MODEL SIMULATIONS REVEAL VCAM-1 AUGMENT PAK ACTIVATION RATES TO AMPLIFY P38 MAPK AND VE-CADHERIN PHOSPHORYLATION

摘要

We present an integrated computational analysis that shows VCAM-1 activation increases the rate of PAK activation, while decreasing PAK off rates dramatically affects p38 MAPK phosphorylation. We used the model simulations to provide some insights into the changes in the kinetics of key signaling molecules identified by sensitivity analysis (i.e. PAK and p38). Using computational simulations, we were able to observe an increase in p38 phosphorylation in response to PAK activation during stimulation of VCAM-1 receptors and/or binding of inflammatory cytokines. These theoretical observations suggest that the kinetics of these proteins could lead to an increase in gap formation within a short time, facilitating melanoma cell extravastion.