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ERK3 Interacts with DGKζ and Alters Signaling Lipids in Lung Cancer Cells
Author(s) -
Myers Amanda,
Bedi Shimpi,
Popp Katherine,
Aldharee Hitham,
Long Weiwen
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.03558
Subject(s) - phosphatidic acid , diacylglycerol kinase , microbiology and biotechnology , kinase , pld2 , chemistry , mapk/erk pathway , signal transduction , rac1 , phosphorylation , lysophosphatidic acid , biochemistry , cancer research , biology , protein kinase c , phospholipid , receptor , membrane
Extracellular‐Regulated Kinase 3 (ERK3) promotes migration and invasion in many cancers, including lung cancer. However, the mechanisms by which this atypical Mitogen‐Activated Protein Kinase (MAPK) induces these effects remain poorly understood. The p21‐activated kinase (PAK)‐Rac1 complex, which can be activated by phosphatidic acid, is associated with cell migration and has been shown to activate ERK3. Here, we show ERK3 also binds to phosphatidic acid and treatment of cells with phosphatidic acid results in an increase in ERK3 phosphorylation. Intriguingly, we have also found ERK3 modulates Rac1 activity and PAK phosphorylation, suggesting a positive feedback loop. In ERK3 knockdown cells, total diacylglycerol level was elevated while total phosphatidic acid level was decreased. 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 appears to occur through the C34 domain of ERK3. By immunofluorescence, these proteins were shown to co‐localize in cells with ERK3 enhancing cytoplasmic localization of DGKζ. Together, these data suggest ERK3 may regulate DGKζ to facilitate phosphatidic acid production, thereby activating the Rac1‐PAK complex and inducing cell migration. Support or Funding Information NCI 1R01 CA193264‐01Wright State University start‐up fund