AUTHOR=Myers Amanda K. , Morel Marion , Gee Stephen H. , Hoffmann Katherine A. , Long Weiwen 

TITLE=ERK3 and DGKζ interact to modulate cell motility in lung cancer cells

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=Volume 11 - 2023

YEAR=2023

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2023.1192221

DOI=10.3389/fcell.2023.1192221

ISSN=2296-634X

ABSTRACT=Extracellular-regulated kinase 3 (ERK3) promotes cell migration and tumor metastasis in multiple cancer types, including lung cancer. ERK3 protein has a unique structure. Besides the N-terminal kinase domain, ERK3 includes a conserved in ERK3 and ERK4 (C34) domain and an extended C-terminus. However, relatively little is known regarding the role(s) of the C34 domain. A yeast two-hybrid assay using ERK3 as bait identified diacylglycerol kinase ζ (DGKζ) as a binding partner. DGKζ was shown to promote migration and invasion in some cancer cell types, but its role in lung cancer cells has yet to be described. The interaction of ERK3 and DGKζ was confirmed by co-immunoprecipitation and in vitro binding assays, consistent with their colocalization at the periphery of lung cancer cells. The C34 domain of ERK3 was sufficient for binding to DGKζ while ERK3 bound to the N-terminal and C1 domains of DGKζ. In surprising contrast to ERK3, DGKζ suppresses lung cancer cell migration, suggesting DGKζ might inhibit ERK3-mediated cell motility. Indeed, co-overexpression of exogenous DGKζ and ERK3 completely blocked the ability of ERK3 to promote cell migration, but DGKζ did not affect the migration of cells with stable ERK3 knockdown. Further, DGKζ had little effect on cell migration induced by overexpression of an ERK3 mutant missing the C34 domain, suggesting DGKζ requires this domain to prevent ERK3-mediated increase in cell migration. In summary, this study has identified DGKζ as a new binding partner and negative regulator of ERK3 in controlling lung cancer cell migration.