BRIEF RESEARCH REPORT article
Front. Cardiovasc. Med.
Sec. Cardiovascular Biologics and Regenerative Medicine
Volume 12 - 2025 | doi: 10.3389/fcvm.2025.1526676
TNIK-driven regulation of ERK5 transcriptional activity in endothelial cells
Provisionally accepted
- Houston Methodist Research Institute, Houston, United States
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Extracellular signal-regulated kinase 5 (ERK5) is essential for cardiovascular development and endothelial cell (EC) function. Activation of ERK5 through MEK5mediated phosphorylation at threonine 218 and tyrosine 220 (T218/Y220) drives the transcriptional activation of myocyte enhancer factor-2 (MEF2), promoting the expression of KLF2 and KLF4 -key transcription factors that maintain vascular homeostasis. We previously demonstrated that ponatinib suppresses ERK5 transcriptional activity without affecting laminar-flow (l-flow)-induced T218/Y220 phosphorylation, suggesting a non-canonical regulatory mechanism. Since ponatinib inhibits Traf2-and Nck-interacting kinase (TNIK), I hypothesized that TNIK modulates ERK5 transcriptional activity. Using a mammalian one-hybrid assay and quantitative RT-PCR (qRT-PCR), we show that TNIK knockdown reduces ERK5 transcriptional activity and downregulates KLF2, KLF4, and eNOS expression, whereas TNIK overexpression enhances ERK5 transcriptional activity. Constitutively active MEK5 (CA-MEK5α) rescues ERK5 transcriptional activity in TNIK-depleted cells, but TNIK overexpression fails to overcome inhibition by dominant-negative MEK5 (DN-MEK5), indicating a MEK5-dependent mechanism. Moreover, phosphorylation-deficient TNIK mutants (S764A and S769A) retain the ability to enhance ERK5 transcriptional activity, suggesting a kinaseindependent regulatory role.TNIK knockdown also increases NFκB activity and EC apoptosis, linking TNIK to the regulation of inflammatory and survival pathways. These findings identify TNIK as a novel modulator of ERK5 signaling through both MEK5-dependent and independent
Keywords: Erk5, TNIK, Transcriptional activity, Inflammation, Endothelial Cells
Received: 12 Nov 2024; Accepted: 05 May 2025.
Copyright: © 2025 Le. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Nhat Tu Le, Houston Methodist Research Institute, Houston, United States
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