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

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Abstract

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-1β 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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References

  1. Arroyo, A. G., P. Sánchez-Mateos, M. R. Campanero, I. Martín-Padura, E. Dejana, and F. Sánchez-Madrid. Regulation of the VLA integrin-ligand interactions through the beta 1 subunit. J. Cell Biol. 117:659–670, 1992.

    Article  Google Scholar 

  2. Bhalla, U. S., and R. Iyengar. Emergent properties of networks of biological signaling pathways. Science 283:381–387, 1999.

    Article  Google Scholar 

  3. Bishop, A. L., and A. Hall. Rho GTPases and their effector proteins. Biochem. J. 348:241–255, 2000.

    Article  Google Scholar 

  4. Brodland, D. G., and J. A. Zitelli. Mechanisms of metastasis. J. Am. Acad. Dermatol. 27:1–8, 1992.

    Article  Google Scholar 

  5. Chiang, A. C., and J. Massague. Molecular basis of metastasis. N. Engl. J. Med. 359:2814–2823, 2008.

    Article  Google Scholar 

  6. Cook-Mills, J. M., J. D. Johnson, T. L. Deem, A. Ochi, L. Wang, and Y. Zheng. Calcium mobilization and Rac1 activation are required for VCAM-1 (vascular cell adhesion molecule-1) stimulation of NADPH oxidase activity. Biochem. J. 378:539–547, 2004.

    Article  Google Scholar 

  7. Eikemo, H., T. Skomedal, F. O. Levy, and J. B. Osnes. Calculating reaction rate constants and estimating the efficacy of selective enzyme inhibitors. Anal. Biochem. 383:323–325, 2008.

    Article  Google Scholar 

  8. Goeckeler, Z. M., and R. B. Wysolmerski. Myosin light chain kinase-regulated endothelial cell contraction: the relationship between isometric tension, actin polymerization, and myosin phosphorylation. J. Cell Biol. 130:613–627, 1995.

    Article  Google Scholar 

  9. Hendriks, B. S., F. Hua, and J. R. Chabot. Analysis of mechanistic pathway models in drug discovery: p38 pathway. Biotechnol. Prog. 24:96–100, 2008.

    Article  Google Scholar 

  10. Hoppe, A. D., and Swanson JA.Cdc42, Rac1, and Rac2 display distinct patterns of activation during phagocytosis. Mol. Biol. Cell 15:3509–3519, 2004.

    Article  Google Scholar 

  11. Khanna, P., T. Yunkunis, H. S. Muddana, H. H. Peng, A. August, and C. Dong. p38 MAP kinase is necessary for melanoma-mediated regulation of VE-cadherin disassembly. Am. J. Physiol. Cell Physiol. 298:1140–1150, 2010.

    Article  Google Scholar 

  12. Kramer, R. H., and G. L. Nicolson. Interactions of tumor cells with vascular endothelial cell monolayers: a model for metastatic invasion. Proc. Natl Acad. Sci. USA 76:5704–5708, 1979.

    Article  Google Scholar 

  13. Liang, S., and C. Dong. Integrin VLA-4 enhances sialyl-Lewisx/a-negative melanoma adhesion to and extravasation through the endothelium under low flow conditions. Am. J. Physiol. Cell Physiol. 295:C701–C707, 2008.

    Article  Google Scholar 

  14. Marjan Varedi, K. S., P. J. Woolf, and X. N. Lin. Minimum protein oscillator based on multisite phosphorylation/dephosphorylation. IET Syst. Biol. 5:27, 2011.

    Article  Google Scholar 

  15. Nicolson, G. L. Metastatic tumor cell attachment and invasion assay utilizing vascular endothelial cell monolayers. J. Histochem. Cytochem. 30:214–220, 1982.

    Article  Google Scholar 

  16. Peng, H. H., and C. Dong. Systemic analysis of tumor cell-induced endothelial calcium signaling and junction disassembly. Cell Mol. Bioeng. 2:375–385, 2009.

    Article  Google Scholar 

  17. Peng, H. H., L. Hodgson, A. J. Henderson, and C. Dong. Involvement of phospholipase C signaling in melanoma cell-induced endothelial junction disassembly. Front. Biosci. 10:1597–1606, 2005.

    Article  Google Scholar 

  18. Raeburn, C. D., C. M. Calkins, M. A. Zimmerman, Y. Song, L. Ao, A. Banerjee, A. H. Harken, and X. Meng. ICAM-1 and VCAM-1 mediate endotoxemic myocardial dysfunction independent of neutrophil accumulation. Am. J. Physiol. Regul. Integr. Comp. Physiol. 283:477–486, 2002.

    Google Scholar 

  19. Schmidt, H., and M. Jirstrand. Systems Biology Toolbox for MATLAB: a computational platform for research in systems biology. Bioinformatics 22:514–515, 2006.

    Article  Google Scholar 

  20. Schoeberl, B., C. Eichler-Jonsson, E. D. Gilles, and G. Müller. Computational modeling of the dynamics of the MAP kinase cascade activated by surface and internalized EGF receptors. Nat. Biotechnol. 20:370–375, 2002.

    Article  Google Scholar 

  21. Schraufstatter, I. U., J. Chung, and M. Burger. IL-8 activates endothelial cell CXCR1 and CXCR2 through Rho and Rac signaling pathways. Am. J. Physiol. Lung Cell Mol. Physiol. 280:1094–1103, 2002.

    Google Scholar 

  22. Singh, R. K., and M. L. Varney. IL-8 expression in malignant melanoma: implications in growth and metastasis. Histol. Histopathol. 15:843–849, 2000.

    Google Scholar 

  23. Stockton, R. A., E. Schaefer, and M. A. Schwartz. p21-activated kinase regulates endothelial permeability through modulation of contractility. J. Biol. Chem. 279:46621–46630, 2004.

    Article  Google Scholar 

  24. Tran, M. A., R. Gowda, A. Sharma, et al. Targeting V600 EB-Raf and Akt3 using nanoliposomal small interfering RNA inhibits cutaneous melanocytic lesion development. Cancer Res. 68:7638–7649, 2008.

    Article  Google Scholar 

  25. van Wetering, S., N. van den Berk, J. D. van Buul, F. P. Mul, I. Lommerse, R. Mous, J. P. ten Klooster, J. J. Zwaginga, and P. L. Hordijk. VCAM-1-mediated Rac signaling controls endothelial cell–cell contacts and leukocyte transmigration. Am. J. Physiol. Cell Physiol. 285:C343–C352, 2003.

    Google Scholar 

  26. Vera, J., C. Sun, Y. Oertel, O. Wolkenhauer, and P. L. Maddon. A power-law module for the Matlab SBToolbox. Bioinformatics 23:2638–2640, 2007.

    Article  Google Scholar 

  27. Vestweber, D., M. Winderlich, G. Cagna, and A. F. Nottebaum. Cell adhesion dynamics at endothelial junctions: VE-cadherin as a major player. Trends Cell Biol. 19:8–15, 2008.

    Article  Google Scholar 

  28. Weis, S., J. Cui, L. Barnes, and D. Cheresh. Endothelial barrier disruption by VEGF-mediated Src activity potentiates tumor cell extravasation and metastasis. J. Cell Biol. 167:223–229, 2004.

    Article  Google Scholar 

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Acknowledgments

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.

Conflict of interest

None of the listed authors have any financial or other interests with regard to the submitted manuscript that might be construed as a conflict of interest.

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Authors and Affiliations

  1. Department of Bioengineering, Penn State University, 233 Hallowell Bldg., University Park, PA, 16802, USA

    Payal Khanna, Eric Weidert & Cheng Dong

  2. Department of Chemical Engineering, Pennsylvania State University, University Park, PA, 16802, USA

    Francisco Vital-Lopez, Antonios Armaou & Costas D. Maranas

Authors
  1. Payal Khanna
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  2. Eric Weidert
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  3. Francisco Vital-Lopez
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  4. Antonios Armaou
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  5. Costas D. Maranas
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  6. Cheng Dong
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Corresponding author

Correspondence to Cheng Dong.

Additional information

Associate Editors John Shyy and Yingxiao Wang oversaw the review of this article.

Payal Khanna and Eric Weidert contributed equally to this work.

Appendix

Appendix

Table A1 Reactions and parameters used in network (Fig. 4)
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Table A2 Initial conditions of network
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Khanna, P., Weidert, E., Vital-Lopez, F. et al. Model Simulations Reveal VCAM-1 Augment PAK Activation Rates to Amplify p38 MAPK and VE-Cadherin Phosphorylation. Cel. Mol. Bioeng. 4, 656–669 (2011). https://doi.org/10.1007/s12195-011-0201-z

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