Model Simulations Reveal VCAM-1 Augment PAK Activation Rates to Amplify p38 MAPK and VE-Cadherin Phosphorylation

作者：Khanna Payal; Weidert Eric; Vital Lopez Francisco; Armaou Antonios; Maranas Costas D; Dong Cheng^*

来源：Cellular and Molecular Bioengineering, 2011, 4(4): 656-669.

DOI：10.1007/s12195-011-0201-z

• Chemokines
• Melanoma
• Receptor binding
• Tumor conditioned medium
• Signaling
• Endothelial junctions

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-1 beta 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.

• 出版日期2011-12