DGKζ interacts with ERK3 and counteracts the promoting role of ERK3 in lung cancer migration

Abstract

Extracellular‐Regulated Kinase 3 (ERK3) promotes cell migration and invasion in many cancers, including lung cancer. However, the mechanisms by which this atypical mitogen‐activated protein kinase (MAPK) is regulated remain poorly understood. In a yeast two‐hybrid assay, ERK3 was shown to interact with diacylglycerol kinase ζ (DGKζ), an enzyme which converts diacylglycerol to phosphatidic acid. This interaction has been confirmed by co‐immunoprecipitation and occurs through the C34 domain of ERK3 and the N‐terminus and C1 domain of DGKζ. By immunofluorescence, these proteins were shown to mainly co‐localize at protruding regions of the plasma membrane in cells. Interestingly, DGKζ reduces cell migration in lung cancer cell lines in a kinase‐independent manner. While ERK3 promotes cell motility in lung cancer cell lines, DGKζ overexpression negates this effect entirely in the transwell assay. Further, DGKζ reduces ERK3 accumulation at protrusions of the cell membrane but cannot alter localization of a mutant ERK3 lacking the C34 domain. In conclusion, we have identified DGKζ as a new interaction partner and inhibitor of ERK3 in regulating lung cancer cell migration.