfied. In all three cases CDE0 = 2.0, CIE0 = 2.0 and (A) (EGF0, R0) = (1.2, 1.5), (1.6, 1.3), (2.3, 1.3), (1.4, 2.5); (B) (2.5, 3.0), (3.1, 2.4), (3.1, 4.5), (5.0, 2.8); (C) (4.3, 4.7), (5.0, 5.2), (5.5, 5.0), (5.3, 6.0).
Mentions: We systematically scanned the space of initial values of the model (equations 1.1 – 1.7) to investigate the effect of EGF stimulation on receptor distribution into CDE or CIE (see Methods). Figure 2 shows the time trajectories of Ri_cde and Ri_cie for three different classes of initial conditions, each represented by four different sets of values (see Figure caption). The three classes of initial values have distinct effects on the internalization-behavior of R_EGF, the activated receptor. They represent assumptions on the relative quantities of EGF-molecules, unbound receptors and endocytosis adaptors.

Bottom Line: We demonstrate the robustness of the sorting effect for large parameter variations and give an analytic derivation for alternative steady-states that are reached.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division Theoretical Bioinformatics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. H.Schmidt-Glenewinkel@dkfz.de

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.

Conclusion: 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.

Show MeSH
Related in: MedlinePlus