P38 MAP kinase is necessary for melanoma-mediated regulation of VE-cadherin disassembly

Payal Khanna, Tara Yunkunis, Hari S. Muddana, Hsin Hsin Peng, Avery August, Cheng Dong

Research output: Contribution to journalArticle

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Abstract

Vascular endothelial (VE)-cadherin is localized to the endothelial borders and the adherens junctions, which are regulated by changes in mitogen-activated protein (MAP) kinases, GTPases, and intracellular calcium. We previously showed that melanoma cells induce VE-cadherin disassembly through contact with human umbilical vein endothelial cells in coculture. However, the exact mechanism by which melanoma cells signal endothelial cells to induce VE-cadherin junction disassembly is not well understood. In this study, VE-cadherin junction disassembly was further examined under fluorescence microscopy. We found that melanoma-induced VE-cadherin junction disassembly and upregulation of p38 MAP kinase in endothelial cells is regulated by both soluble factors from melanomas, particularly interleukin (IL)-8, IL-6, and IL-1β, and through vascular cell adhesion molecule-1. Neutralizing melanoma-secreted soluble factors reduced endothelial gap formation. Endothelial cells transfected with MAP kinase kinase 6, a direct activator of p38 MAP kinase, increased VE-cadherin-mediated gap formation, facilitating melanoma transendothelial migration. In contrast, endothelial cells transfected with small-interfering RNA against p38 MAP kinase expression largely prevented melanoma transendothelial migration in Boyden chamber experiments. These findings indicate that p38 MAP kinase proteins regulate VE-cadherin junction disassembly, facilitating melanoma migration across endothelial cells.

Original languageEnglish (US)
Pages (from-to)C1140-C1150
JournalAmerican Journal of Physiology - Cell Physiology
Volume298
Issue number5
DOIs
StatePublished - May 1 2010

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p38 Mitogen-Activated Protein Kinases
Melanoma
Endothelial Cells
Transendothelial and Transepithelial Migration
MAP Kinase Kinase 6
Adherens Junctions
Vascular Cell Adhesion Molecule-1
cadherin 5
GTP Phosphohydrolases
Human Umbilical Vein Endothelial Cells
Coculture Techniques
Mitogen-Activated Protein Kinases
Interleukin-8
Interleukin-1
Fluorescence Microscopy
Small Interfering RNA
Interleukin-6
Up-Regulation
Calcium

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cell Biology

Cite this

Khanna, Payal ; Yunkunis, Tara ; Muddana, Hari S. ; Peng, Hsin Hsin ; August, Avery ; Dong, Cheng. / P38 MAP kinase is necessary for melanoma-mediated regulation of VE-cadherin disassembly. In: American Journal of Physiology - Cell Physiology. 2010 ; Vol. 298, No. 5. pp. C1140-C1150.
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P38 MAP kinase is necessary for melanoma-mediated regulation of VE-cadherin disassembly. / Khanna, Payal; Yunkunis, Tara; Muddana, Hari S.; Peng, Hsin Hsin; August, Avery; Dong, Cheng.

In: American Journal of Physiology - Cell Physiology, Vol. 298, No. 5, 01.05.2010, p. C1140-C1150.

Research output: Contribution to journalArticle

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