Mixed lineage kinase (MLK) controls tumor development and angiogenesis
Shashi Kant1, Amada D Caliz2, Hyung-Jin Yoo2
1Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA. skant1@bwh.harvard.edu.
Angiogenesis
|May 2, 2025
Summary
Mixed lineage kinases 2 and 3 (MLK2 and MLK3) are vital for tumor growth and blood vessel formation (angiogenesis). These kinases, acting through H19 long noncoding RNA, control endothelial cell functions essential for tumor progression.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Cancer, particularly solid tumors, relies on angiogenesis for growth.
- Tumor-induced hypoxic stress activates stress kinases like mixed lineage kinases (MLKs).
- MLK2 and MLK3 expression is observed in human lung tumors.
Purpose of the Study:
- To investigate the role of MLK2 and MLK3 in tumor growth and angiogenesis.
- To elucidate the mechanism by which MLKs regulate endothelial function in tumors.
Main Methods:
- Utilized three distinct mouse models of tumor development.
- Analyzed MLK2 and MLK3 expression in tumor endothelium.
- Investigated the impact of MLKs on endothelial cell proliferation and migration.
- Examined the regulation of angiogenic factors and metalloproteinases by MLKs.
- Studied the involvement of the H19 long noncoding RNA (lncRNA) in the MLK pathway.
Main Results:
- MLK2 and MLK3 are essential for tumor growth and angiogenesis in vivo.
- MLK2 and MLK3 are highly expressed in tumor endothelium and crucial for endothelial proliferation, migration, and angiogenesis.
- MLKs regulate the expression of pro-angiogenic factors (Pgf, Vegfa, Angptl4) and metalloproteinases (Adam8, Mmp9) in endothelial cells.
- The MLK-H19 axis controls the expression of these pro-angiogenic factors in the endothelium.
Conclusions:
- The MLK2 and MLK3 kinases are critical regulators of tumor angiogenesis and growth.
- The MLK-H19 signaling axis plays a central role in coordinating endothelial cell function, angiogenesis, and tumor progression.
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