TY - JOUR
T1 - Model simulations reveal vcam-1 augment PAK activation rates to amplify p38 MAPK and VE-cadherin phosphorylation
AU - Khanna, Payal
AU - Weidert, Eric
AU - Vital-Lopez, Francisco
AU - Armaou, Antonios
AU - Maranas, Costas D.
AU - Dong, Cheng
N1 - Funding Information:
This study was supported by NIH CA-125707 and NSF CBET-0729091 (C.D.); and Penn State Institute for CyberScience Seed Grant (C.D.M. and C.D.). This work was supported by NIH-CA97306 and CA-125707 (C.D.) and Penn State Institute for CyberScience Seed Grant (C.D.M. and C.D.). We would like to thank Dr. Adam D. Hoppe for providing Rac-YFP and PBD-CFP plasmids.
PY - 2011/12
Y1 - 2011/12
N2 - 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.
AB - 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.
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U2 - 10.1007/s12195-011-0201-z
DO - 10.1007/s12195-011-0201-z
M3 - Article
AN - SCOPUS:84856438793
SN - 1865-5025
VL - 4
SP - 656
EP - 669
JO - Cellular and Molecular Bioengineering
JF - Cellular and Molecular Bioengineering
IS - 4
ER -