Endothelial Mitogen-Activated Protein Kinase Kinase Kinase Kinase 4 Is Critical for Lymphatic Vascular Development and Function

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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Constitutive Activation of Mitogen-activated Protein Kinase Kinase (MEK1) in Ileal Enterocytes Leads to Dysplasia and a Predisposition to Cancer

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00065.2020 ◽

2021 ◽

Author(s):

Benjamin L. Shneider ◽

Nahir Cortes-Santiago ◽

Deborah A. Schady ◽

Swapna Krishnamoorthy ◽

Sundararajah Thevananther ◽

...

Keyword(s):

Body Weight ◽

Protein Kinase ◽

Cell Fate ◽

Dose Dependence ◽

Mitogen Activated Protein Kinase ◽

Proteomic Profiling ◽

Invasive Adenocarcinoma ◽

Reduced Body ◽

Mitogen Activated Protein ◽

Protein Kinase Kinase

Activation of Mitogen-activated protein kinases (MAPKs) is a key factor in the pathogenesis of cancer, although the specific role of mitogen-activated protein kinase kinase (MEK1) is not well understood. Villin promoter driven cre expression was used to excise a floxed stop cassette from a phosphomimetically constitutively activated MEK1 (caMEK1) expression construct in the intestine of C57BL/6 mice. Zygosity status of caMEK1 afforded assessment of the dose dependence of the effect. The expected mendelian distribution of genotypes and sex was observed in 443 progenies. Between 21 and 63 days of life caMEK1 had no effect on body weight in male mice, but reduced body weight in female mice homozygous for caMEK1. At 10 weeks of age, the ileum of caMEK1 expressing mice was characterized by the finding of dysplasia and profound changes in overall architecture. Paneth cells were nearly absent in caMEK1 homozygotes. Targeted proteomic profiling via reverse phase protein array analyses with confirmatory western blotting revealed significant changes in protein and phosphoprotein expression including up-regulation of proteins downstream of MEK1, associated with enhanced markers of proliferation, diminished apoptosis, alterations in cell-fate determination, cell-cell interactions and tight junctions. Long-term viability of caMEK1 homozygous mice was reduced with no survival beyond one year. Invasive adenocarcinoma developed in three of ten older mice (15 [homozygous], 26 [homozygous] and 35 weeks [heterozygous] of age). Expression of caMEK1 in enterocytes leads to marked derangements in the intestinal epithelium, which is associated with a predisposition to the development of invasive cancer.

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VEGFD regulates blood vascular development by modulating SOX18 activity

Blood ◽

10.1182/blood-2013-04-495432 ◽

2014 ◽

Vol 123 (7) ◽

pp. 1102-1112 ◽

Cited By ~ 47

Author(s):

Tam Duong ◽

Katarzyna Koltowska ◽

Cathy Pichol-Thievend ◽

Ludovic Le Guen ◽

Frank Fontaine ◽

...

Keyword(s):

Transcription Factor ◽

Protein Kinase ◽

Vascular Development ◽

Mitogen Activated Protein Kinase ◽

Extracellular Signal Regulated Kinase ◽

Extracellular Signal ◽

Key Points ◽

Mitogen Activated Protein ◽

Protein Kinase Kinase

Key Points Haploinsufficiency of Sox18 reveals an important role for VEGFD in regulating blood vascular development in vivo in vertebrates. VEGFD acts through mitogen-activated protein kinase kinase–extracellular signal-regulated kinase to modulate the activity and nuclear concentration of endothelial-specific transcription factor SOX18.

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The Mitogen-Activated Protein Kinase Kinase Kinase Kinase GCKR Positively Regulates Canonical and Noncanonical Wnt Signaling in B Lymphocytes

Molecular and Cellular Biology ◽

10.1128/mcb.00209-06 ◽

2006 ◽

Vol 26 (17) ◽

pp. 6511-6521 ◽

Cited By ~ 20

Author(s):

Chong-Shan Shi ◽

Ning-Na Huang ◽

Kathleen Harrison ◽

Sang-Bae Han ◽

John H. Kehrl

Keyword(s):

B Cells ◽

Protein Kinase ◽

Wnt Signaling ◽

Cell Fate ◽

B Lymphocytes ◽

Target Genes ◽

Control Cell ◽

Mitogen Activated Protein Kinase ◽

Mitogen Activated Protein ◽

Protein Kinase Kinase

ABSTRACT Wnt ligands bind receptors of the Frizzled (Fz) family to control cell fate, proliferation, and polarity. Canonical Wnt/Fz signaling stabilizes β-catenin by inactivating GSK3β, leading to the translocation of β-catenin to the nucleus and the activation of Wnt target genes. Noncanonical Wnt/Fz signaling activates RhoA and Rac, and the latter triggers the activation of c-Jun N-terminal kinase (JNK). Here, we show that exposure of B-lymphocytes to Wnt3a-conditioned media activates JNK and raises cytosolic β-catenin levels. Both the Rac guanine nucleotide exchange factor Asef and the mitogen-activated protein kinase kinase kinase kinase germinal center kinase-related enzyme (GCKR) are required for Wnt-mediated JNK activation in B cells. In addition, we show that GCKR positively affects the β-catenin pathway in B cells. Reduction of GCKR expression inhibits Wnt3a-induced phosphorylation of GSK3β at serine 9 and decreases the accumulation of cytosolic β-catenin. Furthermore, Wnt signaling induces an interaction between GCKR and GSK3β. Our findings demonstrate that GCKR facilitates both canonical and noncanonical Wnt signaling in B lymphocytes.

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Pengaruh Likopen terhadap Penurunan Aktivitas Mitogen-Activated Protein Kinase (MAPK) dan Ekspresi Endothelin-1 (ET-1) pada Kultur Huvecs yang Dipapar Leptin

Jurnal Natur Indonesia ◽

10.31258/jnat.13.2.162-167 ◽

2012 ◽

Vol 13 (2) ◽

pp. 162

Author(s):

Heni Fatmawati ◽

Satuman Satuman ◽

Ahmad Rudijanto ◽

Muhammad Rasjad Indra

Keyword(s):

Endothelial Cells ◽

Endothelial Cell ◽

Protein Kinase ◽

Endothelial Dysfunction ◽

Vascular Function ◽

In Vitro Study ◽

Mitogen Activated Protein Kinase ◽

Optimum Dose ◽

Mitogen Activated Protein

The effect of obesity on vascular function is mediated by hormon leptin. Leptin has been proved to increaseoxidative stress in endothelial cell. The previous study has proven that leptin caused the endothelial dysfunction asa step of the atherogenesis. Lycopene, an antioxidant, is presumed having the ability to block the atherogenesismechanism, which is stimulated a proinflamatory cytokine and adhesion molecules by MAPK and transcriptionfactor ET-1. Therefore, the aim of this research was to prove and to determine whether lycopene could decreasethe MAPK and ET-1 expression in Human Umbillical Vein Endothelial Cells (HUVECs) culture induced by 500 ng/mlleptin. In vitro study used primary culture of the HUVECs were devided in to 7 groups, there were (1) 0 ng/ml leptinand 0 ìM lycopene, (2) induced by 500 ng/ml leptin for 12 hours, (3) induced by leptin and lycopene with concentration10; 25; 40; 55 and 75 ìM for 12 hours. Then the identification of MAPK was applied by using imunocytochemistrycompared with ELISA procedure on cell endothel culture lysate and ET-1 expression was measured by using RTPCR. It was showed that lycopene 10-25 ìM decreased MAPK and ET-1 expression significantly in HUVECs cultureinduced by leptin 500 ng/ml. Leptin was increased ERK1/2 MAPK and ET-1 expression in HUVECs culture and candecrease by lycopene. Optimum dose of lycopene is 10-25 ìM.

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