Model simulations reveal vcam-1 augment PAK activation rates to amplify p38 MAPK and VE-cadherin phosphorylation

Our previous work shows that melanoma cells induce VE-cadherin disassembly possibly via binding of their VLA-4 receptors to VCAM-1 receptors on endothelial cells or secretion of chemokines. Interestingly enough we found during junction disassembly Rac/PAK molecules initially reside at endothelial junctions and then dissociate over time in response to VCAM-1 binding. However, other studies have also found that Rac/PAK interactions are mediated by chemokines, in particular, interleukin-8 (IL-8). Currently, studies have focused on the regulation of p38 MAPK via IL-8 and IL-1b signaling; however, the role of VCAM-1 in the regulation of p38 MAPK has not been elucidated. Using computational methods, we found that VCAM-1 binding increases PAK activation rates to augment p38 and VE-cadherin phosphorylation levels downstream. Furthermore, decreasing the PAK off rate resulted in a rapid increase in p38 and VE-cadherin phosphorylation.