Hyperactive KRAS/MAPK signaling disrupts normal lymphatic vessel architecture and function
Complex lymphatic anomalies (CLAs) are sporadically occurring diseases caused by the maldevelopment of lymphatic vessels. We and others recently reported that somatic activating mutations in can cause CLAs. However, the mechanisms by which activating mutations cause CLAs are poorly understood. Here,...
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Published in | Frontiers in cell and developmental biology Vol. 11; p. 1276333 |
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Main Authors | , , , , , |
Format | Journal Article |
Language | English |
Published |
Switzerland
Frontiers Media S.A
25.09.2023
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Subjects | |
Online Access | Get full text |
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Summary: | Complex lymphatic anomalies (CLAs) are sporadically occurring diseases caused by the maldevelopment of lymphatic vessels. We and others recently reported that somatic activating mutations in
can cause CLAs. However, the mechanisms by which activating
mutations cause CLAs are poorly understood. Here, we show that KRAS
expression in lymphatic endothelial cells (LECs) during embryonic development impairs the formation of lymphovenous valves and causes the enlargement of lymphatic vessels. We demonstrate that KRAS
expression in primary human LECs induces cell spindling, proliferation, and migration. It also increases AKT and ERK1/2 phosphorylation and decreases the expression of genes that regulate the maturation of lymphatic vessels. We show that MEK1/2 inhibition with the FDA-approved drug trametinib suppresses KRAS
-induced morphological changes, proliferation, and migration. Trametinib also decreases ERK1/2 phosphorylation and increases the expression of genes that regulate the maturation of lymphatic vessels. We also show that trametinib and Cre-mediated expression of a dominant-negative form of MEK1 (
) suppresses KRAS
-induced lymphatic vessel hyperplasia in embryos. Last, we demonstrate that conditional knockout of wild-type
in LECs does not affect the formation or function of lymphatic vessels. Together, our data indicate that KRAS/MAPK signaling must be tightly regulated during embryonic development for the proper development of lymphatic vessels and further support the testing of MEK1/2 inhibitors for treating CLAs. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ORCID: Michael T. Dellinger, https://orcid.org/0000-0002-3315-4239 Alvaro Gutierrez-Uzquiza, Complutense University of Madrid, Spain These authors have contributed equally to this work Maike Frye, University Medical Center Hamburg-Eppendorf, Germany Edited by: Young-Kwon Hong, University of Southern California, United States Reviewed by: Dongwon Choi, University of Southern California, United States |
ISSN: | 2296-634X 2296-634X |
DOI: | 10.3389/fcell.2023.1276333 |