UMass Chan Medical School Faculty Publications

UMMS Affiliation

Program in Molecular Medicine; UMass Metabolic Network

Publication Date


Document Type



Cell Biology | Cellular and Molecular Physiology | Developmental Biology


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.

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DOI of Published Version



Mol Cell Biol. 2016 May 31;36(12):1740-9. doi: 10.1128/MCB.01121-15. Print 2016 Jun 15. Link to article on publisher's site

Related Resources

Link to Article in PubMed

Journal/Book/Conference Title

Molecular and cellular biology

PubMed ID