Endothelial Mitogen-Activated Protein Kinase Kinase Kinase Kinase 4 Is Critical for Lymphatic Vascular Development and Function
| Autor: | Yvonne J. K. Edwards, Laura V. Danai, Michael P. Czech, Chang-An Guo, Joseph C. Yawe, Rachel J. Roth Flach, Sharvari Gujja |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Protein Serine-Threonine Kinases Mitogen-activated protein kinase kinase Chylothorax Cell Line MAP2K7 Mice 03 medical and health sciences Human Umbilical Vein Endothelial Cells Animals Humans ASK1 Molecular Biology Cell Proliferation Lymphatic Vessels biology MAP kinase kinase kinase Cyclin-dependent kinase 4 Akt/PKB signaling pathway Cyclin-dependent kinase 2 Intracellular Signaling Peptides and Proteins Articles Cell Biology Cell biology 030104 developmental biology Animals Newborn biology.protein Cyclin-dependent kinase 9 |
| Zdroj: | Molecular and Cellular Biology. 36:1740-1749 |
| ISSN: | 1098-5549 |
| Popis: | The molecular mechanisms underlying lymphatic vascular development and function are not well understood. Recent studies have suggested a role for endothelial cell (EC) mitogen-activated protein kinase kinase kinase kinase 4 (Map4k4) in developmental angiogenesis and atherosclerosis. Here, we show that constitutive loss of EC Map4k4 in mice causes postnatal lethality due to chylothorax, suggesting that Map4k4 is required for normal lymphatic vascular function. Mice constitutively lacking EC Map4k4 displayed dilated lymphatic capillaries, insufficient lymphatic valves, and impaired lymphatic flow; furthermore, primary ECs derived from these animals displayed enhanced proliferation compared with controls. Yeast 2-hybrid analyses identified the Ras GTPase-activating protein Rasa1, a known regulator of lymphatic development and lymphatic endothelial cell fate, as a direct interacting partner for Map4k4. Map4k4 silencing in ECs enhanced basal Ras and extracellular signal-regulated kinase (Erk) activities, and primary ECs lacking Map4k4 displayed enhanced lymphatic EC marker expression. Taken together, these results reveal that EC Map4k4 is critical for lymphatic vascular development by regulating EC quiescence and lymphatic EC fate. |
| Databáze: | OpenAIRE |
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