The atypical mitogen-activated protein kinase ERK3 is essential for establishment of epithelial architecture

Abstract

Epithelia contribute to physical barriers that protect internal tissues from the external environment and also support organ structure. Accordingly, establishment and maintenance of epithelial architecture are essential for both embryonic development and adult physiology. Here, using gene knockout and knockdown techniques along with gene profiling, we show that extracellular signal-regulated kinase 3 (ERK3), a poorly characterized atypical mitogen-activated protein kinase (MAPK), regulates the epithelial architecture in vertebrates. We found that in embryonic epidermal epithelia, knockdown impairs adherens and tight-junction protein distribution, as well as tight-junction barrier function, resulting in epidermal breakdown. Moreover, in human epithelial breast cancer cells, inhibition of expression induced thickened epithelia with aberrant adherens and tight junctions. Results from microarray analyses suggested that transcription factor AP-2α (TFAP2A), a transcriptional regulator important for epithelial gene expression, is involved in ERK3-dependent changes in gene expression. Of note, knockdown phenocopied knockdown in both embryos and human cells, and was required for full activation of TFAP2A-dependent transcription. Our findings reveal that ERK3 regulates epithelial architecture, possibly together with TFAP2A.

ERK3/MAPK6 controls IL-8 production and chemotaxis

“…As a constantly differentiating system, gut epithelium is an ideal model to identify genes involved in the process (Aliaga et al, 1999). ERK3 has been shown to be required for the maintenance of epithelial architecture, however genetic deletion studies in mice unveiled a non-essential role for this protein (Ronkina et al, 2019;Takahashi et al, 2018). To gain further insights into the potential role of ERK3 in epithelial morphogenesis and differentiation, we studied ERK3 expression levels by employing three-dimensional (3D) gastrointestinal organoids that reflect either murine intestinal or human gastric architecture and cell composition (Almeqdadi et al, 2019;Dotti and Salas, 2018).…”