ERK3 promotes endothelial cell functions by upregulating SRC-3/SP1-mediated VEGFR2 expression

Area of Science:

• Molecular Biology
• Cell Biology
• Biochemistry

Background:

• Extracellular signal-regulated kinase 3 (ERK3) kinase signaling is under renewed investigation.
• Molecular mechanisms regulating ERK3 gene expression and activity remain largely uncharacterized.
• While ERK3 gene disruption leads to neonatal lethality, its cell-specific functions require exploration.

Purpose of the Study:

• To elucidate the molecular regulation of ERK3 gene expression in endothelial cells.
• To investigate the role of ERK3 signaling in endothelial cell functions.
• To uncover the downstream pathways modulated by ERK3.

Main Methods:

• Analysis of ERK3 gene expression regulation by cytokines and c-Jun in endothelial cells.
• Investigation of c-Jun binding to the ERK3 gene promoter.
• Assessment of ERK3's role in endothelial cell migration, proliferation, and tube formation.
• Examination of VEGFR2 expression and its regulation by ERK3, SRC-3, SP-1, and CBP.

Main Results:

• Cytokines upregulate ERK3 gene expression in endothelial cells through c-Jun.
• c-Jun directly binds to the ERK3 gene promoter, regulating its transcription.
• ERK3 signaling enhances endothelial cell migration, proliferation, and tube formation.
• ERK3 upregulates SRC-3/SP-1-mediated VEGFR2 expression.

Conclusions:

• A novel regulatory mechanism for ERK3 gene expression involving cytokines and c-Jun has been identified.
• ERK3 plays a significant role in regulating endothelial cell functions, including migration, proliferation, and angiogenesis.
• The findings reveal ERK3-stimulated transcriptional complex formation (SRC-3, SP-1, CBP) as key to VEGFR2 expression.