Fig 1.
Pathway Structure of Insulin-MAPK/ERK Interactions.
Fig 2.
Simplified signaling network.
Table 1.
Interactions appearing in the cross-talk in Fig 2.
Fig 3.
Steady-state response curve of AKT to insulin (parameter λ in the model) without the cross-talk.
LP: Limit Point bifurcation also called the turning point. The switch between the low and high stable branches occurs at the turning points and it is shown by the arrows. H: Hopf bifurcation.
Fig 4.
Steady-state response of ERK to E1tot without the cross-talk.
Fig 5.
Effect of the feedback inhibition of RAS on ERK activation.
Parameter k5 indicates the strength of the inhibitory feedback signal.
Fig 6.
Dynamic responses of ERK to a pulse E1tot stimulus with different negative feedback gains.
Fig 7.
The positive feedback loop FB(k3,k4).
Fig 8.
Steady state AKT responses when ERK inhibits pIRS1.E1tot = 9×10−5.
k4 = 0. Parameter k3 indicates the strength of the inhibition.
Fig 9.
Steady-state ERK response curves for different pAKT inhibitions.
E1tot = 9×10−5. k3 = 0.
Fig 10.
Steady-state ERK response curves when for different insulin levels.
k4 = 1×10−6.
Fig 11.
AKT response to insulin when β = 2.
k4 = 1×10−5.
Fig 12.
ERK responses to insulin when β = 2.
k4 = 1×10−5.
Fig 13.
AKT response when the positive feedback loop FB(k3,k4) is closed.E1tot = 9×10−5.
Inset Fig is the response plotted without the asymptotes for clarity.
Fig 14.
ERK responses to E1tot modified by the interpathway positive feedback loop FB(k3,k4) λ = 0.8.
Fig 15.
AKT response to insulin when k3 = 1 (higher inhibition of pIRS by ERK).
Fig 16.
AKT response to insulin when k3 = 0.1 (lower inhibition of pIRS by ERK).
Fig 17.
ERK response to insulin when k3 = 0.1 (lower inhibition of pIRS by ERK).
Fig 18.
ERK response to insulin when k3 = 1 (higher inhibition of pIRS by ERK).
Fig 19.
Dynamic response of ERK to a change in insulin showing the switching behavior.
AKT switches similarly. E1tot = 9×10−5. k3 = 0.1. For k3 = 1, AKT and ERK show sustained non-switching responses (both ERK and AKT rest at their high values) which are not shown in the Fig.
Fig 20.
Effect of internal ERK-RAS negative feedback k5 on bistability.
Fig 21.
The positive feedback loop FB(k2,k4).
Fig 22.
AKT response of the positive feedback loop FB(k2,k4).
E1tot = 9×10−5.
Fig 23.
The negative feedback loops FB(k1,k3) and FB(k1,k2) functioning together with the positive loops.
Fig 24.
EKT responses for different strengths (k1) of ERK activation by pIRS1.
Fig 25.
AKT responses for different strengths (k1) of ERK activation by pIRS1.
Fig 26.
Inhibition introduced in the ERK-Gab1-PI3K pathway (e.g. increasing k3) alleviates the activation of ERK due to mTOR inhibition (after ramapycin treatment).